noradrenergic drugs/alpha blockers

8/7/2019 Noradrenergic Drugs/alpha blockers

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Introduction

The adrenergic antagonists (also called blockers orsympatholytic agents) bind to adrenoceptors but do not triggerthe usual receptor-mediated intracellular effects

They are competitive antagonist at & or both & adrenergic receptors and differ in important ways fromadrenergic neurone blocking agents, which act by interferingwith the release of adrenergic neurotransmitter on nervestimulation.


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Alpha-Receptor Antagonist Drugs

These drugs inhibit adrenergic response mediated through the adrenergic receptor without affecting those mediated through receptor.

These drugs act by either reversibly or irreversibly attaching tothe receptor, thus preventing its activation by endogenouscatecholamines.

They are classified as 1, 2-adrenoceptor antagonist drugs andnon equilibrium & equilibrium type.


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classification

I . Non equilibrium typei. - Haloalkylamines- phenoxybenzamine

II . Equilibrium type (competitive)A. Non selectivei. Ergot alkaloids-Ergotamine, ergotoxineii. Hydrogenated ergot alkaloids-Dihydroergotamine (DHE),

dihydroergotoxiniii. I midazolines- Tolazoline, phentolamineiv. Miscellaneous-Chlorpromazine


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C lassification (cont.)

B . 1selective Prazosin Terazosin

Doxazosin Tamsulosin

C. 2 selective yohimbine


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Me chanism of action

-receptor antagonists may be reversible or irreversible in theirinteraction with these receptors .

Reversible antagonists can dissociate from receptors & theblock can be surmounted with sufficiently high concentration ofagonist.

Whereas irreversible antagonists cannot be dissociated andcannot be surmounted.


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Me chanism of action (cont.)

The duration of action of a reversible antagonist is largelydependent on the half-life of the drug in the body and the rateat which it dissociates from its receptor.

The shorter the half-life of the drug in the body, the less timeit takes for the effects of the drug to dissipate .

I n contrast, the effects of an irreversible antagonist maypersist long after the drug has been cleared from the plasma


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G e n e ral pharmacologic e ff e ctsof -block e rs

-receptor antagonist drugs cause a lowering of peripheralvascular resistance and blood pressure.

These drugs can prevent the pressor effects of usual doses ofagonists.

Alpha-receptor antagonists often cause orthostatic hypotensionand reflex tachycardia.

Non selective blockers usually cause significant tachycardia ifblood pressure is lowered below normal.

blockers can inhibit ejaculation


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Tachycardia may be more marked with agents that block 2-presynaptic receptors in the heart, since the augmented releaseof norepinephrine will further stimulate receptors in theheart.

Blockade of receptors in other tissues elicits miosis (smallpupils) and nasal stuffiness.

Alpha1 receptors are expressed in the base of the bladder andthe prostate, and their blockade decreases resistance to theflow of urine .

Alpha blockers, therefore, are used therapeutically for the

treatment of urinary retention due to prostatic hyperplasia.


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Sp ecific Agents


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P h e noxyb e nzamin e

I t is more selective to 1 receptor.

I t binds covalently to receptors, causing irreversible blockadeof long duration (1448 hours or longer).

I t inhibits the reuptake of released norepinephrine bypresynaptic adrenergic nerve terminals.

blocks histamine (H1), acetylcholine, and serotonin receptors aswell as -receptors.


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pharmacologic actionspharmacologic actions: The fall in BP caused by phenoxybenzamine is mainly posturalbecause venodilation is more prominent than arteriolardilation.

Cardiac output may be increased because of reflex effects& the blocking of some presynaptic 2 receptors in cardiacsympathetic nerves.I t is lipid soluble & penetrates brain and can produce CNSstimulation ,nausea & vomiting on rapid i.v. injection .

Therapeutic uses:Therapeutic uses: Used in pheochromocytoma


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Pharmacokinetics:Pharmacokinetics: Oral absorption is erratic & incomplete i.m. & s.c. injections are very painful Most of the administered dose is excreted in urine in 24hrs. Chronic administration of phenoxybenzamine leads toaccumulation of in adipose tissue.

Dose:Dose: 20-60 mg/day oral 1 mg/kg by slow i.v. infusion over 1 hour

Adverse effects:Adverse effects: Postural hypotension ,palpitation, nasal blocking, miosis,inhibition of ejaculation


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P h e ntolamin eP h e ntolamin e

I t equally blocks 1 & 2 adrenergic receptor.

Rapidly acting with short duration of action.

I t reduces peripheral resistance through blockade of 1receptors and possibly 2 receptors on vascular smooth muscle.

I t has minor inhibitory effects at serotonin receptors .

Phentolamine has agonist effects at muscarinic and H1 and H2histamine receptors .

Release of histamine.


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I t stimulates the G I T smooth muscles

Use:Use: treatment of pheochromocytoma control of hypertension due to clonidine withdrawal

Adverse effects:Adverse effects: severe tachycardia, arrhythmias, andmyocardial ischemia.

Dose:Dose: 5 mg i.v.


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prazosin

Highly selective 1blocker.I t blocks sympathetically mediated vasoconstriction & producesfall in BP which is attended only in mild tachycardia.

Prazosin relaxes both arterial and venous vascular smoothmuscle

Pharmacokinetics:Pharmacokinetics:I t is extensively metabolized in humans Highly bound to plasma proteins Excreted in bile

Plasma half life is about 3 hoursBioavailability is between 50-60%

UsesUses: antihypertensive, Raynauds disease, prostatichypertrophy


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T e razosin

reversible 1-selective antagonist.

Terazosin has high bioavailability[90%]

I t is extensively metabolized in the liver.

The half-life of terazosin is 912 hours.

I t is used in benign prostatic hyperplasia ( BPH).


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D oxazosin

Long acting, plasma half life is about 22 hours

Extensively metabolized in the liver.

Used in hypertension & BHP.

Dose: 1 mg OD initially ,increases up to 8 mg BD


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T amsulosin

I t is a competitive 1antagonist. Tamsulosin has higher affinity for 1A and 1D receptors than for

the 1B subtype .

I t has a high bioavailability & is extensively metabolized in theliver . Tamsulosin has greater potency in inhibiting contraction in

prostate smooth muscle. Tamsulosin has less effect on standing blood pressure .


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AlfuzosinAlfuzosin : it is 1selective quinazoline derivative that is used in

the treatment of BHPI t has a bioavailability of about 60% & has an elimination half-life of about 5 hours.I ndoraminI ndoramin: it is another 1-selective antagonist that also hasefficacy as an antihypertensive.

YohimbineYohimbine: I t is an indole alkaloid, is an 2-selective antagonist.I t is in the treatment of orthostatic hypotension.

Yohimbine can reverse the antihypertensive effects of an 2-adrenoceptor agonist such as clonidine .


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C linical us e of alpha block e rs

Ph eoc h romocytomaPh eoc h romocytoma ::

Pheochromocytoma is a tumor of the adrenal medulla orsympathetic ganglion cells.

The tumor secretes catecholamines, especially norepinephrineand epinephrine.

There is elevated plasma and urinary norepinephrine,epinephrine, and their metabolites, normetanephrine andmetanephrine.

Alpha-receptor antagonists are most useful in the preoperativemanagement of patients with pheochromocytoma.


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Administration of phenoxybenzamine will help controlhypertension and will tend to reverse chronic changes resultingfrom excessive catecholamine secretion in the preoperativeperiod.

I f the effect of phenoxybenzamine is not as expected ,it will beable to simplify the operative course.

Phenoxybenzamine can be very useful in the chronic treatmentof inoperable or metastatic pheochromocytoma


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H y p ertensive Emergencies:H y p ertensive Emergencies:

Alpha blockers have limited application in the management of

hypertensive emergencies labetalol used in the management of hypertension

P eri p h eral Vascular Disease:P eri p h eral Vascular Disease:

prazosin & phenoxybenzamine are used in the treatment of

peripheral vascular occlusive disease like Raynaud's disease.

Urinary Obstruction:Urinary Obstruction:

Prazosin, doxazosin, and terazosin are all efficacious in patientswith BPH

These drugs are useful in patients who also have hypertension. The mechanism of action is by partial reversal of smooth muscle

contraction in the enlarged prostate and in the bladder base.


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Erectile Dysfunction:Erectile Dysfunction:

A combination of phentolamine with the nonspecific smoothmuscle relaxant papaverine, when injected directly into thepenis, may cause erections in men with sexual dysfunction .

Systemic absorption may lead to orthostatic hypotension .

Long term administration may result in fibrotic reaction.


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Adverse effects

Orthostatic hypotension

Reflex tachycardia

Hypotension

Nasal stuffiness

Diarrhoea increased intestinal mobility

Reduced renal blood flow


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A pplications of A lpha2 A ntagonists

2 antagonists have relatively little clinical usefulness They have limited benefit in male erectile dysfunction


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T h ank you

noradrenergic drugs/alpha blockers

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