Introduction (review)
5 key features of neurotransmitter function, which
can be targets for pharmacotherapy
Synthesis
Storage
Release
Termination of action
Receptor effects
Sympathetic agents
MOA
Direct acting
Directly stimulate the receptor
Indirect acting
Displace/release stored catecholamines from the nerve (ex.
tyramine)
Decrease clearance of NE by
Inhibiting reuptake of catecholamines (ex. cocaine and TCAs)
By inhibiting NET (norepinephrine transporter)
By altering NET to become a reverse transporter
Preventing the metabolism of NE (ex. MAO inhibitors)
Sympathetic agents
NET EFFECT = increase NE activation or supply to
the receptors
Binding of agonist or drug to receptors
Sympathetic agents
MOA to the adrenoceptors
Act on G-protein coupled receptors, which then
activates the 2nd messenger system
Receptor subtypes
Alpha
Beta
Dopamine
Adrenoceptors
Receptor Location
Alpha 1 Postsynaptic effector cells, especially smooth muscle
Alpha 2 Presynaptic adrenergic nerve terminals, platelets,
lipocytes, smooth muscle
Beta 1 Postsynaptic effector cells (heart, lipocytes, brain)
Presynaptic adrenergic and cholinergic nerve
terminals
Juxtaglumerular (JG) apparatus
Beta 2 Postsynaptic effector cells (smooth and cardiac
muscles)
D1 Brain, effector tissues, kidney vascular bed
D2 Brain, effector tissues, smooth muscles
Sympathetic agents
Alpha receptors
alpha1 (α1)
alpha2 (α2)
Beta receptors
Beta1 (β1)
Beta2 (β2)
Beta3 (β3)
Dopamine receptors
D1
D2
Sympathetic agents
Selective
Majority of the drugs are selective (will preferentially
bind to a specific receptor). But as concentration
increases, the other receptors will also be stimulated.
Ex.
Phenylephrine is a selective α1 agonist. If given at higher
doses, it may eventually stimulate α2 and even β receptors
at toxic doses.
Relative receptor affinities
Alpha agonists
Phenylephrine, methoxamine α1 > α2 >>>>> β
Clonidine α2 > α1 >>>>> β
Mixed alpha and beta agonists
Norepinephrine α1 = α2; β1 >> β2
Epinephrine α1 = α2; β1 = β2
Beta agonists
Dobutamine β1 > β2 >>>> α
Isoproterenol β1 = β2 >>>> α
Albuterol, terbutaline β2 >> β1 >>>> α
Dopamine agonist (Dopamine) D1 = D2 >> β >> α
Sympathetic agents
Receptor regulation
More for adrenoceptors than cholinoceptors
Down regulation or desensitization
There will be less response to the agonist
2 mechanisms
Slow desensitization (hours to days)
Decrease in receptor production (down regulation)
Rapid desensitization (minutes)
Decrease in function of a receptor thru phosphorylation
(rapid negative-feedback effect)
Sympathetic agents
Substitution of H by OH at the 3 and 4 carbon atoms in
the benzene ring will produce the group Catechol-
amines
Epinephrine, Norepinephrine, Isoproterenol, Dopamine
Further substitutions or removal of OH among the
different carbon atoms will alter the characteristics of
the succeeding drugs.
Non-catecholamines: phenylephrine, methoxamine,
ephedrine, amphetamine
Catecholamines
Maximal alpha and beta activity
Inactivated by COMT (catechol-O-
methyltransferase)
Found in the gut and liver = does not allow oral
administration of epi and norepi
Absence of one or both OH groups on the phenyl ring
susceptibility to COMT bioavailability after oral
adminstration duration of action
entry of drug to the CNS
Ex. non-catecholamines = phenylephrine and amphetamine
Catecholamines
Alterations in the amine side-chain
Increasing the size of the amino group tends to increase
βreceptor activity, with corresponding decreased αreceptor activity (ex. NE Epi Isoproterenol)
Relative receptor affinities
Alpha agonists
Phenylephrine, methoxamine α1 > α2 >>>>> β
Clonidine α2 > α1 >>>>> β
Mixed alpha and beta agonists
NE α1 = α2; β1 >> β2
Epi α1 = α2; β1 = β2
Beta agonists
Dobutamine β1 > β2 >>>> α
Isoproterenol β1 = β2 >>>> α
Albuterol, terbutaline β2 >> β1 >>>> α
Dopamine agonist (Dopamine) D1 = D2 >> β >> α
Catecholamines and non-
catecholamines
Alterations in the amine side-chain
Substitution at the αcarbon blocks metabolism by
monoamine oxidase (MAO) = duration of action
Ex. Ephedrine and amphetamine
Sympathomimetic agents
General Effects
Cardiovascular system
Compensatory reaction by the parasympathetic system
Alpha1
Arterial and venous vasoconstriction
Reflex response of HR
Skin, nasal mucosa and GIT vessels constrict
Alpha2
Mild vasoconstriction
More prominent CNS effect = vasodilation and chronotropy =
BP
Sympathomimetic agents
General Effects
Cardiovascular system
Beta receptors
Heart = inotropy, chronotropy, dromotropy
Beta2 = vasodilation
Net effect = systolic but diastolic pressure
Dopamine receptors
D1 = Vasodilation of renal, splanchnic (GIT), coronary, cerebral
Improve perfusion to kidneys = urine output
Dopamine activates beta receptors in the heart
Sympathomimetic agents
Noncardiac effects
Lungs = beta2 = bronchodilation
Eye
alpha
pupillary dilation and increase outflow of aqueous humor
Beta antagonism
Decrease aqueous humor production
Genito-urinary
Alpha
Increase urinary sphincter tone (improve continence)
Ejaculation and detumescence
Sympathomimetic agents
Noncardiac effects
Fat cells
Beta2 = glycogenolysis and increase insulin secretion
Beta3 = lipolysis
Diabetogenic
Potassium
Beta2 = promote uptake of potassium into cells
Treatment for hyperK (salb, insulin, calcium)
Renin
Beta1 = increase secretion blood volume BP
Sympathomimetic agents
Noncardiac effects
CNS
Most seen among non-catecholamines
Increased alertness, attentiveness
Elevation of mood, insomnia, euphoria and anorexia
Adrenoceptors - Functions
Type Tissue location Action
α1 Most vascular smooth muscle Contraction
Pupillary dilator muscle Contraction (dilates pupil)
Pilomotor smooth muscle Erects hair
Prostate Contraction
Heart inotropy
α2 Post synaptic CNS neurons Probably multiple (BP)
Platelets Aggregation
Adrenergic and cholinergic nerve
terminals
Inhibits transmitter release
Some vascular smooth muscle Contraction
Fat cells Inhibits lipolysis
Type Tissue location Action
β1 Heart, juxtaglomerular cells chronotropy and
inotropy
renin release
β2 Respiratory, uterine and vascular
smooth muscle
Smooth muscle
relaxation
Skeletal muscle Potassium uptake
Human liver Activates glycogenolysis
β3 Fat cells lipolysis
D1 Smooth muscle Dilates renal blood
vessels
D2 Nerve endings Modulates transmitter
release
Sympathomimetic drugs
Endogenous
catecholamines
Receptor
activity
Effect
Epinephrine α1 = α2; β1
= β2
Vasoconstrictor (except in muscles =
vasodilation)
inotropy, chronotropy in heart
Norepinephrine α1 = α2; β1
>> β2
BP
+ Inotropy, chronotropy
Dopamine D1 = D2 >>
β >> α+ inotropy, chronotropy
Reward stimulus
renal perfusion
Sympathomimetic drugs
Direct Acting Receptor
activity
Effect
Phenylephrine α1 > α2
>>>>> βMydriasis, decongestant, slight inc
in BP
Methoxamine α1 > α2
>>>>> βVasoconstriction and vagally
mediated bradycardia
Alpha2 agonists
Clonidine,
methyldopa
α2 > α1
>>>>> βBP.
Mild sedative
Oxymetazoline α2 >>> α1 Topical decongestant (constrict
nasal mucosa)
Isoproterenol β1 = β2 >>>>
αVasodilator, with increase in
cardiac output with a fall in
diastolic pressure
Direct Acting Receptor
activity
Effect
Beta agonists
Isoproterenol β1 = β2 >>>>
αVasodilator, with increase in
cardiac output with a fall in
diastolic pressure
Dobutamine β1 > β2 >>>>
αCO with less reflex tachycardia
Sympathomimetic drugs
Mixed acting Receptor
activity
Effect
Ephedrine β1 > β2 >>>>
αMild stimulant
Phenylpropanolam
ine
α1 > α2
>>>>> βAppetite suppressant
Cocaine Affects pleasure centers
Uses
Treatment of acute hypotension
Fluids first before sympathomimetic agents
Temporary emergency management of complete
heart block
Drug induced cardiac stress test (dobutamine
injection)
Local vasoconstriction
Mucous membrane decongestants rebound
hyperemia may follow.
Adrenoceptor Antagonists
Selectivity to a receptor depends on chemical structure and dose
MOA
Alpha blockers
Reversible: ex. phentolamine, prazosin, labetalol
Irreversible: covalent bond with receptor
Phenoxybenzamine
Beta blockers
Competitive antagonists
Well absorbed orally, but generally of low bioavailability
Extensive 1st pass effect in the liver
Affected by Cytochrome P450 inducers and inhibitors
Adrenoceptor Antagonists
Beta blockers
Average half life of 3-10 hours
Except esmolol = rapid effect and rapidly inactivated
(10min) = good for hypertensive crisis
Adrenoceptor Antagonists
Receptor Affinity
Alpha antagonists
Prazosin, terazosin, doxazosin α1 >>>>α2
Phenoxybenzamine α1 > α2
Phentolamine α1 = α2
Yohimbine, tolazoline α2 >> α1
Mixed antagonists
Labetalol, carvedilol β1 = β2 ≥ α1 > α2
Beta antagonists
Metoprolol, acebutolol, alprenolol
atenolol, esmolol, nevibolol, etc.
β1 >>> β2
Propanolol, carteolol, pindolol, timolol β1 = β2
Butoxamine β2 >>> β1
Adrenoceptor Antagonists = Opposite
effectType Tissue location Action
α1 Most vascular smooth muscle Contraction
Pupillary dilator muscle Contraction (dilates pupil)
Pilomotor smooth muscle Erects hair
Prostate Contraction
Heart inotropy
α2 Post synaptic CNS neurons Probably multiple (BP)
Platelets Aggregation
Adrenergic and cholinergic nerve
terminals
Inhibits transmitter release
Some vascular smooth muscle Contraction
Fat cells Inhibits lipolysis
Adrenoceptor Antagonists = Opposite
effectType Tissue location Action
β1 Heart, juxtaglomerular cells chronotropy and
inotropy
renin release
β2 Respiratory, uterine and vascular
smooth muscle
Smooth muscle
relaxation
Skeletal muscle Potassium uptake
Human liver Activates glycogenolysis
β3 Fat cells lipolysis
D1 Smooth muscle Dilates renal blood
vessels
D2 Nerve endings Modulates transmitter
release
Alpha Antagonists
Phenoxybenzamine
Irreversible alpha blocker
Also blocks histamine, Ach, and 5HT receptors
Reduces blood pressure when sympathetic tone is high
useful for pheochromocytoma
ADR
orthostatic hypotension and tachycardia
Nasal congestion and inhibition of ejaculation
Alpha Antagonists
Phentolamine
Competitive blocker of α1 and α2
Vasodilation with direct and reflex tachycardia (due to
antagonism to α2 receptors)
ADR: tachycardia, arrythmia
Used for tx of pheochromocytoma
Alpha Antagonists
Prazosin, Terazosin and Doxazosin
α1 blocker
Vasodilation with minimal effect on the heart
Relaxes prostate muscle (useful for BPH)
Half life
Half life (hours)
Prazosin 3
Terazosin 9-12
Doxazosin 22
Beta Antagonists
Propanolol
Non-selective beta blocker
Decreased chronotropy and inotropy
Mild bronchoconstriction
Metoprolol, atenolol
Selective beta1 blocker
Decreased chronotropy and inotropy
Mild hypoglycemia and vasodilation
Beta Antagonist
Nebivolol
Most selective beta1 inhibitor
Esmolol
Ultra short acting beta1 selective antagonist
Treatment for arrythmias, perioperative hypertension
and myocardial ischemia
Mixed Antagonists
Labetalol and carvedilol
β1 = β2 ≥ α1 > α2
Decreased blood pressure, but with less reflex
tachycardia due to low alpha antagonism
Uses – Alpha blockers
Treatment for
Pheochromocytoma
Urinary obstruction and BPH
Other uses (not drug of choice)
Hypertensive emergencies
Chronic hypertension
Peripheral vascular disease
Erectile dysfunction
Uses – Beta blockers
Treatment for
Angina and following myocardial infarction
Decrease work load and oxygen demand of heart
Heart arrythmias
Regulate heart rate and heart conduction speed
Chronic heart failure
Decrease cardiac remodeling
Glaucoma
Hypertension
Especially for patient with uncontrolled diabetes
In combination with a diuretic and a peripheral vasodilator
Uses – Beta blockers
Treatment for
Hyperthyroidism (for Propanolol)
Sympathetic antagonism and decreased peripheral
conversion of T4 to T3 (more active to less active)
Precautions
Beta blockers
Hypercholesterolemia
May increase LDL and decrease HDL
Congestive heart failure?
Beta2 blockers
Patients with asthma
Use another anti-hypertensive drug
Patients with diabetes and inadequate glucose reserves
Inhibits lipolysis and glycogenolysis = available blood glucose = may promote hypoglycemia