Adrenergic Antagonist (Sympatholytics)

Inhibition of sympathetic system by blocking:

Adrenergic receptors (reversible or irreversible blocking of α

or/and β receptors)

Adrenergic neurons (blocking uptake or release)

These drugs competitively inhibit α and β receptor sites. α receptors, α1, α2. One group of drugs is specific for both β1 and β2 receptors. One group is specific for β2 receptors. One group is specific for both α and β receptors.

Adrenergic Blocking Drugs

Adrenergic Receptor Antagonist

α-Blockers:- Non selective: Phenoxybenzamine & Phentolamine

- α1-Blocker: Prazosin, Terazosin, Doxazosin & Tamsulosin

- α2-Blocker: Yohimbine (Sympatholytic ?)

β-Blockers:- Non selective: Propranolol, Timolol & Nadolol

- β1-Blocker: Atenolol, Metoprolol & Esmolol

- β1-Blocker with partial β2 agonist activity: Acebutolol & Pindolol

α & β Blocker: Labetalol & carvidilol

Effects of α-adrenoceptor Antagonists The most important effect is CVS effect

They block α1 receptors causing decrease in peripheral resistance and

consequently BP The resultant hypotension provokes reflex

tachycardia For non selective α-antagonists, the main differences between phenoxybenzamine and phentolamine are:

Phenoxybenzamine is a prodrug that takes few hrs for biotransformation while phentolamine is not a prodrug

Phenoxybenzamine bind covalently (irreversible binding) to α receptors and so the activity last for about 28 hrs. On the other hand, phentolamine is competitive blocker (reversible binding),

so the activity last for 4hr.

– For selective α1 blockers like prazosin (Minipress) and terazosin, they are competitive blocker of α1

receptors causing profound vasodilation and decrease in arterial BP. The hypotensive effect is

more dramatic than non selective. Yohimbine blocks α2 causing increase in

sympathetic flow and so BP. is sometimes used as a sexual stimulant.

Clinical uses of α-adrenoceptor antagonists

Hypertension: α1 selective blockers are more preferred e.g. prazosin. They are used alone or in

combination with other antihypertensive drugs

Phaeochromocytoma: A combination of α- and β- receptor antagonists is the most effective way of

controlling the BPe.g. phenoxybenzamine and atenolol

Flomax (tamsulosin). Used in BPH. Produces smooth muscle relaxation of prostate gland and bladder neck. Minimal orthostatic hypotension.

Priscoline (tolaxoline) used for Pulmonary hypertension in newborn.

Adverse effects of α-adrenoceptor antagonists

1st dose effect: syncope. With alpha 1 blockers, first dose syncope may occur from hypotension. Give low starting dose and at hs.

Postural hypotension

Tachycardia (α1-selective produce less tachycardia because they do not increase NA release from

sympathetic nerve terminal)

Prazosin may cause sodium & water retention, therefore it is frequently used with a diuretic

Orthostatic hypotension dentistry Orthostatic hypotension is a problem with prazosin

analogs and to a lesser extent tamsulosin. Significantly, orthostatsis is a problem that can be seen with any vasodilator that affects the tone on venous smooth muscle.

This would include, organic nitrates, hydralazine, clonidine, minixodil and the many drugs.

Orthostatic hypotension or postural hypotension occurs when systemic arterial blood pressure falls by more than 20 mmHg upon standing.

In this situation, cerebral perfusion falls and an individual may become light headed, dizzy or fatality may occur.

In changing from the supine to the standing position, gravity tends to cause blood to pool in the lower extremities. However, several reflexes, including sympathetically mediated venoconstriction minimize this pooling and maintain cerebral perfusion. If these reflex actions do not occur, then orthostatic hypotension could result.

By blocking the alpha1-receptors associated with venous smooth muscle, prazosin-like drugs, inhibit the sympathetically mediated vasoconstriction associated with postural changes. Hence, orthostatic hypotension can occur.

Drugs like clonidine cause orthostasis due to its CNS actions that block the sympathetic reflexes.

Vasodilators such as nitrates, minoxidil, hydralazine or impotence medications cause orthostasis because of their actions directly on the vasculature.

β-adrenoceptor antagonists They are all competitive blocker, most of them are nonselective or β1 blocking activity (cardioselective)

β-Blockers:- Non selective: Propranolol, Timolol & Nadolol

- β1-Blocker: Acebutolol, Atenolol, Metoprolol & Esmolol

- β1-Blocker with partial β2 agonist activity: Acebutolol & Pindolol

Beside β blocking activity, some blockers may possess one or more of the following properties:

Intrinsic Sympathetic Activity (ISA): i.e. they have the ability to stimulate the occupied receptors, hence

known as partial agonist e.g. pindolol Membrane stabilizing activity: i.e. inhibit

depolarization of excitable membrane (by blocking Na+ channels) and so they have antiarrhythmic and local

anaesthetic action e.g. propranolol

They have ISAIntrinsic Sympathomimetic Activity

Effects of β-adrenoceptor antagonists

Cardiovascular: – Heart:

-ve chronotropic & inotropic (↓CO, O2 consumption & HR)

↓excitability (antiarrhythmic effect) ↓Conductivity (heart block in large dose)

– BV: Block β2 mediated VD No postural hypotension (No α effect) Reflex VC due to ↓CO & BP and so ↓ blood flow to the

periphery– BP: ↓ with no reflex tachycardia

• Reduction in CO• Reduction in renin release

Effects of β-adrenoceptor antagonists

Bronchial smooth muscles:• In asthma & obstructive pulmonary disease, they can cause

severe bronchoconstriction. This danger is less with β1 selective blocker

Metabolism:• Inhibition of glycogenolysis (Caution with insulin treatment?)

• Inhibition of glucagon release• Hypertriglyceridemia & hypercholesterolemia

Decreased production of aqueous humor in eye

May increase VLDL and decrease HDL Diminished portal pressure in clients with

cirrhosis Decreased renin production.

Receptor selectivity

Acetutolol, atenolol, betaxolol, esmolol, and metoprolol are relatively cardioselective

These agents lose cardioselection at higher doses as most organs have both beta 1 and beta 2 receptors.

esmolol is the most rapidly acting, short t ½ (8 minutes), given only IV for management of arrhythmia.

Non-Receptor selectivity

Carteolol, levobunolol, metipranolol, nadolol, propranolol, sotalol and timolol are all non-selective

Can cause bronchoconstriction, peripheral vasoconstriction and interference with glycogenolysis

Combination selectivity

Labetalol and carvedilol (Coreg) block alpha 1 receptors to cause vasodilation and beta 1 and beta 2 receptors which affect heart and lungs

Both alpha and beta properties contribute to antihypertensive effects

May cause less bradycardia but more postural hypotension

Less reflex tachycardia

Intrinsic sympathomimetic activity

Have chemical structure similar to that of catecholamines

Block some beta receptors and stimulate others

Cause less bradycardia Agents include: acebutolol, penbutolol and

pindolol

Clinical Uses of β-adrenoceptor antagonists

Cardiovascular:

• Hypertension: • They are used alone or in combination.

• Mixed α & β blocker, labetalol, is often used in preeclamptic toxaemia (a form of hypertension occurring late in pregnancy)

• Angina pectoris• ↓ Cardiac work & O2 consumption by decreasing rate, BP and contractility

• Chronic management of stable angina (not acute treatment)

• Cardiac arrhythmias

• Following myocardial infarction:• It is preferred to give β-blocker immediately following a myocardial

infarction to reduce infarct size by blocking the action of circulating catecholamines

Useful in pheochromocytoma in conjunction with alpha blockers (counter catecholamine release)

Clinical Uses of β-adrenoceptor antagonists (cont.)

• Glaucoma: Open angel • Particularly timolol, used as eye drops

• ↓ secretion of aqueous humor by the ciliary body• They do not affect the ability of eye to focus for near vision or pupil

size

• Hyperthyroidism : • Preoperatively in thyrotoxicosis by blocking sympathetic

stimulation that occurs in hyperthyroidism, particularly cardiac arrhythmia

• Migraine: • as prophylaxis by blocking catecholamine-induced VD in the brain

vasculature

Specific condtions-beta blockers

With significant bradycardia, may need medication with ISA such as pindolol and penbutolol

Patient with asthma, cardioselectivity is preferred

For MI, start as soon as patient is hemodynamically stable

Special conditions—beta blocers

Should be discontinued gradually. Long term blockade results in increase receptor sensitivity to epinephrine and norepinephrine. Can result in severe hypertension. Taper 1-2 weeks.

Adverse effects of β-adrenoceptor antagonists

Bronchoconstriction

Cardiac failure (large dose), May worsen condition of heart failure as are negative inotropes

Hypoglycemia (with reduced awareness of hypoglycemia in patients receiving insulin)

Physical fatigue (due to reduced cardiac output and reduced muscle perfusion in exercise)

Cold extremities

Adrenergic Neuron Antagonists

They act by:– ↓NA Synthesis e.g. α-methyltyrosine, carbidopa & α-methyldopa

– ↓NA Storage e.g. Resepine

– ↓NA Release e.g.Guanthidine

Inhibitors of NA Synthesis

α-methyltyrosine: – It inhibits tyrosine hydroxylase– Not used clinically

Carbidopa: – It inhibits dopa decarboxylase– Its main use is an adjunct to

treatment of Parkinsonism with L-

dopa

Inhibitors of NA Synthesis

α-methyldopa: It is taken up by noradrenergic neurons, where it is

decarboxylated and hydroxylated to form the false transmitter, α-methyl-nor-adrenaline

The false transmitter is released in the same way as NA but differ in two points:

- It is less active than NA on α1 receptors and thus it is less effective in causing vasoconstriction

- It is more active on presynaptic α2 receptors and so stimulates autoinhibitory feedback mechanism

It is used in treatment of hypertension

Inhibitors of NA Storage

Reserpine a plant alkaloid

It acts by blocking ATP-dependent transport of NA and other amines (e.g. 5-HT & dopamine) into synaptic

vesicles, apparently by binding to the transport protein → depletion of NA from the adrenergic neurons

It induces a gradual decrease in BP with concomitant slowing of heart rate. It has slow onset and longer

duration of action (persist for many days after stopping)

Used for hypertension resistant to other treatment

Inhibitors of NA Release

Guanthidine Overall, the principle action of guanthidine involves

its accumulation by the synaptic vesicles, which are then unable to fuse with the cell membrane in the

normal way, so the exocytosis is prevented i.e. Stop the release

It induce transient increase in BP because guanthidine displace NA in its storage sites

At large doses, it causes structural damage of noradrenergic neurons

It is no longer used clinically