L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Physiology of synapse, neuromuscular junction and
neurotransmitters INTRODUCTION TO
PSYCHOPHARMACOLOGY
L.Mweetwa-PharmacologistUniversity of Zambia Dept of PharmacyFaculty of Medicine
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What is a synapse?
A gap between two neurons
Mostly chemical
Rarely electricalMostly present in lower animals Gap junctions
Synapses could be Axo-dendriticAxo-somaticAxo-axonic
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Many different types
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Basic structure
Presynaptic membrane Contains neurotransmitter
vesicles
Synaptic cleft
Postsynaptic membrane Contains receptors for the
neurotransmitter
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Synaptic transmission¨ Action potential passes from the
presynaptic neuron to the postsynaptic neuron
¨ Although an axon conducts both ways, conduction through synapse is one way
¨ A neuron receives more than 10000 synapses
¨ Postsynaptic activity is an integrated function
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Neurotransmitters Chemicals that facilitate signal transmission across a
synapse
Neurotransmitters are released on the presynaptic side and bind to receptors on the postsynaptic side
Earliest neurotransmitter discovered was acetylcholine
There are different chemical types Amines
▪ Norepinephrine, Epinephrine, dopamine, serotonin (5HT), histamine Amino acids
▪ GABA, Glycine, Glutamate, Aspartate Peptides
▪ Beta endorphin, enkephalins, dynorphin Others
▪ Acetylcholine, nitric oxide
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Neurotransmitter release
“At rest”, the synapse contains numerous synaptic vesicles filled with neurotransmitter
Intracellular calcium levels are very low
Arrival of an action potential causes opening of voltage-gated calcium channels
Calcium enters the synapse
Calcium triggers exocytosis and release of neurotransmitter
Vesicles are recycled by endocytosis
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Ca2+ Ca2+
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Neurotransmitter receptors
Once released, the neurotransmitter molecules diffuse across the synaptic cleft
When they “arrive” at the postsynaptic membrane, they bind to neurotransmitter receptors
Two main classes of receptors: Ligand-gated ion channels
transmitter molecules bind on the outside, cause the channel to open and become permeable to either sodium, potassium or chloride
G-protein-coupled receptors G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic
effects. They can have effects that change an entire cell’s metabolism or an enzyme that activates an internal metabolic change inside the cell activate cAMP activate cellular genes: forms more receptor proteins activate protein kinase: decrease the number of proteins
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Excitation
Excitation 1. Na+ influx cause accumulation of
positive charges causing excitation
2. Decreased K+ efflux or Cl- influx
3. Various internal changes to excite cell, increase in excitatory receptors, decrease in inhibitory receptors.
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Inhibition
Inhibition
1. Efflux of K+
2. Influx of Cl-
3. activation of receptor enzymes to inhibit metabolic functions or to increase inhibitory receptors or decrease excitatory receptors
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EPSP/ IPSP
Excitatory effects of neurotransmitters EPSP: excitatory post synaptic potential
Inhibitory effects of neurotransmitters IPSP: inhibitory post synaptic potential
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Postsynaptic activity
Synaptic integration On average, each neuron in the brain receives about
10,000 synaptic connections from other neurons
Many (but probably not all) of these connections may be active at any given time
Each neuron produces only one output
One single input is usually not sufficient to trigger this output
The neuron must integrate a large number of synaptic inputs and “decide” whether to produce an output or not
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Neurotransmitters
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Acetylcholine (Ach)
First neurotransmitter discovered in 1921 secreted by motor neurons, autonomic nerves, large
pyramidal cells of the motor cortex, basal ganglia (caudate & putamen), hippocampus.
It is generally excitatory receptors
▪ nicotinic (autonomic ganglia, NMJ) - Na influx▪ muscarinic (parasympathetc terminal)
sub types: M1(brain), M2, M3, M4, M5 second messenger cAMP
Common Ach blockers: plant poison (curare), botulinum toxin (food poison)
Loss of Ach neurons in Alzheimer’s patients
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Norepinephrine
present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus of the pons
Mostly it causes excitation but sometimes inhibition also happens
Increases BP and HRcontrol the overall activity of the brain and the mood
receptors 1, 2, 1, 2, 3
second messenger: cAMP
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Dopamine present in the cerebral cortex, hypothalamus secreted by neurons in the basal ganglia Mainly inhibitory Involved in the reward mechanisms in the brain Drugs like cocaine, opium, heroin, and alcohol
increase the levels of dopamine receptors:
D1, D2, D3, D4, D5 second messenger: cAMP
Increased levels associates with schizophrenia, low levels are associated with Parkinsonism
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GABA
Present in the basal ganglia Also present in the spinal cord,
cerebellum & many other areas of the Cortex
Major inhibitory neurotransmitter of the brain occurring in 30-40% of all synapses
receptors▪ GABAA increase Cl- influx
▪ GABAB act via G proteins, increase K+ influx
Low GABA levels are associated with anxiety and epilepsy
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Glycine
Present in the synapses of the spinal cord, interneurons
also present in the retina Inhibitory (increase Cl influx) by its action on NMDA receptors it is
excitatory
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Glutamate & Aspartate
Excitatory amino acids glutamate is present in presynaptic terminals in the sensory
pathways and other cortical areas Involved in the stretch reflex present in basal ganglia Main excitatory neurotransmitter in brain & spinal cord aspartate is present in cortical pyramidal cells & visual cortex receptors: metabotropic receptors, kainate, AMPA, NMDA NMDA receptors are present in hippocampus, involved in
memory & learning
Increased levels are associated with certain neurological diseases
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Serotonin
secreted by the nuclei originating in the median raphe of the brain stem and terminate in dorsal horn of the spinal cord and hypothalamus
Inhibitory Control the mood of the person and
important in sleep also present in GIT, platelets & limbic
system receptors: 1A, 1B, 1D, 2A, 2C, 3, 4
Low levels are associated with depression and other psychiatric disorders. May be involved in migraine
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Histamine
histamine: present in pathways from hypothalamus to
cortical areas & spinal cord receptors: H1, H2, H3 (all present in brain) functions related to arousal, sexual behaviour,
drinking, pain
Substance P found in primary nerve ending in the spinal
cord mediator of pain in the spinal cord
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NEUROPEPTIDES
synthesized by ribosomes in the cell body
ER and Golgi apparatus enzymatically split the large molecule into smaller precursor or active molecules
Golgi apparatus makes vesicles
these vesicles are transported through the axoplasm slowly
remain in the terminal
release by a process similar to the other neurotransmitter
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NEUROPEPTIDES
however vesicle is autolysed and not reused
quantity of neuropeptides released is smaller than that of other neurotransmitters
but the neuropeptides are thousand times more potent
they also cause much more prolonged action
generally only one type of small molecule neurotransmitter is released by a neuron
several neuropeptides could be released
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NEUROPEPTIDES
Removal of neurotransmitter:by diffusion into the surrounding fluidsenzymatic destruction (Ach)active transport re-uptake into the presynaptic terminal
Actions prolonged closure of Ca pores prolonged changes in cell metabolism deactivation of specific genes prolonged changes in excitatory or inhibitory
receptors
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OPIOID PEPTIDES
Endorphin present in pituitary, earliest discovered opioid peptide
enkephalins: met-enkephalin, leu-enkephalin present at substantia gelatinosa in the spinal cord & brain
stem reticular nuclei widely distributed
dynorphin recently discovered
opioid peptides are involved in the descending pain inhibitory pathway
receptors: , ,
Other peptides present in the CNS
Substance P ACTH Oxytocin Glucagon Somatostatin VIP Prolactin LH TRH Releasing hormones,
– GH– Gastrin– CCK– Neurotensin– Insulin– Angiotesin II– Bradykinin– Calcitonin gene
related peptide (CGRP)
– Neuropeptide YL Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
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Nitrous oxide (NO)
nitrous oxide (NO) present in brain probably involved in memory
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Neuromodulators
Neurotransmitters transmit an impulse from one neuron to another
Neuromodulator modulate regions or circuits of the brain
They affect a group of neurons, causing a modulation of that group
Neuromodulators alter neuronal activity by amplifying or dampening synaptic activityeg. dopamine, serotonin, acetylcholine,
histamine, glutamate
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Neuromuscular junction
This is a modified synapse
Consists of Presynaptic
membrane (nerve terminal)
Synaptic cleft Postsynaptic
membrane (motor end plate)
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Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs)
¨ Terminal has synaptic vesicles and mitochondria
¨ Mitochondria (ATP) are present inside the presynaptic terminal
Vesicles containing neurotransmitter (Ach)
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Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs)
¨ Presynaptic membrane contain voltage-gated Ca channels
¨ The quantity of neurotransmitter released is proportional to the number of Ca entering the terminal
¨ Ca ions binds to the protein molecules on the inner surface of the synaptic membrane called release sites
¨ Neurotransmitter binds to these sites and exocytosis occur
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Ca2+ Ca2+
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Postsynaptic membrane (motor end plate)
Postsynaptic membrane contain receptors for the neurotransmitter released
eg: Acetylcholine receptor
AchNa+
•This receptor is Ach-gated Na+ channel•When Ach binds to this, Na+ channel opens up•Na+ influx occurs
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Na+ influx
Na+ influx causes depolarisation of the membrane End Plate Potential (EPP)
▪ This is a graded potential▪ Once this reaches the threshold level▪ AP is generated at the postsynaptic
membrane
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Ach release
An average human end plate contains 15-40 million Ach receptors
Each nerve impulse release 60 Ach vesicles
Each vesicle contains about 10,000 molecules of Ach
Ach is released in quanta (small packets)
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End plate potential
Even at rest small quanta are released
Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP)
When an impulse arrives at the NMJ quanta released are increased in several times causing EPP
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Acetylcholinerase (AchE)
After the Ach binding is over
Cholinesterase present in the synaptic cleft will hydrolyse Ach into choline and acetate
Choline is reuptaken to the presynaptic terminal
AchE is also found in RBC membranes
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Axoplasmic transport
A cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the axoplasm
anterograde transport movement toward the synapse is called
retrograde transport Movement toward the cell body
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Smooth muscles
NMJ not well developed
Smooth muscle does not depend on motor neurons to be stimulated
However, motor neurons (of the autonomic system) reach smooth muscle and can stimulate it — or relax it — depending on the neurotransmitter they release (e.g. noradrenaline or nitric oxide, NO))
Smooth muscle can also be made to contract by other substances released in the vicinity (paracrine stimulation)
Example: release of histamine causes contraction of the smooth muscle lining our air passages (triggering an attack of asthma)
by hormones circulating in the blood Example: oxytocin reaching the uterus stimulates it to contract to begin
childbirth.
The contraction of smooth muscle tends to be slower than that of striated muscle
It also is often sustained for long periods
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FACULTY
1. Treatment of Parkinson Disease
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Parkinson’s disease
Parkinsonism is a progressive degenerative, extrapyramidal disorder of muscle movement, due to dysfunction in basal ganglia, comprising four cardinal features:- Bradykinesia or hypokinesia. Muscle rigidity. Resting tremor. Impairment of postural balance leading to
disturbances of gait, and falling. The secondary manifestations are mask-like face, siallorrhoea, difficulty in speech, slowing of mental process and dementia.
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Bradykinesia:
It is slowness in initiating and carrying out voluntary movements. It is called poverty and suppression of voluntary movements. It is caused partly by muscle rigidity and partly by inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate. It is hard to start walking, and once in progress, the patient can not stop quickly.
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Muscle rigidity:
Rigidity is due to increased muscle tone. The rigidity affects the opposing muscles equally, flexors and extensors. Rigidity is detectable as an increased resistance in passive limb movement.
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Tremors:
Tremors are defined as rhythmic oscillatory movements caused by the opposing muscles around a joint. Tremors of Parkinsonism are slow. Hand tremors involve all the fingers and thumb (pill rolling tremor) which tend to diminish during voluntary activity. The “resting tremors” are present at rest and disappear (abate) during voluntary movements.
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Dyskinesia: Abnormal involuntary movements
Chorea: It consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impaired voluntary activity.
Athetosis: Abnormal movements are slow and writhing in character
Dystonia: The abnormal movements are slow in character and are sustained so that they are regarded as abnormal postures
Tics: They are coordinated abnormal movements that tend to occur repetitively particularly about the face and head, especially in children
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Etiology
The degeneration of neurons occurs in substantia nigra pars compacta and the nigrostriatal tract that are dopaminergic and inhibit the activity of striatal GABA ergic neurons. This results in deficiency of dopamine in striatum which controls muscle tone and coordinates movements. Nerve fibers from cerebral cortex and thalamus secrete acetylcholine in the neostriatum causing excitatory effects that initiate and regulate gross intentional movements of the body. In Parkinson’s disease, due to deficiency of dopamine in striatum, an imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system occurs, leading to excessive excitatory actions of cholinergic neurons on striatal GABA ergic neurons.
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Etiology cont…d
Substantia Nigra: The substantia nigra pars compacta is the source
dopaminergic neurons that travel through nigrostriatal tract to terminate in the striatum. These dopaminergic neurons from the substantia nigra fire tonically, to produce a sustained influence on motor activity.
Striatum: The striatum is connected to the substantia nigra par
reticulata by neurons that secrete the inhibitory transmitter GABA at their endings in the substantia nigra. In turn, cells of the substantia nigra send neurons back to the striatum, secreting the inhibitory transmitter dopamine at their endings. Nerve fibers from the cerebral cortex and thalamus secrete Acetylcholine in the neostriatum causing excitatory effects.
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Strategy of Treatment
In Parkinson’s disease dopaminergic inhibitory activity is reduced and cholinergic excitatory activity is increased. Therefore, therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effects of cholinergic neurons.
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Drugs used for Parkinsonian Disease:
Drug therapy is aimed at restoring the balance between the dopaminergic and cholinergic components, which is achieved by: Increasing the central dopaminergic
activityOR
Decreasing the central cholinergic activity
OR BOTH.
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Types of Parkison’s Diaease
Idiopathic Parkinson's disease Idiopathic Parkinson's disease - or Parkinson's - is
the most common type of parkinsonism. Unlike some other forms which have specific causes it is not known why idiopathic Parkinson's occurs.
The main symptoms of idiopatic Parkinson's are tremor, rigidity and slowness of movement.
Symptoms and the rate at which the condition progresses vary from person to person. This can make diagnosis difficult.
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Vascular Parkinsonism:
Vascular parkinsonism is one of the atypical forms of parkinsonism.
The most likely causes of vascular parkinsonism are hypertension and diabetes. A stroke (cerebrovascular accident), cardiac disease or carotid artery pathology (another form of stroke) may also be involved.
Symptoms of vascular parkinsonism may include difficulty speaking, making facial expressions or swallowing.
Other signs can include problems with memory or confused thought, cognitive problems and incontinence.
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Drug Induced Parkinsonism
A small number (around 7%) of people diagnosed with parkinsonism have developed their symptoms following treatment with particular medications.
Drugs - known as neuroleptic drugs - used to treat schizophrenia and other psychotic disorders block dopamine. These drugs are thought to be the biggest cause of drug-induced parkinsonism.
Dopamine is a chemical in the brain which allows messages to be sent to the parts of the brain that co-ordinate movement.
The symptoms of Parkinson's appear when the level of dopamine falls.
The symptoms of drug-induced parkinsonism tend to be static. Only in rare cases do they change in the manner that the symptoms of Parkinson's do.
Most people will recover within months, and often within hours or days, of stopping the drug that caused the dopamine block.
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Dementia with Lewy bodies:
Dementia with Lewy bodies is similar, in some ways, to Parkinson's and Alzheimer's.
Symptoms differ slightly from Parkinson's and include problems with memory and concentration, attention, language and the ability to carry out simple actions.
People who have dementia with Lewy bodies commonly experience visual hallucinations and some Parkinson's-type symptoms, such as slowness of movement, stiffness and tremor.
Dementia with Lewy bodies is also a progressive condition, which means that the symptoms can become worse over time. Currently, there is no cure or treatment for the condition.
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Inherited Parkinson's There is no conclusive evidence that Parkinson's
is a hereditary condition that can be passed on within families, apart from in exceptionally rare cases.
It is thought that although it is not directly inherited, some people may have genes that increase the possibility of developing Parkinson's.
People who have genes that are prone to Parkinson's may be more likely to develop the condition when combined with other factors, such as environmental toxins or viruses.
At present, it is estimated that up to 5% of people with Parkinson's may have a genetic cause.
The role genetics may play in the development of Parkinson's is currently the subject of much research.
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Juvenile Parkinson's:
Juvenile Parkinson's is a term used when the condition affects people under the age of 20.
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Causes of parkinsonism:
1) Idiopathic PD: - Due to loss of dopaminergic neurons of
the substantia nigra- Progressive loss of dopamine-containing neurons is a feature of normal aging; however, most people do not lose the 70% to 80% of dopaminergic neurons required to cause symptomatic PD- Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism
2) Secondary PD: e.g., following stroke, and intoxication with
dopamine-receptor antagonists as antipsychotics and antiemetics.
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Treatment of parkinsonism
Aim of treatment is to enhance dopaminergic pathway or inhibit cholinergic pathway in the brain
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ATI-PARKINSONIAN DRUGS
-Amantadine -Antimuscarinic agents e.g
benztropine,biperiden,trihexyphenidyl Bromocriptine Carbidopa Deprenyl (selegilline) Levodopa Pramipexole Ropinirole Tolcapone
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Drugs used in the treatment of parkinsonism 1- Levodopa (1)
Levodopa is (the most effective drug used in the treatment of parkinsonism) Chemistry:• It is the metabolic precursor of dopamineMechanism of action:• In the brain, levodopa is converted to dopamine by decarboxylation
primarily within the presynaptic terminals of dopaminergic neurons in the stratium (by action of L-aromatic amino acid decarboxylase). The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) .
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Drugs used in the treatment of parkinsonism 1- Levodopa (2)
If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the peripheral sites so that little unchanged drug reaches the cerebral circulation.
In addition, dopamine release into the circulation by peripheral conversion of levodopa produces undesirable effects,
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Drugs used in the treatment of parkinsonism 1- Levodopa (3)
• In practice, levodopa is administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the CNS.
• Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that crosses the blood-brain barrier and reduces the incidence of peripheral side effects.
• The most commonly prescribed form of carbidopa/levodopa is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa.
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Drugs used in the treatment of parkinsonism 1- Levodopa (4)
Adverse effects:A) Central:
1) long-term therapy leads to "wearing off" phenomenon: each dose of levodopa improves mobility for 1 to 2 hours, but rigidity and akinesia return at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias (excessive and abnormal involuntary movements). Patients may fluctuate between being "off," having no beneficial effects from their medications, and being "on" but with dyskinesias, a situation called the on/off phenomenon.
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Drugs used in the treatment of parkinsonism 1- Levodopa (5)
2) Mental effects Depression, anxiety, agitation, insomnia, delusions, hallucinations, euphoria
3) Dyskinesias (excessive and abnormal involuntary movements) as chorea and tremor
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Drugs used in the treatment of parkinsonism 1- Levodopa (6)
B. Peripheral: Due to formation of dopamine peripherally1. The most common peripheral side effects are anorexia,
nausea, and vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone in the medulla oblongata).
2. Cardiovascular side effects in the form of orthostatic hypotension and cardiac arrhythmias
Abrupt withdrawal of levodopa may precipitate the neuroleptic malignant syndrome.
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Drugs used in the treatment of parkinsonism 1- Levodopa (7)
Drug Interactions:1. Pharmacologic doses of pyridoxine (vitamin B6)
enhance the extracerebral metabolism of levodopa and prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken.
2. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance, because such a combination can lead to hypertensive crises.
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Drugs used in the treatment of parkinsonism 1- Levodopa (7)
Contraindications1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Melanoma
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Drugs used in the treatment of parkinsonism 2- Dopamine receptor agonists (1)
• Four orally administered dopamine-receptor agonists are available for treatment of PD:
1) Ergot derivatives: as bromocriptine or pergolide
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Mechanism of action
Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and D4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D2 and D3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D2-receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT)1D, dopamine D3, 5-HT1A, 5-HT2A, 5-HT1B, and 5-HT2Creceptors, antagonist activity on α2A-adrenergic, α2C, α2B, and dopamine D1 receptors, partial agonist activity at receptor 5-HT2B, and inactivates dopamine D4 and 5-HT7 receptors.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Mode of Action Summary
The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D2receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Non ergot derivatives
E.g ropinirole Mechanism of actionRopinirole binds the dopamine receptors D3 and D2.
Although the precise mechanism of action of ropinirole as a treatment for Parkinson's disease is unknown, it is believed to be related to its ability to stimulate these receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that ropinirole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 2- Dopamine receptor agonists (2)
Adverse effects:I. Central:• Dyskinesias , mental Disturbances
II. Peripheral:A) Gastrointestinal Effects:• Anorexia and nausea and vomitingB) Cardiovascular effects:
1. postural hypotension2. cardiac arrhythmias 3. peripheral vasospasm (with ergot derivatives)
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 2- Dopamine receptor agonists (3)
Contraindications1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Peripheral vascular disease (ergot
derivatives).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 3- Monoamine oxidase inhibitors (1)
Two types of monoamine oxidase (MAO) have been distinguished. Monoamine oxidase (A) metabolizes norepinephrine and serotonin; monoamine oxidase (B) metabolizes dopamine.
Selegiline:Mechanism of action:• It is therefore used as adjunctive therapy for patients with a declining response to levodopa. Although the mechanisms for selegiline's beneficial action in the treatment of
Parkinson's disease are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B (MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression.
Side effects:• May cause insomnia when taken later during the day. Drug interactions:• It should not be taken by patients receiving tricyclic antidepressants, or serotonin reuptake inhibitors
because of the risk of acute toxic interactions. • The adverse effects of levodopa may be increased by selegiline.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
COMT inhibitors
Periphery CNS (striatum)
3-O-Methyldopa
L-DOPA
Dopamine
L-DOPA Dopamine
DOPAC
3-Methoxy tyramine
MAO-B
COMT
COMT
AAD
AAD
carbidopa x
tolcapone x
tolcapone x
selegiline x-
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 3- Catechol O methyl transferase inhibitors (1)
Tolcapone• Mechanism of action:
1. Inhibit catechol O methyl transferase (COMT) which is responsible for the conversion of dopa into methyl dopa. Elevated levels of methyldopa decreases the response to levodopa, because methyldopa competes with levodopa for an active carrier mechanism that governs its transport across the blood-brain barrier.
2. prolong the action of levodopa by diminishing its peripheral metabolism.
• These agents may be helpful in patients receiving levodopa to reduce dose and decrease fluctuations in response
• Side effects are similar to levodopa
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 4- Amantadine(1)
Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclearClinical Use• Amantadine is less potent than levodopa and its effects disappear after only a few
weeks of treatment• Mechanism of Action The mechanism of its antiparkinsonic effect is not fully
understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated
Adverse Effects1. Central nervous system effects 2. Peripheral edema3.Headache 4. Heart failure . 5.postural hypotension 6. urinary retention 7. gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry
mouth).
Contraindications• Amantadine should be used with caution in patients with a history of seizures or heart failure.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs used in the treatment of parkinsonism 5.Antimuscarinic agents - Acetylcholine blocking
drugs(1)
Benztropine Mechanism of Action Benztropine is a selective M1 muscarinic acetylcholine
receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Benztropine partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement.
Clinical Use Antimuscarinic drugs may improve the tremor and rigidity of
parkinsonism but have little effect on bradykinesia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Adverse Effects 1) Central nervous system effects, including drowsiness,
restlessness, confusion, agitation, hallucinations, and mood changes. Dyskinesias occur in rare cases
2) Atropine – like actions: dryness of the mouth, blurring of vision, urinary retention, nausea and vomiting, constipation, tachycardia, palpitations, and cardiac arrhythmias.
withdrawal should be gradual in order to prevent acute exacerbation of parkinsonism.
Contraindications1. Prostatic hyperplasia, 2. Obstructive gastrointestinal disease (eg, paralytic ileus)3. Angle-closure glaucoma.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
THANK You End
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology2.Anxiolytic and Hypnotic Drugs
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
ANXIETY
Def: Anxiety is an unpleasant state of
tension, apprehension or uneasiness arising from unknown source. Anxiety is the most common mental disorder.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS
SEDATION Reduction of anxiety Calming effectANXIOLYTIC Drug that reduces anxiety SedativeHYPNOSIS Induction of sleep
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Manifestations of anxiety:
Verbal complaints. The patient says he/she is anxious, nervous, edgy.
Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, weeping and often gastrointestinal disorders.
Social effects. Interference with normal productive activities.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pathological Anxiety
Generalized anxiety disorder (GAD): People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month.
Phobic anxiety: Simple phobias. Agoraphobia, fear of animals, etc.Social phobias.
Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD.
Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Causes of Anxiety2). Drug-Induced:
Stimulants▪ Amphetamines, cocaine, TCAs, caffeine.
Sympathomimetics▪ Ephedrine, epinephrine, pseudoephedrine
phenylpropanolamine. Anticholinergics\Antihistaminergics
▪ Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin.
Dopaminergics▪ Amantadine, bromocriptine, L-Dopa,
carbid/levodopa.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Causes of Anxiety
Miscellaneous:▪ Baclofen, cycloserine, hallucinogens,
indomethacin.
3). Drug Withdrawal:▪ BDZs, narcotics, BARBs, other
sedatives, alcohol.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Anxiolytics
Strategy for treatmentReduce anxiety without causing sedation.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drug Classification
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Sedative/Hypnotics
1) Benzodiazepines (BZDs):
Alprazolam, diazepam, oxacepam, triazolam
2) Barbiturates:
Pentobarbital, phenobarbital
3) Alcohols:
Ethanol, chloral hydrate, paraldehyde, trichloroethanol,
4) Imidazopyridine Derivatives:
Zolpidem
5) Pyrazolopyrimidine
Zaleplon
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Sedative/Hypnotics6) Propanediol carbamates:
Meprobamate
7) PiperidinedionesGlutethimide
8) AzaspirodecanedioneBuspirone
9) -Blockers**Propranolol
10) 2-AR partial agonist**Clonidine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Sedative/Hypnotics
Others:11) Antyipsychotics **
Ziprasidone12) Antidepressants **
TCAs, SSRIs
13) Antihistaminic drugs **Dephenhydramine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Sedative/Hypnotics
The benzodiazepines are the most important sedative hypnotics.
Developed to avoid undesirable effects of barbiturates (abuse liability).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Mechanism of Action of Benzodiazepines
Benzodiazepines (BDZs) bind to the gamma sub-unit of the GABA-A receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. BDZs do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BDZ Mode of Action
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BDZ Actions
BDZ have no antipsychotic activity nor any analgesic action and do not affect the autonomic nervous system.
Actions1. Reduction of anxiety: at low
dose they reduce anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BDZ Actions
2. Sedative and Hypnotic action: All BDZ have sedative action and some produce hypnosis at higher doses.
3. Anticonvulsant action: Several BDZ have anticonvulsant action and used to treat epilepsy and seizure disorders.
4. Muscle relaxant: The benzodiazepines relax spasticity of skeletal muscle probably by increasing presynaptic inhibition in the spinal cord.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Therapeutic Uses
Pharmacokinetic variation and duration of action influence the choice of BDZ
1. Anxiety disorders associated with depression: longer acting drugs such diazepam are often preferred alprazolam is effective but may cause withdrawal reactions.
2. Muscular disorders: such as muscle strain, cerebral palsy diazepam is effective.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Therapeutic Uses
3. Seizures: Clonazepam is useful in chronic treatment of epilepsy, whereas diazepam is the drug of choice in terminating grand mal epileptic seizures and status epilepticus.
Chlordiazepoxide, Clorazepate, diazepam and oxazepam are useful in the acute treatment of alcohol withdrawal.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Therapeutic Uses
4. Sleep disorders: Not all BDZ have hypnotic action although all have sedative or calming action. Drugs of choice for sleep disorders include, long acting - flurazepam, intermediate acting – temazepam and short acting triazolam
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dependence
Psychological and Physical dependence BDZ can develop due to prolonged high dosage use over a prolonged period and abrupt discontinuation. Because of long half-lives of some BDZ, withdrawal symptoms may not occur until after a number of days.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
SIDE EFFECTS
Drowsiness and Confusion Cognitive impairment Early morning insomnia Tolerance
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Benzodiazepine Antagonist
Flumazenil Mechanism of actionFlumazenil, an imidazobenzodiazepine
derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of Benzodiazepines
· Although BDZs are highly protein bound (60-95%), few clinically significant interactions.*
· High lipid solubility high rate of entry into CNS rapid onset.
*The only exception is chloral hydrate
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of Benzodiazepines
· Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).
· Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs).
· All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of Benzodiazepines
· Many have active metabolites with half-lives greater than the parent drug.
· Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr).
· Differing times of onset and elimination half-lives (long half-life => daytime sedation).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Biotransformation of Benzodiazepines
From Katzung, 1998
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Biotransformation of Benzodiazepines
Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.
Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.
All of these drugs and their metabolites are excreted in urine.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Properties of Benzodiazepines
BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence.
BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.
BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity/Overdose with Benzodiazepines
Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored.
Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.
Flumazenil is not effective against BARBs overdose.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drug-Drug Interactions with BDZs BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a greatly reduced margin of safety.
BDZs reduce the effect of antiepileptic drugs.
Combination of anxiolytic drugs should be avoided.
Concurrent use with antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided.
SSRI’s and oral contraceptives decrease metabolism of BDZs.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Barbiturates
Mechanism of action Barbiturates act on GABAA receptors,
increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Barbiturates may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of Barbiturates are likely the result of polysynaptic midbrain reticular formation, which controls CNS arousal.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Actions
1. Depression of CNS: is dose dependant 2. Respiratory Depression: barbiturates
suppress the hypoxic and chemoreceptor response to CO2 and over dosage is followed by respiratory depression and death.
3. Enzyme induction: they induce Cyt-P450 microsomal enzymes in the liver and reduce the action of many drugs administered together with barbiturates.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Therapeutic Uses
1. Anaesthesia: e.g short acting drugs like thiopental.
2. Anticonvulsant : e.g Phenobarbital
3. Anxiety : used as a mild sedative to relieve anxiety nervous tension and insomnia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of Barbiturates
Rapid absorption following oral administration.
Rapid onset of central effects.Extensively metabolized in liver (except
phenobarbital), however, there are no active metabolites.
Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of Barbiturates
In the elderly and in those with limited hepatic function, dosages should be reduced.
Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity/Overdose
Strong physiological dependence may develop upon long-term use.
Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity/Overdose
Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions.
Drugs with long-half lives have mildest withdrawal (.
Drugs with quick onset of action are most abused.
No medication against overdose with BARBs.
Contraindicated in patients with porphyria.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Miscellaneous Drugs
BuspironeChloral hydrateHydroxyzineMeprobamate (Similar to
BARBS)Zolpidem (BZ1 selective)Zaleplon (BZ1 selective)
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BUSPIRONE
Most selective anxiolytic currently available. The anxiolytic effect of this drug takes
several weeks to develop => used for GAD. Buspirone does not have sedative effects
and does not potentiate CNS depressants. Has a relatively high margin of safety, few
side effects and does not appear to be associated with drug dependence.
No rebound anxiety or signs of withdrawal when discontinued.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BUSPIRONE
Side effects:• Tachycardia, palpitations,
nervousness, GI distress and paresthesias may occur.
• Causes a dose-dependent pupillary constriction.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
BUSPIRONE
Mechanism of Action:• Buspirone binds to 5-HT type 1A serotonin
receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics of BUSPIRONE
Not effective in panic disorders. Rapidly absorbed orally. Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2-pyrimidyl-piperazine, 1-PP)
Well tolerated by elderly, but may have slow clearance.
Analogs: Ipsapirone, gepirone, tandospirone.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Zolpidem
Structurally unrelated but as effective as BDZs.
Minimal muscle relaxing and anticonvulsant effect.
Rapidly metabolized by liver enzymes into inactive metabolites.
Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Zolpidem
Mechanism of Action:• Zolpidem modulates the alpha-subunit,
known as the benzodiazepine receptor, within the GABAA receptor chloride channel macromolecular complex. Unlike the benzodiazepines,which non-selectively interact with all three alpha-receptor subtypes, Zolpidem preferentially binds to the alpha-1 receptor.
• Actions are antagonized by flumazenil
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Hydroxyzine
Mechanism of action Hydroxyzine competes with histamine
for binding at H1-receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of hydroxyzine occur at the subcortical level of the CNS. Secondary to its central anticholinergic actions, hydroxyzine may be effective as an antiemetic.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Non Barbiturate Sedatives drugs.
Chloral hydrate Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) from plasma proteins.
Extensive biotransformation.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Properties of Other Drugs
2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.• Has been used for the treatment of panic
attacks.• Has been useful in suppressing anxiety
during the management of withdrawal from nicotine and opioid analgesics.
• Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive crisis.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Properties of Other Drugs
-Adrenoreceptor Antagonists (eg. Propranolol)
• Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.
• Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
OTHER USES1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone
2. Phobic Anxietya. Simple phobia. BDZsb. Social phobia. BDZs
3. Panic DisordersTCAs and MAOIs, alprazolam
4. Obsessive-Compulsive BehaviorClomipramine (TCA), SSRI’s
5. Posttraumatic Stress Disorder (?)Antidepressants, buspirone
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
End
THANK You End
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology3. CNS Stimulants
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Overview
We will look at two groups of drugs that act primarily to stimulate the central nervous system, i.e Psychomotor stimulants and Psychotomimetic drugs.
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CNS STIMULANTS
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Classification of CNS Stimulants
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CNS stimulants
Few clinical uses, Important as drugs of abuse.Factors that limit the therapeutic usefulness
include:1. Dependence: Psychological and physiological.2. Tolerance to the euphoric and anorectic effects
are classified according to their action into:3. Psychomotor stimulants4. Hallucinogen (psychotomimetic or
psychedelics) drugs
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CNS stimulants
1. Psychomotor stimulants cause: Excitement, Euphoria, Decrease feeling of fatigue & Increase motor activityEx., Methylxanthines (caffeine, theobromine, theophylline),
nicotine, cocaine, amphetamine, atomoxetine, modafinil, methylphenidate.
2. Hallucinogens (psychotomimetic):Affect thought, perception, and mood, therefore
produce profound changes in thought patterns & mood, little effect on the brain stem & spinal cord
Ex., Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol (THC), Rimonabant.
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Psychomotor stimulantsQ. What are Stimulants?Answer. Chemical stracture are similar to
monoamine neurotransmitters. All are indirect-acting sympathomimetics:
1. Many CNS stimulants release catecholamines, Therefore, their effects are abolished by prior treatment with reserpine or guanethidine
Ex: amphetamine, dextroamphetamine, methamphetamine, methylphenidate (Ritalin), ephedrine, pseudoephedrine (a stereoisomer of ephedrine), tyramine.
2. Other CNS stimulants block the reuptake of catecholamines (NE and DA) and serotonin:
EX. Cocaine, sibutramine (reduct)®, modafinil
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Psychomotor stimulants
3. Drugs with stimulant effects; however, they are marketed as antidepressants include:
Atomoxetine– a relatively selective NE reuptake inhibitor (ADHD),
Bupropion – blocks the reuptake of both NE and DA.4. The methylxanthines are adenosine receptor
antagonists. Drugs within this class are NOT generally considered “psychomotor” stimulants, but they have distinct stimulant effects caffeine, theophylline.
NB: MAO and COMT inhibitors (indirect-acting adrenergic agonists), but they are not traditionally considered to be stimulants.
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Therapeutic Indications and Contraindications for CNS Stimulants
Obesity (anorectic agents). Attention Deficit Hyperactivity Disorder (ADHD); lack the ability to be involved in any one activity for longer than a few minutes. Narcolepsy: It is a relatively rare sleep disorder, that is characterized by uncontrollable bouts of sleepiness during the day. It is sometimes accompanied by catalepsy, a loss in muscle control, or even paralysis brought on by strong emotion, such as laughter.Contraindications: patients with anorexia, insomnia, asthenia, psychopathic personality, a history of homicidal or suicidal tendencies.
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1. Psychomotor stimulants
A. methylxanthines1. Theophylline (found in tea) : long-acting,
prescribed for night-time asthma2. Theobromine: found in cocoa. 3. Caffeine: (short-acting) the most widely
consumed found in coffee (200 mg/cup), carbonated soft drinks (60 mg/can), cocoa and chocolate
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Mechanism of action: includeseveral mechanism have been proposedMechanism of action of methylxanthine1-It inhibits phosphodiesterase enz. → ↑ cAMP
2- Adenosine (A1, A2 and A3) receptors antagonist almost equally, which explains many of its cardiac effects
A2 receptors antagonist responsible for CNS stimulation & smooth muscles relaxation
↓calcium inSmooth muscles
↑ calcium inCNS & heart
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Actions
a. CNS: decrease in fatigue, increased alertness: 100-200 mg caffeine in 1 or 2
cups of coffees Anxiety & tremors- 1.5 g of caffeine: 12-15 cups of coffee Spinal cord stimulation: 2-5 g (very high dose)
Tolerance can rapidly developWithdrawal symptoms: feeling of fatigue & sedation.
b. CVS; at high dose of caffeine +ve inotropic and chronotropic effects on the heart, ↑COPc. Diuretic action: mild ↑ urinary output of Na+, Cl- and K+
d. Gastric mucosa: all methylxanthines stimulate secretion of HCl
e. Respiratory smooth muscle: bronchodilator, Rx asthma replaced by β-agonists, corticosteroids.
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Pharmacokinetics
Pharmacokinetics The methylxanthines are well absorbed orally. Caffeine distributes throughout the body, including the
brain. The drugs cross the placenta to the fetus and is secreted into the mother's milk.
All are metabolized in the liver, generally by the CYP1A2 pathway, the metabolites are then excreted in the urine.
Adverse effects Moderate doses: insomnia, anxiety, agitation High doses: emesis, convulsion Lethal dose (10 gm of caffeine): cardiac arrhythmia Suddenly stop: lethargy, irritability, headache
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B. Nicotine
Nicotine is the active ingredient in tobacco.
Used in smoking cessation therapy, Nicotine remains important, because:
it is 2nd only to caffeine as the most widely used CNS stimulant
and 2nd only to alcohol as the most abused drug.
Actions of Nicotine:Low dose: ganglionic depolarizationHigh dose: ganglionic blockade
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Actions of Nicotine
I. CNS: 1. Low dose: euphoria, arousal, relaxation,
improves attention, learning, problem solving and reaction time.
2. High dose: CNS paralysis, severe hypotension (medullary paralysis)
II. Peripheral effects: Stimulation of sympathetic ganglia and adrenal
medulla→↑ BP and HR (harmful in HTN patients) Stimulation of parasympathetic ganglia→↑ motor
activity of the bowel At higher doses, BP falls & activating ceases in
both GIT and bladder
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Pharmacokinetics: highly lipid soluble absorbed everywhere (oral
mucosa, lung, GIT, skin). Crosses the placental membrane, secreted with
milk. Most cigarettes contain 6-8 mg of nicotine, by
inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette.
the acute lethal dose is 60 mg, 90% of nicotine inhaled in smoke is absorbed. Tolerance to toxic effects of nicotine develops
rapidly.
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Adverse effects CNS; irritability and tremors Intestinal cramps, diarrhea ↑HR & BP
Withdrawal syndrome: nicotine is addictive substance, physical dependence on
nicotine develops rapidly and can be severe.
Bupropion: can reduce the craving for cigarettes
Transdermal patch and chewing gum containing nicotine
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C. Varenicline (Chantix in the USA and Champix in Canada):
partial agonist at Nn receptor in CNS.
It produces less euphoric effects than those produced by nicotine itself (nicotine is full agonist at these receptors).
Thus, it is useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptom.
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D. Cocaine (highly addictive drug)
1. Mechanism of action: blockade of reuptake of the monoamines (NE, serotonin and dopamine)Thus, potentiates and prolongs the CNS and peripheral actions of these monoamines.
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1. Mechanism of action
Initially produces the intense euphoria by prolongation of dopaminergic effects in the brain’s pleasure system (limbic system).
Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression.
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2. Actions: a. CNS-behavioral effects result from powerful
stimulation of cortex and brain stem. Cocaine acutely increase mental awareness and
produces a feeling of wellbeing and euphoria similar to that produced by amphetamine.
Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity.
Cocaine increases motor activity, and at high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression.
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2. Actions b. Sympathetic NS: peripherally potentiate the
action of NE→ fight or flightc. Hyperthermia: impair sweating & cutaneous vasodilation ↓Perception of thermal discomfort d. local anesthetic action: blockade of voltage-
activated Na+ channel. Cocaine is the only LA that causes
vasoconstriction, chronic inhalation of cocaine powder → necrosis and perforation of the nasal septum
Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous (IV) injection.
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Adverse effects:
Anxiety reaction that includes: hypertension, tachycardia, sweating, and paranoia.
Because of the irritability, many users take cocaine with alcohol. A product of cocaine metabolites and ethanol is cocaethylene, which is also psychoactive and cause cardiotoxicity. Depression: Like all stimulant drugs, cocaine stimulation
of the CNS is followed by a period of mental depression. Addicts withdrawing from cocaine exhibit physical and
emotional depression as well as agitation. The latter symptom can be treated with benzodiazepines or phenothiazines.
Toxic effects: Seizures RX I.V diazepam fatal cardiac arrhythmias. propranolol
E. Amphetamine Is a non catecholamine, (shows neurologic and
clinical effects quite similar to those of cocaine), dextroamphetamine is the major member of this
class compounds. methamphetamine (speed) is a derivative of
amphetamine that can be smoked and it is preferred by many abusers.
Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties.
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
1. Mechanism of action:
Amphetamine, act by releasing intracellular
stores of catecholamines.
also inhibits MAO, high level CAOs are readily released into synaptic spaces.
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2. Actions:a. CNS: the major behavioral effects of
amphetamine result from a combination of its dopamine and NE release enhancing properties.
Amphetamine stimulates the entire cerebrospinal axis, brainstem, and medulla.
This lead to increase alertness, decrease fatigue, depressed appetite, and insomnia.
b. Sympathetic Nervous System: indirectly stimulating the receptors through NE release.
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Narcolepsy
Amphetamine, methylphenidate. Recently, a new drug, modafinil and its R-
enantiomer derivative, armodafinil, have become available to treat narcolepsy.
Modafinil produces fewer psychoactive and euphoric effects as well as, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants.
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4. Adverse effects:
The amphetamines may cause addiction, dependence, tolerance, and drug seeking behavior.a. CNS: insomnia, irritability, weakness, dizziness, tremor, hyperactive reflex, confusion, delirium, panic states, and suicidal tendencies, especially in mentally ill patients. -Chronic amphetamine use produce a state of “amphetamine psychosis” that resembles the psychotic episodes associated with schizophrenia.-Whereas long-term amphetamine is associated with psychic and physical dependence, tolerance to its effects may occur within a few weeks.
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4. Adverse effects:
Overdoses are treated with chlorpromazine or haloperidol, which relieve the CNS symptoms as well as the HTN because of their α–blocking effects. The anorectic effect of amphetamine is due to its action in the lateral hypothalamic feeding center.b. CVS: palpitations, cardiac arrhythmia, HTN, anginal
pain, and circulatory collapse. Headache, chills, and excess sweating may also occur.
c. GIT: anorexia, nausea, vomiting, abdominal cramps, and diarrhea.
Contraindications: HTN, CV diseases, Hyperthyroidism, Glaucoma, Patients with a history of drug abuse
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Atomoxetine
approved for ADHD in children and adults. It is a NE reuptake inhibitor (should not be taken
by individual on MAOI). It is not habit forming and is not a controlled
substance.
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Methylphenidate (Ritalin)® It has CNS stimulant properties similar to those of
amphetamine and may also lead to abuse, although its addictive potential is controversial.
It is taken daily by 4-6 million children in the USA. The pharmacologically active isomer, Dexmethylphenidate, has been approved in the USA for the Rx of ADHD.
Methylphenidate is a more potent dopamine transport inhibitor than cocaine, thus making more dopamine available.
It has less potential for abuse than cocaine, because it enters the brain much more slowly than cocaine and, does not increase dopamine levels as rapidly.
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2. Therapeutic uses:
Methylphenidate has been used for several decades in the treatment of ADHD in children aged 6 to 16.
It is also effective in the treatment of narcolepsy.
Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy.
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3. Adverse reactions:
GIT effects are the most common; abdominal pain and nausea.
Other reactions include anorexia, insomnia, nervousness, and fever.
In seizure patients, methylphenidate seems to increase the seizure frequency, especially if the patient is taking antidepressants.
Methylphenidate is contraindicated in patients with glaucoma.
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II. Hallucinogens (psychotomimetic)
A few drugs have the ability to induce altered perceptual states reminiscent of dreams, are accompanied by bright, colourful changes in the environment and by a plasticity of constantly changing shapes and colour.
The individual under the influence of these drugs is incapable of normal decision making, because the drug interferes with rational thought.
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A. Lysergic acid diethylamide Multiple sites in the CNS are affected by lysergic
acid diethylamide (LSD). The drug shows serotonin (5-HT) agonist activity
at presynaptic 5-HT1 receptors in the midbrain, and also stimulates 5-HT2 receptors.
Activation of the sympathetic nervous system occurs, which causes pupillary dilation, increased BP, piloerection, and increased body temperature.
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A. Lysergic acid diethylamide Adverse effects:
include hyperreflexia, nausea, and muscular weakness.
High doses may produce long-lasting psychotic changes in susceptible individuals.
Haloperidol and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome.
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B. Tetrahydrocannabinol (THC)
The main psychoactive alkaloid contained in marijuana is tetrahydrocannabinol (THC), which is available as dronabinol.
THC can produce euphoria, followed by drowsiness and relaxation.
affect short-term memory and mental activity, decreases muscle strength and impairs highly skilled motor activity, such as
that required to drive a car. Its wide range of effects includes:
appetite stimulation, xerostomia, visual hallucinations, delusions, and enhancement of sensory activity
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Mechanism of action:
THC receptors, designated CB1 receptors, have been found on inhibitory presynaptic nerve terminals. CB1 is coupled to a G protein.
Interestingly, endocannabinoids have been identified in the CNS.
These compounds, which bind to the CB1 receptors, are membrane-derived and are synthesized on demand, and they may act as local neuromodulators.
The action of THC is believed to be mediated through the CB1 receptors but is still under investigation.
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Mechanism of action:
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Pharmacokinetics:
The effects of THC appear immediately after the drug is smoked, but maximum effects take about 20 minutes. By 3 hours, the effects largely disappear.
Dronabinol is administered orally and has a peak effect in 2 to 4 hours. Its psychoactive effects can last up to 6 hours, but its appetite-stimulant effects may persist for 24 hours.
It is highly lipid soluble and has a large volume of distribution.
THC itself is extensively metabolized by the mixed-function oxidases.
Elimination: is largely through the biliary route.
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Therapeutic uses of Dronabinol
1. as an appetite stimulant for patients with acquired immunodeficiency syndrome who are losing weight.
2. It is also sometimes given for the severe emesis caused by some cancer chemotherapeutic agents.
Adverse effects: include increased heart rate, decreased blood pressure, and reddening of the conjunctiva. At high doses, a toxic psychosis develops.
Tolerance and mild physical dependence occur with continued, frequent use of the drug.
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Rimonabant:
Rimonabant: The CB1-receptor antagonist, 1. Obesity (decrease appetite and body weight in
humans). 2. induce psychiatric disturbances, such as anxiety
and depression, during clinical trials.
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Phencyclidine:
Phencyclidine (also known as PCP, or “angel dust”)
inhibits the reuptake of dopamine, 5-HT, and norepinephrine.
The major action of phencyclidine is to block the ion channel regulated by the NMDA subtype of glutamate receptor. This action prevents the passage of critical ions (particularly Ca2+) through the channel.
Phencyclidine also has anticholinergic activity but, surprisingly, produces hypersalivation.
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Phencyclidine:
Phencyclidine, an analog of ketamine, causes dissociative anesthesia (insensitivity to pain, without loss of consciousness) and analgesia.
At increased dosages, anesthesia, stupor, or coma result, but strangely, the eyes may remain open. Increased sensitivity to external stimuli exists, and the CNS actions may persist for a week.
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CNS STIMULANTS
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Drugs Affecting the CNS
CNS Pharmacology4. Anesthetics
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
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Overview
General anesthesia (GA) is the state produced when a patient receives medications for amnesia, analgesia, muscle paralysis, and sedation. An anesthetized patient can be thought of as being in a controlled, reversible state of unconsciousness. Anesthesia enables a patient to tolerate surgical procedures that would otherwise inflict unbearable pain, potentiate extreme physiologic exacerbations, and result in unpleasant memories.
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Overview
The combination of anesthetic agents used for general anesthesia often leaves a patient with the following clinical constellation:
1. Unarousable even secondary to painful stimuli 2. Unable to remember what happened
(amnesia) 3. Unable to maintain adequate airway
protection and/or spontaneous ventilation as a result of muscle paralysis
4. Cardiovascular changes secondary to stimulant/depressant effects of anesthetic agents
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General anesthesia
General anesthesia uses intravenous and inhaled agents to allow adequate surgical access to the operative site. A point worth noting is that general anesthesia may not always be the best choice; depending on a patient’s clinical presentation, local or regional anesthesia may be more appropriate.
Anesthesia providers are responsible for assessing all factors that influence a patient's medical condition and selecting the optimal anesthetic technique accordingly. Attributes of general anesthesia include the following:
Advantages Reduces intraoperative patient awareness and recall Allows proper muscle relaxation for prolonged periods of time Facilitates complete control of the airway, breathing, and circulation Can be used in cases of sensitivity to local anesthetic agent Can be administered without moving the patient from the supine
position Can be adapted easily to procedures of unpredictable duration or
extent Can be administered rapidly and is reversible
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General anesthesia
Disadvantages Requires increased complexity of care and associated costs
Requires some degree of preoperative patient preparation
Can induce physiologic fluctuations that require active intervention
Associated with less serious complications such as nausea or vomiting, sore throat, headache, shivering, and delayed return to normal mental functioning
Associated with malignant hyperthermia, a rare, inherited muscular condition in which exposure to some (but not all) general anesthetic agents results in acute and potentially lethal temperature rise, hypercarbia, metabolic acidosis, and hyperkalemia
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Drug Classification
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Some Functions of adjuncts to anesthesia
1. Relieve anxiety- Benzodiazepines
2. Relax Muscles- Muscle relaxants 3. Prevention of fluids into the
respiratory tract- Anticholinergics 4. Rapid Induction of anesthesia-
Short acting Barbiturates 5. Prevention of Post Surgical
vomiting- antiemetic drugs
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Ether Operation 1846
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Introduction
General anesthesia includes: Analgesia Amnesia Loss of consciousness Inhibition of sensory and autonomic
reflexes Skeletal muscle relaxation. For the purpose of this lecture, only
commonly used anesthetic drugs will be discussed in details.
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Mechanism of Action
Anesthetics depress activity of neurons in many regions of the brain.
A primary target of many anesthetics is the GABAA receptor channel
Anesthetics directly activate GABAA receptors, but can also facilitate the action of GABA.
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Mechanism of Action Cont’d
Ketamine does not affect GABAA it antagonizes glutamic acid on NMDA receptor.
Inhaled anesthetics also cause membrane hyperpolarization via activation of potassium channels.
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Stages of Anesthesia
1. Analgesia: first analgesia, later analgesia and amnesia.
2. Excitement: delirium, excitement, irregular respiration, vomiting & incontinency.
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Stages of Anesthesia Cont’d
3. Surgical Anesthesia: the recurrence of regular respiration. The most reliable indication is loss of the eyelash reflex and regular respiratory pattern.
4. Medullary Depression: severe depression of the vasomotor and respiratory center.
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
MAC
MAC stands for: Minimum Alveolar Anesthetic Concentration
In steady state, the partial pressure of an inhaled anesthetic in the brain equals that in the lung
MAC is the concentration that results in immobility in 50% of patients when exposed to a noxious stimulus (eg, surgical incision).
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MAC Cont’d
MAC values decrease in elderly patients and with hypothermia, but are not affected by sex, height, and weight.
Presence of adjuvant drugs can reduce MAC dramatically.
Nitrous oxide can be used as a "carrier" gas at 40% of its MAC, decreasing the anesthetic requirement of other inhaled anesthetics to 70% of their MAC
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Equilibrium Dynamics
The rate at which a given concentration of anesthetic in the brain is reached depends on: Solubility properties
Concentration in the inspired air
Pulmonary ventilation
Pulmonary blood flow
Arteriovenous concentration gradient
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Solubility Properties
Blood:gas partition coefficient defines the relative affinity of an anesthetic for the blood compared to air.
The partition coefficients for poorly soluble gases are < 0.5 and for very soluble gases can be more than 10
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Solubility Properties Cont’d
If blood solubility is low, few molecules raise the arterial tension quickly and vice versa
Compounds that are not very soluble in blood, rapidly equilibrate with the brain and have fast onset of action.
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Concentration in Air
It is directly proportionate to the rate of induction of anesthesia by increasing the rate of transfer into the blood.
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Pulmonary Ventilation
The rise of gas tension in arterial blood is directly dependent on both the rate and depth of ventilation.
Increase in ventilation has a slight effect for gases with low blood solubility but significantly increases tension of agents with moderate or high blood solubility.
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Pulmonary Blood Flow
Increase in pulmonary blood flow (increased cardiac output) slows the rate of rise in arterial tension.
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Arteriovenous Concentration Gradient
Pulmonary veins contain less anesthetic than arteries. The greater this difference, the more has been taken up by the body and achievement of equilibrium with the brain is more delayed.
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Elimination
One of the most important factors governing rate of recovery is the blood:gas partition coefficient
Elimination by hyperventilation is limited since the concentration in the lungs cannot be reduced below zero.
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Elimination Cont’d
Gases that are relatively insoluble in blood and brain are eliminated faster.
The duration of exposure to the anesthetic have a marked effect on the time of recovery, especially for more soluble gases.
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Elimination Cont’d
Despite their solubilities, the elimination of halothane is more rapid than enflurane because 40% of halothane versus 10% of enflurane is metabolized.
Sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding "compound A" that causes renal damage if high concentrations are absorbed.
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Elimination Cont’d
In terms of the extent of metabolism of inhaled anesthetics, the rank order is:
Methoxyflurane > Halothane > Enflurane > Sevoflurane > Isoflurane > Desflurane > Nitrous Oxide
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Cardiovascular System
All gases decrease arterial pressure in direct proportion to their alveolar concentration.
Halothane and enflurane reduce cardiac output
Isoflurane, desflurane, and sevoflurane decrease systemic vascular resistance
Bradycardia is often seen with halothane (vagal stimulation).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Cardiovascular System Cont’d
Nitrous oxide in combination with potent gases produces sympathetic stimulation that minimizes cardiac depressant effects.
Halothane & isoflurane sensitize the myocardium to catecholamines. Arrhythmias may occur in patients with cardiac disease who are given sympathomimetics or are anxious.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Respiratory System
All gases are respiratory depressants but it is lessened by surgical stimulation.
Isoflurane and enflurane are the most depressant.
Inhaled anesthetics decrease the ventilatory response to hypoxia.
Concentrations that still exist during recovery depress the increase in ventilation during hypoxia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Respiratory System Cont’d
Inhaled anesthetics are bronchodilators.
Halothane and sevoflurane the anesthetics of choice in patients with airway problems.
The pungency of enflurane may elicit breath holding, which can decrease the speed of induction.
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Nervous System
Most volatile agents decrease cerebral vascular resistance, increase cerebral blood flow and ICP.
It is prudent not to use enflurane in patients with a history of seizure.
Nitrous oxide has analgesic and amnesic actions which in combination with other agents is useful in general and dental anesthesia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Other Systems
Kidney All gases decrease GFR and renal plasma flow
in spite of well-maintained or even increased perfusion pressures
Liver All gases decrease hepatic blood flow from 15%
to 45%.
Uterine smooth muscle The halogenated gases are potent uterine
muscle relaxants. (Useful for intrauterine fetal manipulation or manual extraction of a retained placenta).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity
Hepatotoxicity Hepatotoxicity due to halothane is one in
20,000–35,000. Obese patients having several exposures to halothane are more susceptible.
Nephrotoxicity Metabolism of methoxyflurane releases
nephrotoxic inorganic fluoride so it is obsolete for most purposes.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity Cont’d
Malignant hyperthermia It is an autosomal dominant genetic
disorder of skeletal muscle occurs by inhaled agents and muscle relaxants (eg,succinylcholine).
Consists of: the rapid onset of tachycardia, hypertension, severe muscle rigidity, hyperthermia, hyperkalemia and acidosis
Treatment consists of correction of metabolic disturbances and administration of dantrolene.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Toxicity Cont’d
Reproduction Female operating room personnel have a
higher than expected incidence of miscarriages but the evidence is not strong.
Hematotoxicity Prolonged exposure to nitrous oxide
causes megaloblastic anemia especially in poorly ventilated dental operating suites.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Intravenous Anesthetics
Intravenous anesthetics have an onset of action faster than the fastest of the gaseous agents so they are used for induction of anesthesia.
Consist of: Barbiturates (thiopental, methohexital)
Propofol
Etomidate
Ketamine
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Thiopental
Thiopental can produce loss of consciousness (hypnosis) in one circulation time.
Because of its rapid removal from brain tissue a single dose of thiopental is so short-acting.
Large doses of thiopental decreases blood pressure and cardiac output and depresses respiration
Cerebral blood flow is decreased. (A desirable drug for patients with head trauma or brain tumors)
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Propofol
Its onset of action is similar to thiopental but recovery is more rapid (similar to the shortest-acting inhaled anesthetics).
Postoperative nausea and vomiting is less common because propofol has antiemetic actions.
Because of strong negative inotropic effects, propofol causes a marked decrease in blood pressure and is a respiratory depressant.
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Etomidate
Etomidate causes minimal cardiovascular and respiratory depression.
Etomidate produces a rapid loss of consciousness and rapid recovery (< 5 minutes).
Etomidate causes a high incidence of pain on injection, myoclonus, and postoperative nausea and vomiting.
Etomidate may cause adrenocortical suppression and decrease in hydrocortisone after a single dose.
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Ketamine
Ketamine produces dissociative anesthesia, characterized by: catatonia, amnesia, and analgesia, with or without loss of consciousness.
Ketamine is the only intravenous anesthetic that possesses analgesic properties and produces cardiovascular stimulation.
Ketamine markedly increases cerebral blood flow and intracranial pressure.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Ketamine Cont’d
Ketamine may produce postoperative sensory and perceptual illusions, disorientation and vivid dreams (emergence phenomena).
It is considered useful for poor-risk geriatric patients and in cardiogenic or septic shock.
It is also used in children undergoing painful procedures (eg, dressing changes for burns).
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Adjuvant Drugs
Remifentanil (opioid) has an extremely short duration of action
Fentanyl and droperidol together produce analgesia and amnesia and are used with nitrous oxide to provide neuroleptanesthesia.
Midazolam is frequently given intravenously before induction of general anesthesia because it causes amnesia (> 50%)
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Thank youTwalumba!
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology5. Antidepressant Drugs
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
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Psychopharmacology
L MWEETWA-Pharmacologist
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antidepressants
Introduction If you fail an important examination, lose a loved
one or a job, or get dumped in a relationship, it is normal to feel depressed. But if you remain depressed for more than two weeks, long after the event has passed, then you may have a common clinical disorder calleddepression. Clinical depression, also called major depressive disorder, is characterized by a sad or blue mood that affects nearly every aspect of your life every day – your family and social relationships, your work or school performance, even your desire to do simple things such as exercise or go out with friends.
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Depression Overview
What causes depression? Like most mental disorders, the
causes of depression are largely unknown. Researchers and clinicians theorize that depression is the result of three related factors – biological, psychological and social
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Symptoms of Depression
loss of interest or pleasure in daily activities consistently for at least a 2 week period.
Depressed mood most of the day, as indicated by either the person’s own feeling (e.g., feeling sad or empty) or as observed by others (e.g., appears tearful). (In children and adolescents, this may be characterized as an irritable mood.)
Significant weight loss when not dieting or weight
Can’t sleep (insomnia) or sleeping too much (hypersomnia) psychomotor agitation, Psychomotor retardation Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate guilt
Diminished ability to think or concentrate, or indecisiveness Recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
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Antidepressant Drug Classification
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AD Classification
1) Tricyclics and Tetracyclics (TCA)Imipramine Doxepin Desipramine Amoxepine TrimipramineMaprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
Tranylcypramine Phenelzine Moclobemide
3) Serotonin Selective Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine
Sertraline Paroxetine Citalopram
4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine Duloxetine
5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
Nefazodone Trazodone 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
Bupropion 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
Mirtazapine 8) Noradrenalin Specific Reuptake Inhibitor (NRI)
Reboxetine 9) Serotonin Reuptake Enhancer
Tianeptine
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Mechanism of Action TCA
They inhibit the reuptake of norepinephrine and serotonin almost equally and also inhibit the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity.
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SIDE EFFECTS OF TCA
TCA are effective in treating severe major depression but have the following side effects:-
1. Antimuscarinic effects e.g dry mouth,urinary retention due to blockade of Ach receptors.
2. CV e.g slowing of atrioventricular conduction 3. Othorstatic hypotension and reflex
tachycardia 4. Prominent sedation in early weeks 5. Use with caution in manic Patients as it can
unmask disease
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Mechanism of Action of SSRI
Blocks the reuptake of serotonin selectively at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.
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Side effects of SSRI
1. Nausea 2. Insomnia 3. Anorexia 4. Sexual Dysfunction, loss of libido,
delayed ejaculation and anorgasmia. 5.Weight loss 6. Tremors
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Mechanism of Action of MAO Irreversibly block the action of monoamine oxidase
(MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. MAO are nonselective inhibitors, they bind irreversibly to monoamine oxidase–A (MAO-A) and monoamine oxidase–B (MAO-B). The reduced MAO activity results in an increased concentration of these neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors.
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Side effects of MAO
Used in patients who are unresponsive to/ or allergic to TCA
Side effects are severe and unpredictable:- 1. Tyramine induced side effects, foods such as
aged cheeses, chicken liver,beer and red wine is normally inactivated by MAO in the gut. Individuals receiving MAO inhibitors are unable to degrade tyramine obtained from the diet. Tyramine causes the release of large amounts of stored catecholamine from nerve terminals resulting in headache,tachycardia, Hypertension,cardiac arrhythmias and stroke.
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Side effects of MAO
2. Blurred Vision 3. Dryness of mouth Constipation
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Mechanism of Action of Lithium
The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown. It is possible that Li+ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression. Another mechanism by which.
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Mechanism of Action of Lithium lithium might help to regulate mood include the non-
competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium's action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. GSK-3B has also been implicated in the control of cellular response to damaged DNA. GSK-3 normally phosphorylates beta catenin, which leads to beta catenin degratation. When GSK-3 is inhibited, beta catenin increases and transgenic mice with overexpression of beta catenin express similar behaviour to mice treated with lithium. These results suggest that increase of beta catenin may be a possible pathway for the therapeutic action of lithium
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Side effects of lithium
1. Ataxia 2.Tremors 3. Confusion All the stated side effects are less
common.
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Drugs Affecting the CNS
CNS Pharmacology6. Neuroleptics/AntipsychoticsL.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Schizophrenia
Schizophrenia is a mental disorder characterized by a breakdown of thought processes and by impairedemotional responses.Common symptoms include delusions, such as paranoid beliefs; hallucinations; disorganized thinking; and negative symptoms, such as lack of emotion and lack of motivation. Schizophrenia causes significant social and work problems. Diagnosis is based on observed behaviour and the person's reported experiences
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Schizophrenia
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Causes of Schizophrenia
1. A combination of genetic and environmental factors play a role in the development of schizophrenia ]People with a family history of schizophrenia who have a transient psychosis have a 20–40% chance of being diagnosed one year later.
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Causes of Schizophrenia
Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients:
1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia
IdiopathicBiological Correlates4) Genetic Factors5) Neurodevelopmental abnormalities.6) Environmental stressors.
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Causes of Schizophrenia
4. Substance use About half of those with schizophrenia use drugs
or alcohol excessively, Amphetamine, cocaine 5. Developmental factors Factors such as hypoxia and infection, or stress
and malnutrition in the mother during fetal development, may result in a slight increase in the risk of schizophrenia later in life. People diagnosed with schizophrenia are more likely to have been born in winter or spring (at least in the northern hemisphere), which may be a result of increased rates of viral exposures in utero.
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Definition
Neurosis Abnormal behavior characterized by increased
anxiety, tension and emotionalism
Psychosis Severe psychiatric illness with distortion of
thought and behaviors, capacity to recognized reality and of perception Depression
Depressant
Mental state characterized by depressed mood with feelings of frustration and hopelessness
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Psychotic disorders
1.) Psychoses (a) Schizophenia (split mind)
splitting of perception and interpretation from reality
inability of thinking coherently
(b) Mania Elation, hyperactivity,
uncontrollable thought and speech
maybe associated with violet behaviour
(c) Depression Sadness, guilt, physical and
mental slowing self-destructive ideation
2.) Neuroses (less seriousness)
(a) AnxietyAn unpleasant emotional state associated with uneasiness and concern for the future
(b) Obsessive / Compulsivelimited abnormality of talk or behaviour
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Schizophrenia
One of the psychotic disorders Major disturbances in:
Thought Emotion Behavior
Disordered thinking Faulty perception and attention Inappropriate or flat emotions Bizarre motor activity Disrupted interpersonal relationships
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Schizophrenia
Disorder impacts families & friends Difficult to live with someone who experiences delusions,
hallucinations, and paranoia. Social skills deficits common
▪ Isolation, few social contacts Symptoms impact employability
Often lead to unemployment & homelessness Substance abuse & suicide rates high
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Positive Symptoms: Behavioral excesses
Delusions Firmly held beliefs Contrary to reality Resistant to
disconfirming evidence Persecutory delusions
common▪ “The CIA has planted a
listening device in my head”
Hallucinations Sensory experiences in the
absence of sensory stimulation Types of hallucinations
Audible thoughts Voices commenting Voices arguing
Increased levels of activity in Broca’s area during hallucinations
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Symptoms: Behavioral excesses
Positive Symptoms. Hallucinations, delusions, paranoia, ideas of
reference.
Negative Symptoms. Apathy, social withdrawal, anhedonia, emotional
blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.
These symptoms are progressive and non-responsive to
medication.
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Negative Symptoms: Behavioral deficits
Avolition Lack of interest and drive
Alogia Poverty of speech Poverty of content
Anhendonia Inability to experience pleasure
Flat affect Exhibits little or no affect in face or voice
Asociality Inability to form close personal relationships
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Other Symptoms
Catatonia Motor abnormalities Repetitive, complex gestures
▪ Usually of the fingers or hands Excitable, wild flailing of limbs
Catatonic immobility Maintain unusual posture for long periods of time
▪ e.g., stand on one leg Waxy flexibility
Limbs can be manipulated and posed by another person
Inappropriate affect Emotional responses inconsistent with situation
▪ e.g., laugh uncontrollably at a funeral
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Neuroleptic Drug Classification
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Neuroleptic Drug Classification
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
CLASSIFICATION
A. Typical Antipsychotics: (traditional/older)
1.Phenothiazines:
a. Aliphatic side chain: Chlorpromazine,
Triflupromazine
b. Piperidine side chain: Thioridazine
c. Piperazine side chain: Trifluoperazine,
perphenazine Fluphenazine
2.Butyrophenones: Haloperidol, Trifluperidol, Penfluridol,
droperidol, domperidone
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CLASSIFICATION
3.Thioxanthenes: Flupenthixol 4. Other heterocyclics: Pimozide, Loxapine,
molindone, sulpiride, amisulpiride, penfluridol, Remoxipride, metoclopramide
B. Atypical/newer antipsychotics:: Clozapine,
Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone,
paloparidone
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Traditional Vs. Atypical
Mainly DA Mainly D2 Treat mostly
POSITIVE symptoms
More adverse effects
Less useful in refractory disease
DA and 5HT D2+D4+5HT Treat POSITIVE and
NEGATIVE symptoms
Lesser adverse effects
Useful in refractory disease
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Mechanism of Action:
-Antipsychotic blocks D₂receptors in the brain'sDopaminergic pathway.
-Some also block or partially
block serotonin receptors(particularly 5HT2A, C and5HT1A receptors) -But antipsychotic drugs
can alsoblock wide range of
receptortargets.
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In the Mesolimbic- Mesocortical and Nigrostriatal pathway Antipsychotic blocks:
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In the Tuberoinfundibular pathway Antipsychotics block:
Dopamine released at this site regulates the secretion of prolactinfrom anterior the pituitary gland.Antipsychotics blocks D₂ receptor at this site.
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Antipsychotic blocks D₂ receptors
Some also block or partially block serotonin receptors
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Pharmacology of Antipsychotics:Typical Antipsychotics
Phenothiazine Absorption Concentration Metabolism Vd Dose
Chlorpromazine (CPZ)
More consistent effect in IV and IM administration
Highly bound to plasma and tissue protein
Metabolized in liver by CYP2D6 enzyme
Large 20 L/kg
Acute single dose lasts 6-8 hours t⅟₂ is 18-30 hrs
Triflupromazine More potent than CPZ
-- -- --
Thioridazine Low potency with anticholinergic action
-- -- --
Trifluoperazine, Fluphenazine
High potency with Autonomic action
-- -- -- Depot IM inj every 2-4 weeks (25mg/ml )
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Butyrophenones Potency t⅟₂ Dose
Haloperidol Potent antipsychotic Produces few autonomic effects
24 hours. --
Trifluperidol Similar toHaloperidol but slightly more potent
-- --
Penfluridol Exceptional long acting neuroleptic, used for chronic Schizophrenia, affective withdrawl and social mal-adjustment
-- 20-60 mg , once weekly
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Thioxanthenes
Flupenthixol Less sedative than CPZ, indicated for Schizophrenia and other Psychoses.
Other heterocyclics t⅟₂
Pimozide Specific DA antagonist with little adrenergic or cholinergic blocking activity. Used in Gilles de la Tourett’s syndrome and ticks. Long Duration of action.
48-60 hrs. (after single dose)
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Atypical Antisychotic drugs
These are newer 2nd
Generation antipsychotics
that have weak D₂ receptor
blocking but potent 5-HT₂
antagonistic activity. They
May improve the impaired
Cognitive function inpsychotics.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Atypical Blocking activity Metabolism(Enzyme)
t⅟₂ and Dose
Clozapine A very potent antipsychotic
D₂, D₄, 5HT₂, α receptors
By CYP3A4 t⅟₂ - 12 hours
Risperidone
-- Combination of D₂+5HT₂ , High affinity for α₁, α₂ and H₁ receptors
-- Dose - Low dose <6 mg/day
Olanzapine Potent antipsychotic Broader spectrum of efficacy
Monoaminergic (D₂, 5HT₂, α₁, α₂) as well as muscarinic and H₁ receptors
By CYP1A2 and Glucuronyl transferase
t⅟₂ - 24-30 hours
Quetiapine New short- acting antipsychotic
5HT₁А, 5HT₂, D₂, α₁, α₂ and H₁ receptor
By CYP3A4 --
Aripiprazole
Unique antipsychotic which is partial agonist at D₂ and 5HT₁А
5HT₂ By CYP2D6 and CYP3A4
t⅟₂ - 3days
Ziprasidone Latest antipsychotic , moderately potent inhibitor.
Combination D₂+5HT₂A/₂C +H₁ + α₁,Na reuptake
-- t⅟₂ - 8 hours
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Adverse effects:
On CNS: - Drowsiness - lethargy - mental confusion - seizure. CVS: - Postural hypotension - palpitation - arrythmia in elderly Anticholinergic: - Dry mouth - blurring of vision - constipation - urinary
inconsistency
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Endocrine: - Hyperprolactinemia - amenorrhoea - infertility - gelactorrhoea and gynaecomastia. Extrapyramidal disorders: - Parkinsonism - Acute muscular
dystonias - Akathisia - Malignant Neuroleptic
Syndrome - Tardive dyskinesia Miscellaneous: - Weight gain - Blood sugar – lipid rise - worsening of diabetes.
Adverse effects:
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
DRUG TREATMENT OF PSYCHOSIS
To understand the management of schizophrenia its important to understand the etiology of the disease.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Psychosis Producing Drugs
Drugs inducing psychosis1) Levodopa2) CNS stimulants
a) Cocaine b) Amphetaminesc) Khat, cathinone, methcathinone
3) Apomorphine 4) Phencyclidine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Etiology of Schizophrenia
Idiopathic
Biological Correlates1) Genetic Factors2) Neurodevelopmental
abnormalities.3) Environmental stressors.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Etiology of Schizophrenia
Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients:
1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine Theory of Schizophrenia
Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine Theory of Schizophrenia
Dopamine Correlates:• Antipsychotics reduce dopamine synaptic activity.• These drugs produce Parkinson-like symptoms.• Drugs that increase DA in the limbic system cause
psychosis.• Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.• Increased DA receptor density (Post-mortem, PET).• Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine Theory of Schizophrenia
Evidence against the hypothesis Antipsychotics are only partially effective in
most (70%) and ineffective for some patients.
Phencyclidine, an NMDA receptor antagonist, produces more schizophrenia-like symptoms in non-schizophrenic subjects than DA agonists.
Atypical antipsychotics have low affinity for D2 receptors.
Focus is broader now and research is geared to produce drugs with less extrapyramidal effects.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine System
There are four major pathways for the dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway.II. The Mesolimbic Pathway.III. The Mesocortical Pathway.IV. The Tuberoinfundibular Pathway.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
THE DOPAMINERGIC SYSTEM
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Catecholamines
Tyrosine Tyrosine hydroxylase
L-Dopa Dopa decarboxylase
Dopamine (DA) Dopamine hydroxylase
Norepinephrine (NE)(Noradrenaline)
Phenylethanolamine-
-N-methyltransferase
Epinephrine (EPI)(Adrenaline)
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine System
DOPAMINE RECEPTORS
There are at least five subtypes of receptors:ReceptorD1D2D3D4D5
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dopamine Reuptake System
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic treatments
Schizophrenia has been around perhaps, since the beginning of humankind, however, it was not until the last century that it was established as a separate entity amongst other mental disorders.
Many treatments have been devise:
Hydrotherapy: “The pouring of cold water in a stream, from a height of at least four feet onto the forehead, is one of the most certain means of subsiding violent, maniacal excitement that we have ever seen tried”... wrote an anonymous physician in the early 1800’s.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic treatments
Lobotomies (Egaz Moniz received the Nobel Prize).
In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.
In 1955, chlorpromazine was developed as an antihistaminic agent by Rhône-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics treatment
Antipsychotics/Neuroleptics Antipsychotics are the drugs currently
used in the prevention of psychosis. They have also been termed neuroleptics,
because they suppress motor activity and emotionality.
** These drugs are not a cure ** Schizophrenics must be treated with
medications indefinitely, in as much as the disease in lifelong and it is preferable to prevent the psychotic episodes than to treat them.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs used mainly in the treatment of schizophrenia, they are also used in the treatment of other psychoses associated with depression and manic-depressive illness, and psychosis associated with Alzheimer’s disease. These conditions are life-long and disabling.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Three major groups :1) Phenothiazines2) Thioxanthines
3) Butyrophenones
OLDER DRUGS
Antipsychotics/Neuroleptics
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
Old antiphsychotics /neuroleptics are D2 dopamine receptor antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
dopaminereceptorantagonist
D2
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.
The affinities of most older “classical” agents for the D2 receptors correlate with their clinical potencies as antipsychotics.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens.
Clozapine has a higher affinity for the D4 receptors than for D2.
Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
Antipsychotics produce catalepsy (reduce motor activity).
BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behavior).
BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.
BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PharmacokineticsAbsorption and
Distribution Most antipsychotics are readily but incompletely absorbed.
Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-
98%). High volumes of distribution (>7 L/Kg). Slow elimination.**Duration of action longer than expected,
metabolites are present and relapse occurs, weeks after discontinuation of drug.**
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics
Metabolism
Most antipsychotics are almost completely metabolized.
Most have active metabolites, although not important in therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pharmacokinetics
Excretion
Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.
Elimination half-lives are 10-24 hrs.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
1) Phenothiazines
Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine
Mesoridazine AcetophenazineCarphenazineProchlorperazineTrifluoperazine
Aliphatic Piperidine Piperazine*
* Most likely to cause extrapyramidal effects.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
[Drug dose]
Eff
ect
Piperazine
Aliphatic
Piperidine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
2) ThioxanthinesThiothixeneChlorprothixene
Closely related to phenothiazines
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
3) ButyrophenonesHaloperidolDroperidol
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
[Drug dose]
Eff
ect
Phenothiazine d.
Thioxanthene d.
Butyrophenone d.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
Newer drugs have higher affinities for D1, 5-HT or -AR receptors.
NE, GABA, Glycine and Glutamate have also been implicated in schizophrenia.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.
Blockade of D2 receptors
Short term/Compensatory effects:Ý Firing rate and activity of nigrostriatal
and mesolimbic DA neurons.Ý DA synthesis, DA metabolism, DA release
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotics/Neuroleptics
Presynaptic EffectsBlockade of D2 receptors
Compensatory Effects
Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.
Ý DA synthesis, DA metabolism, DA release.
Postsynaptic EffectsDepolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Receptor Supersensitivity
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
PimozideMolindoneLoxapineClozapine
OlanzapineQetiapine
RisperidoneSertindole
ZiprasidoneOlindone
Newer Drugs
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Clinical Ex. Py.Drug Potency toxicity Sedation
Hypote.Chlorpromaz. Low Medium MediumHighHaloperidol High Very High Very High LowThiothixene High Medium Medium MediumClozapine Medium Very low Low MediumZiprasidone Medium Very Low Low Very lowRisperidone High Low Low LowOlanzapine High Very Low Medium Very lowSertindole High Very Low Very low Very Low
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2
>H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1
= 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect2) Significant toxicity
a) Parkinson-like symptomsb) Tardive Dyskinesia (10-30%)c) Autonomic effectsd) Endocrine effectse) Cardiac effects
3) Poor Concentration
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Some antipsychotics have effects at muscarinic acetylcholine receptors:
▪ dry mouth▪ blurred vision▪ urinary retention▪ constipation
ClozapineChlorpromazine
Thioridazine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Some antipsychotics have effects at -aadrenergic receptors:
• orthostatic hypotension
ChlorpromazineThioridazine
Some antipsychotics have effects at H1-histaminergic receptors:
• sedation
RisperidoneHaloperidol
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic (antipsychotic) therapy that can be lethal. It can arise at any time in the course of treatment and shows no predilection for age, duration of treatment, antipsychotic medication, or dose.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome Occurs in pts. hypersensitive to the Ex.Py. effects
of antipsychotics. Due to excessively rapid blockade of postsynaptic
dopamine receptors. The syndrome begins with marked muscle rigidity. If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with this syndrome may be mistaken for an infection.
Autonomic instability with altered blood pressure and heart rate is another midbrain manifestation.
Creatine kinase isozymes are usually elevated, reflecting muscle damage.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment Vigorous treatment with antiparkinsonian
drugs is recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antipsychotic/Neuroleptics
Drug Interactions Additive effects with sedatives. Additive effects with anticholinergics. Additive effects with
antihistaminergics. Additive effects with -AR blocking
drugs. Additive effects with drugs with
quinidine-like action (thioridazine).
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
THANK YOU
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology7. Antiepileptic Drugs
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
ANTISEIZURE DRUGS
Antiepileptic drugs
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Epilepsy
Chronic disorder characterized by recurrent seizures
Seizures is a sudden, excessive, abnormal discharge of cerebral neurons
Causes of seizures Heredity – major contributing factor may occur due to infection, neoplasm or head
injury Environmental causes-alteration in blood gases,
pH, electrolytes, or glucose availability
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Seizure classified into two broad groups
Partial: simple or complex
Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PARTIAL SEIZURES
Simple partial seizures (without loss of consciousness) confined to a single locus in brain abnormal activity in one limb or muscles With autonomic symptoms (nausea, blood
pressure changes,...)
Complex partial seizures (with loss of consciousness) Simple partial followed by a loss of
consciousness Impaired consciousness from the onset Exhibits complex sensory hallucination Motor dysfunction may involve chewing
movements, diarrhea or urination
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Generalized seizures
Electrical discharge spread to both hemisphere
May be convulsive (shaken repeatedly) or non convulsive
Immediate loss of consciousness occurs Types
generalized tonic-clonic (grand mal) seizures
absence (petit mal) seizurestonic seizuresatonic seizuresclonic and myoclonic seizuresfebrile seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Seizures
Partial Seizures localized onset of attack ascertained, either by clinical observation or by EEG – attack begins in a specific locus in brain
Simple Partial seizures – least complicated, characterized by minimal spread of abnormal discharge, normal consciousness and awareness are preserved – pt may have a sudden onset of clonic jerking of an extremity lasting 60-90 secs; residual weakness lasts for 15-30 mins after attack.
Pt completely aware of attack, can describe it in detailEEG may show an abnormal discharge highly localized to the involved portion of brain
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Seizures
Complex Partial seizures – localized onset, discharge becomes more widespread (usually bilateral) and almost always involves limbic systemmost (not all) CPS arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia or infection
Clinically, pt may have a brief warning followed by an alteration of consciousness during which some pts may stare and others may stagger or even fallMore, however, demonstrate fragments of integrated motor behavior called automatisms for which pt has no memoryafter 30-120 secs, pt makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after attack
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Generalized Seizures Tonic-clonic seizures
characterized by tonic phase continuous rigidity of all
extremities
clonic phase massive jerking of body ( rapid contraction and relaxation)
Tongue or cheek bitten, urinary incontinence common
Seizure followed by period of confusion and exhaustion due to depletion of energy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Absence seizure (petit mal)
Typical absence seizures consists of staring for a few seconds (altered consciousness) then returning to full function, as if nothing occurred
Brief duration (< 10 secs) ass with mild clonic jerking of eyelids,
patient stares & exhibit rapid eye blinking
begin in childhood or adolescence and may occur up to hundreds of times a day
The patient has no recollection of the event.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Myoclonic seizures
Myoclonic jerking – seen in generalized tonic-clonic seizures, partial seizure, absence seizures, and infantile spasms
Short episode of muscle contractions
Occurs due to permanent nurologic damage due to hypoxia, uremia, encephalitis or drug poisoning
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Atonic seizures
sudden loss of postural tone, if standing pt falls suddenly and may be injured, if seated, may suddenly drop forward
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Infantile spasms
characterized clinically by brief recurrent myoclonic jerks of body with sudden flexion or extension of the body and limbs
90% of affected pts have their 1st attack before age of 1 yr
Most pts mentally retarded cause infection, kernicterus and
hypoglycemia
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Febrile fits
Frequently occurs in young children (6 months- 6 yrs) during high grade fever
Characterized by tonic clonic convulsions of short duration (1 to 5 min), eye rolling & unresponsiveness
Benign, do not cause death, nurologic damage, injury, or learning disorder
Status epilepticus Continuous, rapid, recurrent seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antiepileptic drugs
Primary drugs Phenytoin Carbamazepine Clonazepam (BZ) Clorazepate (BZ) Diazepam (BZ) Ethosuximide Lorazepam (BZ) Phenobarbital Primidone Valproic acid
Adjunct drugs Fel bamate Gaba pentin Lamo trigine Leve tira cetam Tiaga bine Topira mate Zoni samide Viga batrin
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pathophysiology of Seizures
Increased CNS excitability
Membrane depolarization Increased excitatory input Decreased inhibitory (GABA) input
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Strategies in Treatment
Stabilize membrane by blockade of voltage gated channels (Na & Ca) prevent depolarization by action on ion channels
Increase GABAergic transmission
Decrease Excitatory glutamate transmission
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Classification of Anticonvulsants
Action on Ion Channels
Enhance GABATransmission
Inhibit glutamateTransmission
Na+: Phenytoin, Carbamazepine, LamotrigineTopiramateValproic acidCa++: EthosuximideValproic acid
Benzodiazepines BarbituratesValproic acid GabapentinVigabatrinTopiramateFelbamate
FelbamateTopiramate
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenytoin
Diphenylhydantoin – oldest antiseizure drug
Mechanism of action. Blocks voltage gated Na+ channels in
inactive state, slows recovery blocks repetitive firing of action potentials,
promotes stabilization of membrane, reduce propagation of abnormal impulse in brain
At higher dose blocks Ca 2+ conductance Interfere with release of neurotransmitters
norepinephrine, acetylcholine Produces drowsiness and lethargy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenytoin /Clinical use
Highly effective in Partial seizures (simple and complex) Tonic-clonic seizures Status epilepticus Arrhythmia
Not effective in absence seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenytoin /Adverse effects
Depression of CNS Sedation, Nystagmus, diplopia and ataxia, confusion & hallucination
Reversible Gingival hyperplasia and hirsutism
GIT nausea & vomitingLong term use Coarsening of facial features occurs in
children Mild peripheral neuropathy deep
tendon reflexes in lower extremities Osteomalacia due to abnormalities of
vitamin D metabolism
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenytoin /Adverse effects
Megaloblastic anemia due to folate deficiency
Inhibition of antidiuretic hormone secretion
Hyperglycemia and glycosuria insulin secretion
Teratogenic effects fetal hydantoin syndrome includes cleft lip, cleft palate, congenital heart disease, growth retardation and mental deficiency
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenytoin/ Drug Interactions
Phenytoin metabolism decrease by Cimetidine, isoniazid, Chloramphenicol, dicumarol, sulfonamide
Phenytoin metabolism increase by Carbamazepine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Carbamazepine
M.O.A By blocks sodium channels reduce the
propagation of abnormal impulses inhibits high-frequency repetitive firing in
neurons decrease synaptic transmission, inhibits
uptake and release of NE from brain postsynaptic action of GABA
potentiated
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Carbamazepine /Clinical use
Drug of choice in all partial seizures Highly effective in tonic–clonic
seizures Trigeminal neuralgia Use in Manic depressive patient to
decrease the symptoms
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Carbamazepine Adverse effects
Respiratory depression Drowsiness, vertigo, diplopia, blurred
vision, ataxia & coma Irritating to stomach n & v may occurs Serious liver toxicity hyponatremia and water intoxication Idiosyncratic blood dyscrasias,including
fatal cases of aplastic anemia and agranulocytosis
Is an enzyme inducer
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs inhibiting metabolism of Carbamazepine
Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenobarbital
clinically useful as antiseizure drugs phenobarbital, mephobarbital, metharbital,
Mechanism of Action Elevate seizure threshold Limits the spread of seizure discharge in
brain Binds to a regulatory site on GABA
receptor, prolonging the openings of Cl- channels
Blocks excitatory responses induced by glutamate
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenobarbital/ clinical uses
Doc in children with febrile fits Effective in simple partial seizuresRecurrent tonic clonic seizuresRelieve anxiety insomnia
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Phenobarbital adverse effects
Sedation Ataxia Nystagmus Vertigo N &v Morbilliform rash (measles like) Agitation & confusion Rebound seizures can occur on
discontinuation of drug
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Primidone
2-deoxyphenobarbital Metabolized to Phenobarbital and
phenyl-ethyl-malonamide All 3 are active anticonvulsants M.O.A. – similar to Phenobarbital Effective against partial and tonic
clonic seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Valproic acid
Drug of choice for myoclonic seizures Effective in tonic clonic & absence
seizures Block sodium channels & enhance
GABAergic transmission Adverse effects N, V, ataxia,
sedation, tremors, rash & alopecia
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Ethosuximide
Inhibit T-type calcium channels in brain reduce propagation of abnormal electrical activity
First choice in absence seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Benzodiazepines
Benzodiazepines are safest antiepileptic drugs
Clonazepam use for chronic treatment of absence & myoclonic seizures
Chlorazepate effective in partial seizures Diazepam & lorazepam drug of choice
in acute treatment of status epilepticus (interrupt repeated seizures)
A/E sedation, drowsiness, fatigue, ataxia, respiratory and cardiac depression
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Adjunct antiepileptic drugs
Newer agents Use as add on therapy in refractory
epilepsies Also effective as monotherapy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Lamotrigine
M.O.A. –blocks sodium channels, voltage activated calcium channels & decreased synaptic release of glutamate
Add on therapy, monotherapy for partial seizures, absence and myoclonic seizures in children
Dizziness, headache, diplopia, nausea, somnolence, and skin rash – potentially life-threatening dermatitis develops in 1-2% of pediatric pts
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Felbamate
Broad spectrum Use only in refractory cases (may
cause aplastic anemia & hepatic failure)
block sodium channels & inhibits glycin & glutamate transmission
Effective in partial seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Gabapentin
Amino acid, analog of GABA, effective against partial seizures
M.O.A. – in spite of its close structural relationship to GABA, it appears not to act on GABA receptors, interfere with voltage gated calcium channels
Used in Partial and G tonic clonic seizures, diabetic neuropathic pain, postherpetic neuroralgia in adults
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
To-pira-mate
Effective in refectory partial and secondary generalized seizures
M.O.A. Blocks voltage dependent sodium
channels Potentiate inhibitory effect of GABA,
acting at a site different from BNZs or barbs
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Ti-aga-bine
M.O.A. – inhibitor of GABA uptake Prolongs inhibitory action of synaptically
released GABA Indicated for adjunctive treatment of
partial seizures
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Zonisamide
Primary site of action is on sodium channel
Also act on voltage dependent calcium channels
Effective against partial and G tonic clonic seizures, also against infantile spasms and certain myoclonias
S/E – drowsiness, cognitive impairment, serious skin rashes
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Levetiracetam
M.O.A. – unknown Effective for the treatment of
refectory partial seizures S/E – somnolence, asthenia,
dizziness
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Acetazolamide
Inhibits carbonic anhydrase Mild acidosis in brain – mech by
which drug exerts its antiseizure activity
Used for all types of seizures Use severely limited by rapid
development of tolerance usually within weeks
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Drugs Affecting the CNS
CNS Pharmacology7. Opioid Analgesics and
Antiepileptic DrugsL.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Opioid Analgesics
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
INTRODUCTION
Analgesics are medications used to relieve pain without reducing the consciousness of the patient.
They work by reducing the amount of pain felt and this is generally achieved by interfering with the way the pain message is transmitted by the nerves. Analgesics will not treat the cause of the pain but they will provide temporary relief from pain symptoms.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Types of Opioid Analgesics
• OPIOID
ANALGESICS
• NON - OPIOID
ANALAGESCIS
• ADJUVANT
ANALGESICS
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
OPIOID ANALGESICS
The opioid analgesics which are prescription only medicines that are very potent, being chemically related to morphine.
Opioid analgesics are prescribed for moderate to severe pain, particularly of visceral origin, and are used in step two and step three of the analgesic ladder.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dependence and tolerance are well known features with regular use although this should not inhibit prescribing in palliative care.
Some chronic non-malignant conditions benefit from analgesic control with opioids, but patients should be reviewed regularly.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
OPIUM, the greek name for poppy juice. Is obtained from the juice of the papaver somniferum.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
ACTIONS OF OPIOID ANALGESICS
Opioid analgesics interacts with four major receptors in the CNS
Mu receptorsKappa receptorsSigma receptors and Delta receptors
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
RECEPTORS EFFECTS
MU Analgesia, Respiratory depression and euphoria
KAPPA Respiratory depression, sedation
SEGMA Hallucination, Dysphoria, Seizures
DELTA Analgesia
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
CLASSIFICATION OF OPIOID ANALGESICS
Natural Alkaloids Morphine CodeineSemi Synthetic Compounds Pethidine Methadone TramadolMixed Agonist-Antagonists
PentazocineBuprenorphine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
MORPHINE
Morphine is the most important alkaloid of of opium.
Morphine produces analgesia through actions in the brain and spinal cord.
Morphine is readily absorbed from the GI tract and subcutaneous and muscle tissue.
Morphine is administered intravenously, epidurally, and intrathecally.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PHARMACOTHERAPEUTICS
Morphine sulfate is primarily used to relieve moderate to severe pain.
It is used pre operatively, its effect is on reducing patients anxiety and in assisting in induction of anesthesia.
It is the drug of choice for clients with pain from MI, Pulmonary edema and dyspnea from acute left ventricular failure.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PHARMACOKINETICS
Absorption• It depends on the route of
administration,• Morphine ingested orally is
generally absorbed in one and half to two hours.
• It reaches liver for metabolism before reaching systemic circulation.
• Absorption after IM or SC injection occurs in 30 to 60 minutes.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PHARMACOKINETICS
Distribution• It occurs quickly.,• After administration morphine
leaves the blood and directly enters the kidney, lungs, liver and spleen.
• Its action on skeletal muscle is limited, since the drug is not very lipid soluble, it does not cross the BBB easily
• .
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
DURATION OF ACTION
METHOD OF ADMINISTRATION ONSET OF ACTION
Oral 4 to 12 hours
IM or SC 10 to 30 minutes
IV 15 to 30 minutes
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PHARMACOKINETICS
BIOTRANSFORMATION• It occurs in the liver.• Excretion occurs in the kidney.
• Only traces of morphine is founded in body after 48 hours..
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
PHARMACODYNAMICS
Morphine produces analgesia by binding preferentially to the mu and delta receptors.
Morphine targets the areas involved with regulation of pain perception, respiration and affective behaviors.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
THERAPEUTIC USES
AnalgesiaSuppression of cough and
dyspnea.Sedation In the treatment of diarrheaAs preanesthetic medication In the treatment of the left
ventricular failure.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
CONTRAINDICATIONS
Head Injury, because morphine can cause increased intracranial tension, which can leads to marked respirator depression.
Myxedema Bronchial asthma – Morphine releases
histamine which can trigger bronchoconstriction.
Elderly patients In hypotensive states.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
ADVERSE REACTIONS
CNS Side effectsConfusion, anxiety, lethargy, nausea
and vomiting.GIT Side effectsConstipationOther Side effectsUrinary retention, dry mouth,
dysphoria, hypotension, skin rash, itching and urticaria.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
MORPHINE POISONING
Acute poisoning with morphine and other opioids occurs with overdoses.
Signs and SymptomsComa, Pinpoint pupils, and respiratory depression which frequently called triad.
TREATMENTAdministration of antagonist
Naloxone,NaltrexoneSupport of Respiratory and Cardio
Vascular function.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
END
Thank YOU
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dugs Affecting the CNS
CNS Pharmacology9. Alzheimer's Disease
L.Mweetwa-Pharmacologist
University of Zambia Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
What is Alzheimer’s?
Alzheimer's is the most common form of dementia. It is a neurodegenerative disease that occurs in the
brain. Alzheimer’s disease causes a deterioration in the brain
by destroying the nerve cells. Once the nerve cells begin to deteriorate it causes a reduction of responses to other nerve cells.
The condition spreads out causing chemical interruptions, the transmission of impulses is slow, and finally tissues in the brain begin to get worse.
In Alzheimer’s disease, nerve cells in the brain die gradually. This makes it increasingly difficult for your brain’s signals to be sent properly.
There are 7 stages of Alzheimer's
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
How you get the disease?
They still don’t know how the Alzheimer’s disease process begins, it seems likely that damage to the brain starts a decade or more before problems become evident.
People who have relatives with Alzheimer’s have a higher risk than the general population for developing the disease.
People who have a parent or sibling with Alzheimer's disease are 3.5 times as likely to develop it.
This strong tendency of Alzheimer's disease to run in families is due, in part, to mutations in certain genes.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Where does AD affect
Alzheimer’s affects the brain. Alzheimer's causes neurons to die which causes the
brain to shrink. This leads to a loss of functioning capabilities in almost all parts of brain, not just the ones that affect memory.
This leads to the formation of clumps and tangles within the brain and eventually leads to death.
When you have Alzheimer’s the cerebral cortex shrinks massively. The cerebral cortex is the outer surface of the brain and it is responsible for all intellectual functioning.
The spaces in the folds of the brain (the sulci) are grossly enlarged.
You cannot catch or spread Alzheimer’s
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Normal Brain Alzheimer’s Brain
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
When do you get Alzheimer's?
Alzheimer’s disease can occur at any age, even as young as 40 years, but its occurrence is much more common as the years go by
Early Alzheimer's starts at 65 years of age or younger. Late Alzheimer's starts after age 65
One in ten people over 65 years of age suffer from the disease, and over half the people over 85 have Alzheimer’s disease.
At first the symptoms are difficult to recognise. In the first 2 stages of Alzheimer's you cannot
recognise that you have it. Often it is difficult to pinpoint when the Alzheimer’s
disease actually began in a person.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Symptoms of Alzheimer's
Short term memory loss – forgetting recent events, names and places
Difficulty performing familiar tasks Disorientation especially away from your normal
surroundings Increasing problems with planning and managing Trouble with language Rapid, unpredictable mood swings Lack of motivation Changes in sleep and confusion about the time of
day Reduced judgement e.g. being unaware of danger
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
7 stages of Alzheimer’s
Stage 1: Normal Stage 2: Normal aged
forgetfulness Stage 3: Mild cognitive impairment Stage 4: Mild Alzheimer’s Stage 5: Moderate Alzheimer’s
disease Stage 6: Moderately severe
Alzheimer's disease Stage 7: Severe Alzheimer's
disease
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Cure and Treatment for Alzheimer’s
Currently there is no cure for Alzheimer’s. However there are several drugs that may be prescribed to help people with Alzheimer’s. They are not a cure, but can help with some of the symptoms of the disease.
Drugs such as donepezil (Aricept), rivastigmine (Exelon), and galantamine which is a competitive acetylcholinesterase inhibitor (Reminyl) are used to treat symptoms in Alzheimer's disease.
Antidepressants, anti-anxiety medications, and antipsychotics are used to treat the symptoms of depression, anxiety, agitation, and the hallucinations and delusions that may occur in Alzheimer's disease patients
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Risk Factors for Alzheimer’s disease
Age Family history Lifestyle Physical exercise Mental exercise Diet Tobacco Head injury Hypertension Elevated serum cholesterol Elevated serum homocysteine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Pathophysiology
Beta amyloid plaques
Neurofibrillary tangles (NFT)
Amyloid formed from APP (amyloid precursor
protein) by secretase NFT - silver stained fibrils of
abnormally phosporylated Tau protein
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Biochemical changes
Decrease in cortical level of Acetyl choline,choline acetyl transferances,nicotinic receptors
Degeneration of cholinergic neurons in nucleus basalis of Meynert.
Degenertion of loculus ceruleus & dorsal raphe
- noradrenergic & serotonergic depletion
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Cascade of mechanism
Amyloid
inflammation abnormal tau phosphorylation
free radical toxicity
synaptic loss
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Cascade of mechanism
cholinergic dysfunction
neuronal loss
norepinephrine dysfunction
serotonergic dysfunction
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Current Treatment
Symptomatic - Cognitive
- Behavioral
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Treatment of mild-moderate AD
Choline esterase inhibitors - Donepezil - Rivastigmine - Galantamine
Improves cognition & daily activities
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Treatment of severe AD
NMDA antagonists - Memantine
Slows intracellular Ca accumulation and delay nerve damage
Used in combination with Donepazil
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dosage
Donepezil – 5mg/day x 4-6 wks,then 10mg/d to max.tolerated dose. min dose-5mg/d
Rivastigmine – 1.5mg bd,then step up monthly to 6mg bd(max). min.dose-6mg/
Galantamine- 8mg/d,monthly increase to 16mg/d 24 mg/d (max). min dose- 16mg/d Memantine – 5mg daily,in a week then 5mg Bd 15mg/d- (5 & 10), max dose-10mg
bd
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Current available therapy
characteristic
DONEPAZIL RIVASTIGMINE
GALANTAMINE
MEMANTINE
Chemical class
piperidine carbamate phenanthrenealkaloid
Similar to amantadine
Primary mechanism
AchE inh AchE inh AchE inh NMDA antagonist
Other mechanism
None
None Nicotine modulator
HT3 receptor antagonist
Half life 70 h 90 min 7 h 70 h
Metabolism Hepatic Renal Hepatic Hepatic
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Current status of AChE Inhibitors
Effective in 6 month & 12 month trials
Early initiation of therapy Delay institutionalization Decrease troublesome behaviours
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Treatment of secondary symptoms
Behavioural intervention Neuroleptic agents - FDA in 2005 black box warning for atypical neuroleptics - 2008 ,
haloperidol,chlorpromazine, thioridazine included -CATIE-AD study showed cognitive decline with atypical neuroleptics -recommended in low doses in frail, elderly
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Treatment
Antidepressants & mood stabilizers -citalopram ( Nyth et al study) - 20 mg /day in elderly ,max-40mg - sertaline & fluvoxetine – no benefits (Wintraub & Petrecca et al study) - mirtazipine has no benefial effect ( Banerjee et al) Anticonvulsants - gabapentin,valproate can be used
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Anti amyloid therapy - vaccination with amyloid species - monoclonal anti amyloid antibodies - IVIG containing amyloid binding
antiboies - selective amyloid lowering agents - chelators of amyloid polymerization - beta secretase inhibitors
Till date no phase 3 trials for anti amyloid therapy shown acceptable efficacy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Vaccination
Anti Abeta immunotherapy reduces amyloid deposition and improved spatial cognition in mice
Clinical trial in 298 patients with AD:18 developed inflammatory meningoencephalitis: study halted
Autopsy in one: “less amyloid than expected”
Orgogozo J-M et al Neurology 2003;61:46 Mathews P & Nixon R Neurology 2003;61:7
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Vaccination
In subgroup of 30 patients, those who generated Abeta antibodies had reduced disease progression
Attempts being made to reformulate vaccine
Passive immunization considered
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antibiotics for AD
Higher than normal titres of Chlamydia in people with AD
Multicentre Canadian double blind placebo controlled RCT
101 patients with mild to moderate AD (MMSE 11-25)
Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Antibiotics for AD
Standardized ADAS Cog @ 6 months difference of 2.75/70 between treated and placebo group (significant @ 6 but not 12 months)
Standardized MMSE score 2.2/30 higher @12 (but not 3 or 6) months
Intriguing results! Larger study in planning stages
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Secretase inhibitors
Inhibit production of Amyloid Tarenflurbil and Semagacestat. Two placebo controlled trials showed
no efficacy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Reversal of excess Tau phosphoryation Free radical scavengers - vitamin E – reduce oxidative stress - high dose Vit E (2000U/day) for 2 yr slowed progression of AD ( large double blind placebo trial ,Sano etal 1997) - Alzheimer Disease Cooperative Study ( 769
pts) showed no benefit vs placebo (Peterson etal
2005) - cause cardiovascular side effects - not recommended currently
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Estrogen replacement therapy - postmenopausal woman - RCT with 351 pts for 2 weeks showed no beneficial effects
Cholesterol lowering agents -no beneficial effects - RCT,double blinded study with 748 pts for 6 months failed to prove efficacy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Lipid lowering and AD
Previous observations suggested lower risk of AD in those taking “statins”
Recently presented at 8th International Symposium on Advances in AD therapy
Atorvostatin treatment associated with less decline in memory, function, mood & behaviour in people with AD
Premature to decide until full details available in peer reviewed publication
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Ongoing trials
Tramiprosate (Alzhemed) - homotaurine - binds to soluble & insoluble Abeta
and in reduction - protect against amyloid neurotoxicity - reduce tau abnormal phosphorylation
RCT, double blind,placebo conrolled trial (2009)
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Cerebrolysin - peptidergic drug from purified pig brain - neurotrophic & neuroprotective
RCT,double blind, placebo controlled trial (2010)
Latreperidine(Dimebom) - anti histamine - inhibit burylcholine esterase, AchE, NMDA signalling pathway RCT, phase 3 trial ongoing ( jan 2011)
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Clincal trials - completed
Selegelline RCT trial conducted in 2010 failed to give promising results Nimodipine - prevent Ca accumulation in neurons - cause vasodilation - RCT in March 2010 in 500 pts showed positive results - given 90mg/d & 180mg/d for 12,24,52
weeks - improves cognition & global impression
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Metal protein attenuating compound(MPAC) (clinoquinol) - solubilize & clearance of Abeta - RCT,double blind study with 36 pts has no change in ADAS Cog @ 36
wks. Mertrifonate - irreversible AchE inhibitor - RCT, double blinded phase 3 study - 60-80mg/d for 26 weeks showed
improvement MMSE-1.86/30 & ADASCog- 3.24/70
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Lecithin - major source of choline - RCT,double blind placebo
controlled study failed to show efficacy
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Huperzine A from chinese club moss
Huperzia serrata reversible AchE inhibitor RCT, double blinded
Chinese study with 482 pts showed
improvement in MMSE-2.8/30 & ADASCog -
1.91/70 @ 6 wks
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Transcutaneous electrical nerve stimulation
(TENS) - change neurotransmitters,help
in neuro regeneration - 3 RCT in Netherland & Japan - duration,waveform,current
amplitude, - data limilted ,shows little
improvement
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Stem cell therapy
South Florida university with Cryo- cell International
Mouse model study in 2009 Several infusions of stem cells from
umblical cord Myeloid protein reduced by 62% Cerebral amyloid angiopathy by 82% Hope to begin human trials by 2014.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Experimental Therapy
Neural growth factor (NGF) -Injecting into spinal cord - trials going to formulate oral
preperation - still on pipe line.
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Dietary measures
No special diet for AD
Axona (caprylidine) improves cognition
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Prevention of ad
Omega 3 fatty acids - French study(2005) showed
decrease in risk of AD in elderly > 60 yr - 2 RCT double blinded studies are
ongoing Mediterranean diet Light to moderate alcohol -Finnish study showed no
beneficial effects
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Who are the AD Caregivers?
• Spouses – the largest group. Most are older with their own health problems.
• Daughters – the second largest group. Called the “sandwich generation,” many are married and raising children of their own. Children may need extra support if a parent’s attention is focused on caregiving.
• Grandchildren – may become major helpers.
• Daughters-in-law – the third largest group.
• Sons – often focus on the financial, legal, and business aspects of caregiving.
• Brothers and Sisters – many are older with their own health problems.
• Others-friends,relatives
Support for Caregivers
Slide 37
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Technology and Caregiving
The NIA is studying how computers can provide information and support to family caregivers through:
These features have become very popular among users because they reach many people at once, are private and convenient, and are available around the clock.
• computer-based bulletin boards• chat rooms• Q & A modules• medical advice forums
Support for Caregivers
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
conclusion
Most common dementing disease worldwide
Pschyco-social,economic burden Current therapy is symptomatic and
limited New clinical trials & treatment
approaches on pipeline Social support for caregivers &
alzheimer support societies .
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
Thank You….