Adrenergic System - Drdhriti

7/31/2019 Adrenergic System - Drdhriti

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Adrenergic System

Department of Pharmacology

NEIGRIHMS, Shillong


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Neurotransmission in ANS


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Noradrenergic transmission

Nor-adrenaline is the majorneurotransmitter of theSympathetic system

Noradrenergic neurons are

postganglionic sympatheticneurons with cell bodies inthe sympathetic ganglia

They have long axonswhich end in varicosities

where NA is synthesizedand stored


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Adrenergic transmission

Catecholamines:

Natural: Adrenaline, Noradrenaline, Dopamine

Synthetic: Isoprenaline, Dobutamine

Non-Catecholamines:

Ephedrine, Amphetamines, Phenylepherine, Methoxamine,Mephentermine

Also called sympathomimetic aminesas most of themcontain an intact or partiallysubstituted amino (NH2)group


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Catecholamines:Compounds containinga catechol nucleus(Benzene ring with 2

adjacent OH groups)and an aminecontaining side chainNon-catecholamineslack hydroxyl (OH)

group


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Biosynthesis ofCatecholamines

Phenylalanine

PH

Rate limiting Enzyme

5-HT, alpha Methyldopa

Alpha-methyl-p-

tyrosine


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Storage of Noradrenaline


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Release of NA Feedback Control


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Regulators of NA release


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Uptake of Catecholamines


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Reuptake

Sympathetic nerves take up amines and releasethem as neurotransmitters

Uptake I is a high efficiency system more specific

for NA Located in neuronal membrane

Inhibited by Cocaine, TCAD, Amphetamines

Uptake 2 is less specific for NA Located in smooth muscle/ cardiac muscle

Inhibited by steroids/ phenoxybenzamine

No Physiological or Pharmacological importance


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Metabolism of CAs

Mono Amine Oxidase (MAO) Intracellular bound to mitochondrial membrane

Present in NA terminals and liver/ intestine

MAO inhibitors are used as antidepressants

Catechol-o-methyl-transferase (COMT) Neuronal and non-neuronal tissue

Acts on catecholamines and byproducts VMA levels are diagnostic for tumours


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Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)


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Adrenergic neurotransmission


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How Many of them ????

Alpha () Beta ()

Adenoreceptors

1 3 21 2

2B 2C 2A

1A 1B 1D


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Potency of catecholamines onAdrenergic Receptors

Adr NA

Iso

Iso Adr

NA

Log Concentration

Aortic strip contraction Bronchial relaxation


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Molecular Effector Differences- Vs

Receptors: IP3/DAG

cAMP

K+ channel opening

Receptors: cAMP

Ca+ channel opening


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Recall: Adenylyl cyclase: cAMPpathway

PKA Phospholamban

Increased

Interaction with

Ca++

Faster relaxation

Troponin

Cardiac

contractility

Other

Functional

proteins

PKA alters the functions of manyEnzymes, ion channels,transportersand structural proteins.

Faster sequestration ofCa++ in SR


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PKc

Also Recall: Phospholipase C:IP3-DAG pathway


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Beta receptors

All receptors activate adenylate cyclase, raising the intracellularcAMP concentration

Type 1: These are present in heart tissue, and cause an increased heart rate by

acting on the cardiac pacemaker cells

Type 2: These are in the vessels of skeletal muscle, and cause vasodilatation, whichallows more blood to flow to the muscles, and reduce total peripheralresistance

Beta-2 receptors are also present in bronchial smooth muscle, and causebronchodilatation when activated

Stimulated by adrenaline, but not noradrenaline

Bronchodilator salbutamol work by binding to and stimulating the 2receptors

Type 3: Beta-3 receptors are present in adipose tissue and are thought to have a

role in the regulation of lipid metabolism


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Differences between 1, 2 and 3

Beta-1 Beta-2 Beta-3

Location Heart and JG cells Bronchi, uterus,Blood vessels,

liver, urinary tract,eye

Adiposetissue

Agonist Dobutamine Salbutamol -

Antagonist Metoprolol, Atenolol Alpha-methylpropranolol

-

Action onNA

Moderate Weak Strong


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Clinical Effects of -receptorstimulation 1: Adrenaline, NA and Isoprenaline:

Tachycardia

Increased myocardial contractility

Increased Lipolysis

Increased Renin Release

2: Adrenaline and Isoprenaline (not NA)

Bronchi Relaxation

SM of Arterioles (skeletal Muscle) Dilatation

Uterus Relaxation

Skeletal Muscle Tremor

Hypokalaemia

Hepatic Glycogenolysis and hyperlactiacidemia

3: Increased Plasma free fatty acid increased O2 consumption -increased heat production


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Adrenergic receptors - alpha

Type 1 Blood vessels with alpha-1 receptors are present in the

skin and the genitourinary system, and during the fight-or-flight response there is decreased blood flow to theseorgans

Acts by phospholipase C activation, which forms IP3 andDAG

In blood vessels these cause vasoconstriction

Type 2

These are found on pre-synaptic nerve terminals Acts by inactivation of adenylate cyclase, cyclic AMP levels

within the cell decrease (cAMP)


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Differences between 1 and 2

Alpha-1 Alpha-2Location Post junctional blood vessels

of skin and mucousmembrane, Pilomotor muscle

& sweat gland, radial musclesof Iris

Prejunctional

Function Stimulatory GU,Vasoconstriction, glandsecretion, Gut relaxation,

Glycogenolysis

Inhibition of transmitterrelease, vasoconstriction,decreased central symp.

Outflow, plateletaggregation

Agonist Phenylephrine, Methoxamine Clonidine

Antagonist Prazosin Yohimbine


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1 adrenoceptorsClinical effects

Eye -- Mydriasis

Arterioles Constriction (rise in BP)

Uterus -- Contraction

Skin -- Sweat Platelet - Aggregation

Male ejaculation

Hyperkalaemia

Bladder Contraction 2 adrenoceptors on nerve endings mediate negative

feedback which inhibits noradrenaline release


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Molecular Basis of AdrenergicReceptors

Also glycogenolysisin liver

Inhibition ofInsulinrelease andPlateletaggregationGluconeogenesis


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Dopamine receptors

D1-receptors are post synaptic receptorslocated in blood vessels and CNS

D2-receptors are presynaptic present in CNS,ganglia, renal cortex


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Summary of agents modifyingadrenergic transmission

Step Actions DrugSynthesis of NA Inhibition - methyl-p-tyrosine

Axonal uptake Block Cocaine, guanethidine,ephedrine

Vesicular uptake Block Reserpine

Vesicular NA Displacement Guanethidine

Membrane NA pool Exchange diffusion Tyramine, Ephedrine

Metabolism MAO-A inhibitionMAO-B inhibitionCOMT inhibition

MoclobemideSelegilineTolcapone

Receptors 1 21 + 21

PrazosinYohimbinePropranololMetoprolol


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Adrenaline as prototype

Potent stimulant of alpha and beta receptors

Complex actions on target organs


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Heart

Beta-1 mediated action - Powerful Cardiac stimulant - +vechronotropic, +ve inotropic

Acts on beta-1 receptors in myocardium, pacemaker cells andconducting tissue

Heart rate increases by increasing slow diastolic depolarization of cellsin SAN

High doses cause marked rise in heart rate and BP causing reflexdepression of SAN unmasking of latent pacemaker cells in AVN andPF arrhythmia (sensitization of arrhythmogenic effects by Halothane)

Cardiac systole is shorter and more powerful

Cardiac output is enhanced and Oxygen consumption is increased

Cardiac efficiency is markedly decreased

Conduction velocity in AVN, atrial muscle fibre, ventricular fibre andBundle of His increased benefit in partial AV block Reduced refractory period in all cardiac cells


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Blood Vessels

Seen mainly in the smaller vesselsarteriolesVasoconstriction (alpha) andvasodilatation (beta)depends on the drug

Decreased blood flow to skin and mucusmembranes and renal bedsalpha effect (1and 2) -

Increased blood flow to skeletal muscles,coronary and liver vessels - (Beta-2 effect)counterbalanced by a vasoconstrictor effectof alpha receptors


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Blood Pressure

Depends on the Catecholamine involved

NA causes rise in Systolic, diastolic and meanBP (no beta-2 action) unopposed alpha action

Isoprenaline causes rise in systolic but fall indiastolic BP mean BP falls (beta-1 and beta-2)

Adr causes rise in systolic BP, but fall in diastolic

BP mean BP generally rises (slow injection) Decreased peripheral resistance at low conc. Beta

receptors are more sensitive to Adr than alphareceptors


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Blood Pressure contd.

Rapid IV injection of Adrenaline marked rise inSystolic and diastolic BP

Large concentration alpha action predominates

vasoconstriction even in skeletal muscle But BP returns to normal in few minutes

A secondary fall in mean BP occurs

Mechanism rapid uptake and dissipation ofAdr at low conc. Alpha action lost but betaaction predominatesDale`s Vasomotorreversal phenomenon


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Dale`s Vasomotor ReversalPhenomenon


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Actions of Adrenaline

Respiratory: Powerful bronchodilator Relaxes bronchial smooth muscle (not NA)

Beta-2 mediated effect

Physiological antagonist to mediators ofbronchoconstriction e.g. Histamine GIT : Relaxation of gut muscles (alpha and beta) and constricted

sphincters reduced peristalsis not clinical importance

Bladder: relaxed detrusor muscle (beta) muscle but constriction of

Trigone both are anti-voiding effect

Uterus: Adr contracts and relaxes Uterus (alpha and beta action)but net effect depends on status of uterus and species pregnantrelaxes but non-pregnant - contracts


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Actions of Adrenaline contd.

Skeletal Muscle: Facilitation of Ach release in NM junction (alpha -1)

Beta-2 acts directly on Muscle fibres

Abbreviated active state and less tension in slowconducting fibres and enhanced muscle spindle firing tremor

CNS: No visible clinical effect in normal doses as low

penetration except restlessness, apprehension andtremor

Activation of alpha-2 in CNS decreases sympathetic outflow andreduction in BP and bradycardia - clonidine


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Metabolic effects

Increases concentration of glucose and lacticacid

Calorigenesis (-2 and-3)

Inhibits insulin secretion (-2)

Decreases uptake of glucose by peripheraltissue

Simulates glycogenolysis - Beta effect Increases free fatty acid concentration in blood

Hypokalaemia initial hyperkalaemia


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ADME

All Catecholamines are ineffective orally

Absorbed slowly from subcutaneous tissue

Faster from IM site Inhalation is locally effective

Not usually given IV

Rapidly inactivated in Liver by MAO andCOMT


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Clinical Question!

Question: A Nurse was injecting a dose of penicillinto a patient in Medicine ward without prior skin testand patient suddenly developed immediate

hypersensitivity reactions. What would you do? Answer: As the patient has developed Anaphylactic

reaction, the only way to resuscitate the patient isinjection of Adrenaline

0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10minutes

Antihistaminics: Chlorpheniramine 10 20 mg IM or IV

Hydrocortisone 100 200 mg


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Adrenaline Clinical uses

Injectable preparations are available in dilutions1:1000, 1:10000 and 1:100000

Usual dose is 0.3-0.5 mg sc of 1: 10000 solution

Used in: Anaphylactic shock

Prolong action of local anaesthetics

Cardiac arrest

Topically, to stop bleeding

Hyperkinetic children ADHD, minimal brain dysfunction

Anorectic


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ADRs

Restlessness, Throbbing headache, Tremor,Palpitations

Cerebral hemorrhage, cardiac arrhythmias

Contraindicated in hypertensives,hyperthyroid and angina poctoris

Halothane and beta-blockers not indicated


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Other Adrenergic Drugs


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Noradrenaline

Neurotransmitter released frompostganglionic adrenergic nerve endings(80%)

Orally ineffective and poor SC absorption

IV administered

Metabolized by MAO, COMT

Short duration of action


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Actions and uses

Agonist at 1(predominant), 2 and 1 Adrenergic receptors Equipotent with Adr on 1, but No effect on 2

Increases systolic, diastolic B.P, mean pressure, pulse pressureand stroke volume Total peripheral resistance (TPR) increases due to vasoconstriction -

Pressor agent Increases coronary blood flow Decreases blood flow to kidney, liver and skeletal muscles Uses: Injection Noradrenal bitartrate slow IV infusion at the rate

of 2-4mg/ minute used as a vasopressor agent in treatment ofhypovolemic shock and other hypotensive states in order to raise

B.P Problems: Down regulation of receptors, Renal Vasoconstriction Septic and neurogenic shock (?)


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Noradrenaline - ADRs

Anxiety, palpitation, respiratory difficulty

Acute Rise of BP, headache

Extravasations causes necrosis, gangrene Contracts gravid uterus

Severe hypertension, violent headache,photophobia, anginal pain, pallor andsweating in hyperthyroid and hypertensivepatients


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Isoprenaline

Catecholamine acting on beta-1 and beta-2 receptors negligibleaction on alpha receptor

Therefore main action on Heart and musclevasculature

Main Actions: Fall in Diastolic pressure, Bronchodilatation andrelaxation of Gut

ADME: Not effective orally, sublingual and inhalation (10mg tab. SL)

Overall effect is Cardiac stimulant (beta-1)

Increase in SBP but decrease in DBP (beta-2) Decrease in mean BP

Used as Bronchodilator and for treatment of AV block, Stokes-AdamSyndrome etc.but not preferred anymore

Adrenaline NA and


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Adrenaline, NA andIsoprenaline - Summary


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Dopamine

Immediate metabolic precursor ofNoradrenalin

High concentration in CNS - basal ganglia,limbic system and hypothalamus and also inAdrenal medulla

Central neurotransmitter, regulates body

movements ineffective orally, IV use only, Short T 1/2 (3-5minutes)


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Dopamine

MECHANISM:

Agonists at dopaminergic D1, D2 receptors

Agonist at adrenergic 1 and 1


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Dopamine

In small doses 2-5 g/kg/minute, it stimulates D1-receptors in renal, mesenteric and coronary vesselsleading to vasodilatation (Increase in cAMP)

Recall: Renal vasoconstriction occurs in CVS shock due tosympathetic over activity

Increases renal blood flow, GFR an causes natriuresis

Interaction with D2 receptors (present in presynaptic adrenergicneurones)suppression of NA release (no alpha effect)


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Dopamine cond.

Moderate dose (5-10 g/kg/minute), stimulates 1-receptors in heart producing positive inotropic andchronotropic actions actions

Releases Noradrenaline from nerves by 1-stimulation

Does not change TPR and HR Great Clinical benefit in CVS shock and CCF

High dose (10-30 g/kg/minute), stimulates vascularadrenergic 1-receptors (NA release)vasoconstriction and decreased renal blood flow


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Why renal and mesentericvasodilatation is useful in Shock?

Increases renal blood flow, GFR ancauses natriuresis

In CVS shock

excessive sympatheticactivity leading to ischemia of gut,sloughening and entry of Bacteria tosystemic circulation - septicemia


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Adrenergic agonists

Selective Alpha-1 Agonists: Phenylepherine, Ephederine, Methoxamine,

Metaraminol, Mephentermine

Selective Alpha-2 Agonists: Clonidine, -methyldopa, Guanfacine and

Guanabenz

-2 Adrenergic agonists:

Salbutamol, Terbutaline, Salmeterol,Reproterol, Oxiprenaline, Fenoterol,Isoxsuprine, Rimiterol, Ritodrine, Bitolterol andIsoetharine

Adrenergic Drugs


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Adrenergic DrugsTherapeutic Classification

Pressor agents: NA, Phenylephrine, ephedrine, Methoxamine, Dopamine

Cardiac Stimulants: Adr, Dobutamine and Isoprenaline, Dopexamine

Nasal Decongestants:

Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline andTetrahydrazoline and Phenylpropanolamine and Pseudoephidrine

Bronchodilators: Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol

Uterine Relaxants: Ritodrine, Salbutamol, Isoxsuprine

Anorectics Fenfluramine, Dexfenfluramine and Sibutramine

CNS Stimulants: Amphetamine, Methamphetamine


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Ph l h i S l i


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Phenylepherine - Selective,synthetic and direct 1 agonist

Actions qualitatively similar to noradrenaline Long duration of action

Resistant to MAO and COMT Does not cross BBB, so no CNS effects

Peripheral vasoconstriction leads to rise in BP but Reflexbradycardia

Produces mydriasis and nasal decongestion

Use: hypovolaemic shock as pressor agent

Sinusitis & Rhinitis as nasal decongestant (common in oral preparations) Mydriatic in the form of eye drops and lowers intraocular pressure

ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity Administered parenteraly & topically (eye, nose)

What are Mucosal


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What are MucosalDecongestants?

Nasal and bronchial decongestants are the drugs usedin allergic rhinitis, colds, coughs and sinusitis as nasaldrops - Sympathomimetic vasoconstrictors with -effects are used

Drugs: Phenylepherine, xylometazoline, Oxymetazoline,PPA, Pseudoephidrine etc.

Drawbacks: Rebound congestion due to overuse

However, mucosal ischaemic damage occurs if used excessively(more often than 3 hrly) or for prolonged periods (>3weeks)

CNS Toxicity Failure of antihypertensive therapy Fatal hypertensive crisis in patients on MAOIs

Use only a few days since longer application reduces ciliary action


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Nasal Decongestants

Pseudoephedrine to Ephedrinebut less CNS and Cardiaceffects Poor Bronchodilator

Given in combination with antihistaminics, antitussives and NSAIDsin common cold and, allergic rhinitis, blocked Eustachian tube etc.

Rise in BP inhypertensives

Phenylpropanolamine (PPA)is similar to ephedrine and usedas decongestants in many cold and cough preparations

Also as weight loosing agent

Xylometazoline, Oxymetazoline etc.


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Amphetamine Synthetic compound similar to Ephedrine Pharmacologically

Known because of its CNS stimulant action psychoactive drug andalso performance enhancing drug

Actions:

alertness, euphoria, talkativeness and increased work capacity fatigue

is allayed (acts on DA and NA neurotransmitters etc.reward pathway) increased physical performance without fatigue short lasting (Banned

drug and included in the list of drugs of Dope Test) deteriorationoccurs

RAS Stimulation wakefulness, sleep deprivation (then physicaldisability)

However, anxiety, restlessness, tremor and dysphoria occurs

Other actions: Stimulation of respiratory centre, Hungersuppression, also anticonvulsant, analgesic and antiemeticactions


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Amphetamine contd.

Drug of abuse marked psychological effect but littlephysical dependence

Generally, Teenage abusers - thrill or kick

High Dose Euphoria, excitement and may progress todelirium, hallucination and acute psychotic state

Also peripheral effects like arrhythmia, palpitation, vascularcollapse etc.

Repeated Dose Long term behavioural abnormalities

Starvation acidic urine

Uses: Hyperkinetic Children (ADHD), Narcolepsy,Epilepsy and Parkinsonism


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Anorectics

Drugs used for suppression of appetite

MOA: Inhibition of NA/DA or 5-HT uptakeenhancement of monoaminergic transmission

NA agents affect the appetite centre andSerotonergics act on satiety centre

Fenfluramine, dexfenfluramine andsibutramineALL ARE BANNED NOW

Reasons: Heart valve defects, fibrosis andpulmonary hypertension etc.


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Clonidine

Centrally acting:Agonist to postsynaptic 2Aadrenoceptors in brain vasomotor centre inbrainstem (presynaptic Ca++ level increased NArelease) Decrease in BP and cardiac output

Peripherally action: High dose activates peripheralpresynaptic autoreceptors on adrenergic nerveending mediating negative feedback suppression of

noradrenaline release Overdose stimulates peripheral postsynaptic 1

adrenoceptors & cause hypertension byvasoconstriction


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Clonidine contd.

Uses: ADHD in children, opioid withdrawal (restless legs, jitters andhypertension), alcohol withdrawal (0.3 to 0.6 mg)

Abrupt or gradual withdrawal causes rebound hypertension

Onset may be rapid (a few hours) or delayed for as long as 2 days andsubsides over 2-3 days

Never use beta-blockers to treat Available as tablets, injections and patches

Sedation, dry mouth, dizziness and constipation etc.

TCAs antagonize antihypertensive action & increase reboundhypertension of abrupt withdrawal

Low dose Clonidine (50-100g/dl) is used in migraine prophylaxis,menopausal flushing and chorea

Moxonidine, Rilmenidine Newer Imidazolines

2 Adrenergic Agonists


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2 Adrenergic Agonists discussed elsewhere!

Short acting : Salbutamol, Metaproterenol, Terbutaline,pirbuterol

Selective for 2 receptor subtype

Used for acute inhalational treatment of bronchospasm.

Onset of action within 1 to 5 minutes

Bronchodilatation lasts for 2 to 6 hours

Duration of action longer on oral administration

Directly relax airway smooth muscle

Relieve dyspnoea of asthmatic bronchoconstriction

Long acting: Salmeterol, Bitolterol, colterol

Uterine Relaxants - discussed


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Uterine Relaxants discussedelsewhere!

Antioxytocics or tocolytic agents

2 agonists relax uterus Used by i.v. infusion to inhibit premature labour Isoxsuprine, Terbutaline, Ritodrine, Salbutamol Tachycardia & hypotension occur Use minimum fluid volume using 5% dextrose as

diluents Ritodrine:50 g/min, increase by 50 g/min every

10 minutes until contractions stop or maternal heartrate is 140 beats/minute. Continue for 12-48 hoursafter contractions stop


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Remember ?

Steps of Biosynthesis of Catecholamine

Distribution of adrenergic receptors

Individual Functions of Adrenergic receptors

All aspects of adrenaline Dale`sPhenomenon

Dopamine/Dobutamine actions

Nasal decongestants - Phenylephrine

Amphetamine and Clonidine - Desirable


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Adrenergic System - Drdhriti