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

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• Catecolamine are metabolized by: 1. MAO monoamine oxidase enzyme of the

mitochondria in the cells and this enzyme is particularly abundant in neurons

2. 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)

• Αlpha: – α 1: activate phospholipase C, thus producing IP3

and DAG as a second messengers;– α2: inhibit adenylate cyclase, and thus decrease

cAMP formation .• Beta: – 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, peripheral vasodilation, relaxation of the visceral smooth muscle and skeletal muscle tremor

• Β3: – Present in fat cells and cause lipolysis

Action of adrenergic receptors

Action of adrenergic receptors

• 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

A. Direct acting :1. Alpha agonists 2. Beta agonists

B. Indirect acting 1. Releasers 2. Reuptake inhibitors

• The direct acting drugs can also be divided in to catecholamine and non-catecholamine

A. Direct acting catecholamines

1. Epinephrine: – α (all types) and β (all types) agonist used to

treat anaphylaxis and with local anesthesia 2. Norepinpherine: – α (all types) and only β1 agonist used to treat

neurogenic shock, last resort therapy in shock patient

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3. 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?

4. Dobutamine:– β 1 agonist used to increase cardiac out-put in

patient with heart failure with little change in heart rate and no effect in blood vessels

α1 adrenoceptors agonist (noncatecholamines)

1. 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

2. Methoxamine: – Used to overcome hypotension during surgery (it

is non selective block α1 and α 2)

α2 agonist1. 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

2. α-methyldopa: – It is a 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

1. Salbutamol :– Short acting β2 agonist used to treat asthma

and to delay premature labor , the most common side effect is tachycardia and tremor .

2. Terbutaline: – Used to treat asthma and delay the labor

3. Ritodrine: – Used for preterm labor .

4. 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.

B. Indirect acting sympathomimetic

• Indirect acting sympathomimetic drugs cause: 1. Norepinephrine release from presynaptic

terminals or 2. Inhibit the uptake of norepinephrine .

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

1. 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.

2. 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

3. 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

4. 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

5. 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.

Adrenergic antagonist(sympatholytic)

Adrenergic antagonist

• These group of drug bind to adrenoceptors but do not trigger the usual receptor-mediated response

• They can be selective or non-selective so they can be classified according to their affinity to the receptors

• These drugs are either reversibly or irreversibly attached to the receptors, thus preventing the action of endogenous catecholamine

A. α blocking agents

1.Phenoxybenzamine: • Action: – Irreversibly block both α1 and2 because it make

covalent bond with receptors – It causes hypotension by blocking α1 receptors in

the blood vessels but blocking α2 may cause more release of NE from the presynaptic neuron which will act on unblocked β receptors in the heart leading to tachycardia so this drug is non suitable for treatment of hypertension

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• Uses: – It is used as pre-surgical treatment of

pheochromocytoma to reduce the effect of catecholamine released during manipulation of tissues, it is also used of treatment of this condition if the tumor is inoperable and metastasized

– It was used for treatment of peripheral vascular disease but this use is now largely obsolete

• Adverse effect: – Include nasal stuffiness , –Postural hypotension–Reflex bradycardia mediated by baroreceptors.

Thus, it is contraindicated in patient with coronary vessels disease

2. Phenatolamine :• Action – Competitively reversibly block both α1 and 2 so

their action last only 4 hours after single administration

• Uses: – It is used for treatment of pheochromocytoma – It was used in the past to treat impotence by

injecting the drug intracavernosally to produce vasodilation of penile arteries

3. Prazosin, terazosin, doxazosin and tamsulosin • Action: – They selectively block α1 receptors .

• Uses: – They are useful in treatment of hypertension not

like non selective blockers – Tamsulosin in particular is important in treatment

of BPH because it reduces the tone of muscle at the bladder neck and facilitate bladder emptying, this drug has minimal effect on blood pressure compared to other drugs of this group because it selectively block Α1a in the bladder smooth muscle.

Continue…• Precautions: – These drugs can cause first dose hypotension thus

need adjustment of the first dose and should be given at bed time

– If given as monotherapy for treatment of hypertension the risk of congestive heart failure is increased .

• Side effect: – Hypotension and male sexual dysfunction – Inhibition of ejaculation and retrograde ejaculation

because it causes relaxation of the ejaculatory duct

4. Yohimbine :• It is selective competitive α2 receptor

antagonist.• It is naturally occurring alkaloids extracted from

Yohimbine tree .• It is CNS and CVS stimulant drug .• It was used historically as sexual stimulant.

5. Labetalol and carvedilol • They block both α and β receptors • Uses: – They cause vasodilation and reduction in the HR and

contractility.– It is effective in treatment of hypertension in black

and elderly patients.– Labetalol is effective in treatment of hypertension

with pregnancy PIH.– Intravenous labetalol is used for treatment of

hypertensive emergencies• Side effects: – Orthostatic hypotension and dizziness

B. β-blocking agents

• They are divided in to two major groups1. Non-selective beta antagonist which block

both types of beta receptors 2. Selective beta antagonist which block

either β1 or β2.

1. Non -selective beta antagonistPropranolol , alprenolol, timolol and nadolol.• Uses: – They are used to reduce blood pressure in

hypertensive patients by reducing cardiac out-put, inhibition of renin release and reduce sympathetic flow from the CNS

– They are also used in treatment of angina, arrhythmias, anxiety, glaucoma (particularly topically applied ones like timolol reduce the secretion of aqueous humor), migraine and hyperthyroidism .

• Adverse effects– Bronchoconstriction , – Arrhythmias, – Sexual impairment ,– Disturbance of metabolism especially glucose

(can cause sever hypoglycemia after administration of insulin because it inhibit glucagon release)

– Cold extremities because they block the peripheral vasodilation caused by beta 2 adrenoceptors .

2. Selective beta antagonist

Acebutolol, atenolol, metoprolol and esmolol• They particularly useful in treatment of: – Hypertension in patient with pulmonary disease – Patients with peripheral vascular disease and – Hypertension in diabetic patients

Antagonist with partial agonist action

Pindolol and acebutolol :• They bound to beta 1 and 2 and cause partial

stimulation of it but not the full effect and they inhibit the binding of more potent catecholamine. Thus these drugs are named blockers with ISA ( intrinsic sympathomimetic action) .

• It used for treatment of hypertension in patients with moderate bradycardia, because a further decrease in the heart rate is less pronounced with these drugs

β2-selective antagonist

• Butoxamine :beta 2 antagonist with weak alpha agonist action .

• No clinical use for this drug .

Drugs affecting NA release

1. Reserpine: • Depletes the stores of NE by inhibiting it is

uptake to the vesicles ,• It was used historically to treat hypertension,• Its action is very slow and once started it

persists for many days after discontinuation of treatment .

2. Guanthethidine: • Inhibit the release of NE and also deplete it and

can cause irreversible damage to NA neurons • This drug cause transient hypertension at the

beginning of treatment then hypotension, • Its use for treatment of hypertension is

obsolete.

References

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

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