ADRENERGIC MEDICATIONS(sympathomimetic drugs)

BY:DR.ISRAA OMAR

Adrenergic transmission(synthesis)• NA is synthesized in the axon of the noradrenergic neurons .• Tyrosine is taken up by these neurons and by the action of

tyrosine hydroxylase it is converted to DOPA • Then by the action of DOPA decarboxylase it is converted to

DOPAMINE and then to noradrenaline by hydroxylase enzyme

• Then in the adrenal medulla NA will change in to adrenaline by the action of phenylethanolamine N-methyl transferase enzyme

• Isoprenaline is a synthetic derivative of NA

Storage and release

• The synthesized NA is stored ,together with ATP and chromogranin , in the vesicles in the nerve terminal and chromaffin cells in the adrenal medulla

• It is released by two ways 1. By exocytosis ;influx of Ca to presynaptic neuron will

lead to release of NE by exocytosis in to the synaptic cleft

2. Non- exocytosis release: certain drugs like amphetamine replace and release the NE from the vesicles

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• Noradrenaline :release is mainly regulated by an auto inhibitory feed back mechanism (the released noradrenaline in the synapse will stimulate α2 receptors in the presynaptic neuron and in turn inhibit the release of NE .

Elimination of catecholamine • Catecholamine(NA, adrenaline ,isoprenaline ) are eliminated

by re- uptake and/or metabolic degradation ,they are removed by one of the 3 mechanisms:

1. Uptake 1:it is uptake to pre synaptic neuron and it is more selective to NA ,it can be inhibited by amphetamine and tricyclic antidepressant

2. Uptake 2:extraneuronal reuptake :it is uptake by effector organ like heart and smooth muscle ,it is relatively selective to adrenaline

3. Some of them may escape in to the vascular system and degraded by hepatic enzymes

Continue..……• CATECOLAMINE are metabolized by MAO

monoamine oxidase enzyme of the mitochondria in the cells and this enzyme is particularly abundant in neurons ,the second enzyme named catechol-O-methyl transferase (COMT)found in variety of neuronal and non- neuronal tissues .

Classification of adrenoceptors

• They are divided in to 2 classes 1. α receptor(α1 andα2)2. βReceptors(β1,β2andβ3)Αlpha1 activate phospholipase C, thus producing IP3 and DAG as a second messengers;α2inhibit adenylate cyclase, and thus decrease Camp formation .Beta receptors 1,2 and 3 stimulate adenylate cyclase and therefore increase cAMP formation

Action of adrenergic receptors• α1 found in the smooth muscle of many organs and they cause

contraction of the blood vessels, relaxation of the GIT and glycogenlysis

• α2 found in presynaptic neuron ,CNS, blood vessels , it inhibit transmitter release, in addition they cause platelets aggregation and blood vessel contraction

• β1 mainly in the heart ,stimulation result in an increase cardiac out put and heart rate

• β2 present in the smooth muscle of many organs and its stimulation lead to bronchodilation, perpherial vasodilation, relaxation of the visceral smooth muscle and skeletal muscle tremor

Action of adrenergic receptors

• β3 present in fat cells and cause lipolysis• Adrenaline, noradrenaline and isoprenaline

act on both α and β receptors but with different potency

• α receptors stimulated more by noradrenaline and less with isoprenaline ,β stimulated more with isoprenaline and less with NE.

SYMPATHOMIMETICS DRUGS

• Direct acting :1. Alpha agonists 2. Beta agonists• Indirect acting 1. Releasers 2. Reuptake inhibitors The direct acting drugs can also be divided in to catecholamine and non-catecholamine

Direct acting catecholamine

• EPINEPHRINE: α(all types) and β(all types) agonist used to treat anaphylaxis and with local anesthesia

• NOREPINPHERINE : α(all types) and only β1 agonist used to treat neurogenic shock ,last resort therapy in shock patient

• Dopamine stimulate D1, β1 and α1,receptors It is used to treat shock and acute renal failure due to insufficient blood flow to the kidney ,it is superior to the NE in management of shock why?

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• Doputamine:B1 agonist used to increase cardiac out-put I patient with heart failure with little change in heart rate and no effect in blood vessels

(α1 adrenoceptors agonist) noncatecholamines

• Phenylephrine :used topically on nasal mucous membrane as nasal decongestant and on the eye to cause mydriasis and for treatment of open angle glaucoma because it cause reduce the secretion of aqueous humor it doesn’t affect the heart directly but can cause reflex bradycardia as a result of vasoconstriction

• Methoxamine: used to overcome hypotension during surgery (it is non selective block α1 and α 2)

α2 agonist

• Clonidine : when administered intravenously or topically(nasal spray) it causes vasoconstriction but when given orally it accumulate in the CNS causing reduction in the sympathetic out flow and hypotension

• α-methyldopa : false transmitter ,which is a potent agonist to α2 receptors thus causing a powerful inhibition to transmitter release and also have central action ,this drug is used to treat hypertension in pregnancy PIH.

β1 agonist

• Only dobutamine which is catecholamine drug is selective agonist to this type of receptors .

Β2 selective agonist in high concentration will lose selectivity and stimulate this receptors

β2 agonist

• Salbutamol :short acting β2 agonist used to treat asthma and to delay premature labor ,the most common side effect is tachycardia and tremor .

• Terbutaline: used to treat asthma and delay the labor • Ritodrine: used for preterm labor . • Clenbuterol: an anabolic drug used illicitly by athletes

to improve performance; because in long tem it changes the expression of sarcoplasmic reticulum protein ,and thereby increase the rate and force of contraction of the skeletal muscle

Β3 agonist

• Still under clinical trials .• If completely developed it will help in weight

reduction, by stimulation of lipolysis by β 3.

Indirect acting sympathomimetic • Indirect acting sympathomimetic drugs cause

norepinephrine release from presynaptic terminals or inhibit the uptake of norepinephrine .

• They potentiate the effect of NE ,but do not directly affect post-synaptic receptors .

Amphetamine• It stimulate CNS and also have peripheral action as it

displace NE from the vesicles, allowing it to escape in to synaptic cleft

• It can cause hypertension by increasing the action of NE α receptors by and increase HR and contractility by increasing the action on β receptors .

• It used clinically for weight reduction as an appetite controller ,narcolepsy and ADD with hyperactivity in children.

• It is also used illicitly by drug abusers to increase concentration and awakens.

Tyramine • It is not clinically useful drug but it is

important because it can be found in fermented food like cheese .

• It displaces stored catecholamine.• Tyramine is particularly important in patient

who are taking MAO inhibitors because it escape destruction by MAO in the GIT leading to sever hypertensive crises

Cocaine • It block the reuptake of NE by blocking Na/K

activated ATPase on the cell membrane of adrenergic neuron, consequently NE accumulate in the synaptic space resulting in enhancement of sympathetic activity

• TCA also inhibit the reuptake 1 so it increase NA in the synaptic cleft

Ephedrine and Pseudoephedrine • It displace the NE from stores• They are plant alkaloids , they are now made synthetically • It is thought that they have direct agonist action on post

synaptic adrenergic receptors• Ephedrine produces CNS stimulation causing alertness and

decrease fatigue , prevent sleep ,it also causes bronchodilation and raises systolic and diastolic blood pressure.

• Note :the clinical use of ephedrine is declining because of the availability of better more potent agents that cause fewer side effects.

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• Pseudoephedrine is used clinically as nasal decongestant and has been illegally converted to methamphetamine . Thus, products containing it have certain restriction and must be kept behind sales counter

Corticosteroids • Inhibit the action of reuptake 2 of NE in the

peripheral tissue.• This action may the cause of it is therapeutic

importance in treating asthma ,but it is probably of minor importance.

References • Rang and Dales pharmacology textbook • Lippincott's illustrated review pharmacology • Pharmacology examination and board review

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