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) Adrenergic Blocking Drugs 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 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 BP e.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

Intrinsic Sympathomimetic Activity They have ISA Intrinsic 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