Non-catecholamines

• Therapeutic uses & effects on the body; • local or systemic constriction of blood vessels () nasal and eye decongestion • dilation of the bronchioles (, , , isoproterenol, levalbuterol, , , and ) • smooth-muscle relaxation (terbutaline). Absorption and distribution

• Absorption of the non-catecholamines depends on the administration route: • Inhaled drugs, such as salbutamol, are absorbed gradually from the bronchi and result in lower drug levels in the body. • Oral drugs are absorbed well from the GI tract and are distributed widely in body fluids and tissues. • Some non-catecholamines, such as ephedrine, cross the blood-brain barrier and can be found in high concentrations in the brain and cerebrospinal fluid • Metabolism • Non-catecholamines are metabolized and inactivated primarily in the liver but also in the lungs, GI tract, and other tissues. Excretion

• Non-catecholamines and their metabolites are excreted primarily in urine. • Some, such as inhaled Salbutamol, are excreted within 24 hours; others, such as oral salbutamol, within 3 days. • Acidic urine increases excretion of many non- catecholamines • alkaline urine slows excretion. Pharmacodynamics

• Non-catecholamines can be: • direct-acting • indirect-acting, or • dual-acting **catecholamines, are primarily direct-acting. • Direct-acting non-catecholamines that stimulate alpha receptors include phenylephrine.

• Those that selectively stimulate beta2 receptors include salbutamol and terbutaline. • Dual-acting non-catecholamines include ephedrine. Pharmacotherapeutics

• Non-catecholamines stimulate the sympathetic nervous system • Phenylephrine, causes vasoconstriction and is used to treat hypotension in cases of severe shock, nasal congestion • Terbutaline is used in asthma & stop preterm labor. Adverse reactions to non- catecholamines

• headache • restlessness • anxiety or euphoria • irritability • trembling • drowsiness or insomnia • light-headedness • incoherence • seizures • hypertension • palpitations • tachycardia • irregular heart rhythm • cardiac arrest • cerebral hemorrhage • tingling or coldness in the arms or legs • pallor or flushing • angina. blocking drugs

• Adrenergic blocking drugs = sympatholytic drugs, • are used to disrupt sympathetic nervous system function. • work by blocking impulse transmission (block sympathetic nervous system stimulation) at adrenergic neurons or sites. • Their action at these sites can be exerted by: • interrupting the action of adrenergic (sympathomimetic) drugs • reducing available • preventing the action of cholinergic drugs. • Adrenergic blocking drugs are classified according to their site of action as: – alpha-adrenergic blockers- alpha blockers – beta-adrenergic blockers - beta blockers. Alpha-adrenergic blockers

• Alpha-adrenergic blockers work by interrupting the actions of the catecholamines epinephrine and norepinephrine at alpha receptors. • This results in: – relaxation of the smooth muscle in blood vessels – increased dilation of blood vessels – decreased blood pressure. Alpha-adrenergic blockers include:

• • • • , , and • . ** is a mixed alpha agonist and antagonist; at high doses, it acts as an alpha- adrenergic blocker. Pharmacodynamics

• Alpha-adrenergic blockers work in one of two ways: • They interfere with or block the synthesis, storage, release, and reuptake of norepinephrine by neurons. • They antagonize epinephrine, norepinephrine, or adrenergic (sympathomimetic) drugs at alpha receptor sites. • Alpha-adrenergic blockers include drugs that block stimulation of alpha1 receptors and that may block alpha2 receptors. • Alpha-adrenergic blockers occupy alpha receptor sites on the smooth muscle of blood vessels.

• This prevents catecholamines from occupying and stimulating the receptor sites.

• As a result, blood vessels dilate, increasing local blood flow to the skin and other organs.

• The decreased peripheral vascular resistance (resistance to blood flow) helps to decrease blood pressure. • Dilation of blood vessels can cause orthostatic hypotension, a drop in blood pressure that occurs when changing position from lying down to standing. • Redistribution of blood to the dilated blood vessels of the legs causes the hypotension. • The therapeutic effect of an alpha-adrenergic blocker depends on the sympathetic tone (the state of partial constriction of blood vessels) in the body before the drug is administered.

• For instance, when the drug is given with the patient lying down, only a small change in blood pressure occurs. In this position, the sympathetic nerves release very little norepinephrine. • On the other hand, when a patient stands up, norepinephrine is released to constrict the veins and shoot blood back up to the heart. • If the patient receives an alpha-adrenergic blocker, however, the veins can’t constrict and blood pools in the legs. • Because blood return to the heart is reduced, blood pressure drops.

**drop in blood pressure that occurs when a person stands up is called orthostatic hypotension. • alpha-adrenergic blockers cause; – smooth muscles to relax – blood vessels to dilate – they increase local blood flow to the skin – they increase local blood flow to other organs – reduce blood pressure. used to treat: • benign prostatic hypertrophy • hypertension • peripheral vascular disorders (diseases of the blood vessels of the extremities) - especially those in which blood vessel spasm causes poor local blood flow e.g. - Raynaud’s disease (intermittent pallor, cyanosis, or redness of fingers), acrocyanosis (symmetrical mottled cyanosis of the hands and feet), and frostbite • pheochromocytoma (a catecholamine-secreting tumor that causes severe hypertension). Drug interactions

• Many drugs interact with alpha-adrenergic blockers, producing a synergistic, or exaggerated, effect. • The most serious interactions are severe hypotension and vascular collapse. • These interactions can occur when these drugs are taken with ergotamine: • Caffeine and macrolide antibiotics can increase the effects of ergotamine. Drug interactions ..c’td

• increases the pressor (rising blood pressure) effect. • Nitroglycerin can produce hypotension from excessive dilation of blood vessels. • Sympathomimetics, including many over-the- counter drugs, can increase the stimulating effects on the heart, possibly resulting in hypotension with rebound hypertension Adverse reactions to alpha-adrenergic blockers • Most adverse reactions are caused primarily by dilation of the blood vessels. – orthostatic hypotension or severe rebound hypertension – bradycardia or tachycardia – edema – difficulty breathing – light-headedness – flushing – arrhythmias – angina – heart attack – spasm of blood vessels in the brain Beta-adrenergic blockers

• The most widely used adrenergic blockers • prevent stimulation of the sympathetic nervous system by inhibiting the action of catecholamines at beta-adrenergic receptors. • Beta-adrenergic blockers can be; – selective or – nonselective.

• Nonselective beta-adrenergic blockers affect:

– beta1 receptor sites (located mainly in the heart)

– beta2 receptor sites (located in the bronchi, blood vessels, and uterus). Nonselective beta-adrenergic blockers include – – – – – Metipranolol – – – – – – . – Carvedilol and – Labetalol

• also block alpha1 receptors • Selective beta-adrenergic blockers primarily affect beta1-adrenergic sites. • They include; – – – – – Esmolol – . • Some beta-adrenergic blockers, such as – pindolol and – Acebutolol • have intrinsic sympathetic activity. • This means that instead of attaching to beta receptors and blocking them, they attach to beta receptors and stimulate them. • These drugs are sometimes classified as partial agonists. • Beta-adrenergic blockers are usually absorbed rapidly and well from the GI tract and are somewhat protein-bound. • Food doesn’t inhibit their absorption and may even enhance their absorption • Beta-adrenergic blockers are distributed widely in body tissues, with the highest concentrations found in the: – heart – liver – lungs – saliva. • Except for nadolol and atenolol, beta- adrenergic blockers are metabolized in the liver. • They’re excreted primarily in urine, either unchanged or as metabolites, but can also be excreted in feces, bile and, to some degree, breast milk. • Beta-adrenergic blockers have widespread effects in the body because they produce their blocking action not only at adrenergic nerve endings but also in the adrenal medulla. Effects on the CVS include:

– increased peripheral vascular resistance – decreased blood pressure – decreased force of the heart’s contractions – decreased oxygen consumption by the heart, – slowed impulse conduction between the atria and ventricles, and – decreased cardiac output How beta-adrenergic blockers work

• By occupying beta receptor sites, beta- adrenergic blockers prevent catecholamines (norepinephrine and epinephrine) from occupying these sites to exert their stimulating effects. • Selective beta-adrenergic blockers, which prefer to block beta1-receptor sites, reduce stimulation of the heart. • referred to as cardioselective beta-adrenergic blockers. • Non-selective beta-adrenergic blockers, which block both beta1- and beta2-receptor sites, – reduce stimulation of the heart – cause the bronchioles to constrict. • nonselective beta-adrenergic blockers can cause bronchospasm in patients with chronic obstructive lung disease.

**This adverse effect isn’t seen when cardioselective drugs are given at lower doses. • Beta-adrenergic blockers can be prescribed after a heart attack to prevent another heart attack or to treat: – angina – heart failure – hypertension – cardiomyopathy – supraventricular arrhythmias • Use of beta-adrenergic blockers after a heart attack reduces the risk of death and another heart attack. However, these drugs aren’t being prescribed for elderly patients. • One study found that only 34% of patients were prescribed a beta-adrenergic blocker after discharge from the hospital following a heart attack. • Many clinicians fear the adverse effects these drugs may produce in older patients. • However, beta-adrenergic blockers are safe for elderly heart attack patients if the lowest effective dose of a selective beta-adrenergic blocker is prescribed. Beta-adrenergic blockers are also used to treat: • anxiety • cardiovascular symptoms associated with thyrotoxicosis • essential tremor • migraine headaches • • pheochromocytoma Adverse reactions to beta-adrenergic blockers • Beta-adrenergic blockers generally cause few adverse reactions; those that do occur are drug- or dose-dependent Adverse reactions to beta-adrenergic blockers include: • hypotension • bradycardia • peripheral vascular insufficiency • atrioventricular block • heart failure • fatigue • bronchospasm • diarrhea or constipation • nausea and vomiting • abdominal discomfort • anorexia • flatulence • rash • fever with sore throat • spasm of the larynx • respiratory distress