adrenergic drugs

Antiadrenergic Drugs:

Antiadrenergic Drugs Adrenergic Receptor Antagonists Department of Pharmacology NEIGRIHMS, Shillong

Introduction:

Introduction Drugs employed to antagonize the actions of Endogenous Catecholamine (NA and Adr) Since catecholamine play a role in a variety of physiologic and pathophysiologic responses, drugs that block adrenoceptors have important effects, some of which are of great clinical value They occupy adrenergic receptors (alpha and beta) but do not produce signal transduction – Affinity is there but without IA Clinically 2 (two) distinct groups – alpha blockers and beta blockers

Contd.:

Contd. For pharmacologic research, alpha -1 and alpha-2 adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic nervous system function Effects vary according to the drug's selectivity for and receptors In clinical therapeutics, nonselective antagonists have been used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and alpha-1 selective antagonists are used in primary hypertension and benign prostatic hyperplasia (BHP) Beta-receptor antagonist - much wider variety of clinical conditions: hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other conditions Blockade of peripheral dopamine receptors is of no recognized clinical importance at present In contrast, blockade of central nervous system dopamine receptors is very important – Antiemetic, Antipsychotic and TCAs

Drugs – Classification:

Drugs – Classification Nonselective: Ergots: Ergotamine and Ergotoxine Betahaloalkylamines: Phenoxybenzamine Hydrogenated ergot alkaloids: DHE, Dihydroergotoxine Imidazolines: Tolzoline, Phentolamine Miscellaneous: Chlorpromazine, Histamine and Serotonin Selective: Alpha-1: Prazosin, Terazosin, Doxzosin and Tmsulosin Aplha-2: Yohimbine

General Effects of alpha Blockade - CVS:

General Effects of alpha Blockade - CVS Arteriolar and venous tone are determined to a large extent by receptors on vascular smooth muscle Blockade of alpha receptor may cause – pooling of blood in capacitance vessels – reduced venous return and Cardiac output – fall in mean BP Reflex tachycardia: VMC and alpha-2 mediated Pressor effects of Adr is not found - Vasomotor reversal of Dale Postural hypotension: Because of inability to contract veins and restore venomotor tone and also inability to contract arterioles in the legs

Effects of alpha Blockade - Others:

Effects of alpha Blockade - Others Nasal stuffiness and Miosis Sodium retention and increased blood volume – because of reduced GFR Tone of the Bladder trigone, sphincter and prostate is maintained by alpha-1(α1A) sympathetic Blockade produces increased urine flow Inhibition of Ejaculation Increased Intestinal Motility

Individual Agents - Phenoxybenzamine:

Individual Agents - Phenoxybenzamine Non specific, long acting irreversible alpha antagonist MOA: Spontaneously cyclizes in the body to give ethyleniminium intermediate – forms a strong covalent bond with alpha receptors – blockade of alpha receptor (lasts for 3 – 4 days) Blockade occurs in cysteine position Experimental Studies: (Isolated preparations) Shows equilibrium type of DRC – no change in V max till presence of spare receptors Higher doses – non equilibrium type of DRC But Clinically: Tachycardia – alpha-2 blockade Postural fall in BP – because of venodilatation predominates over arteriolar dilatation CNS stimulation – nausea, vomiting on IV injection but oral doses cause depression, tiredness and lethargy

Phenoxybenzamine:

Phenoxybenzamine Pharmacokinetics: Erratic oral absorption and painful on IM or SC injections Most of the administered drug Excretes in urine Small amount may remain in tissue bound covalently – leading to accumulation in adipose tissue Uses: Phechromocytoma Secondary shock Peripheral vascular disease Preparation and dosage: 20-60 mg orally 1 mg/kg IV infusion for 1 Hr.

Phentolamine:

Phentolamine Non specific, short acting reversible alpha antagonist Potent competitive antagonist at both 1 and 2 receptors Quick acting (in minutes) Reduction in Peripheral Resistance - blocking both 1 and 2 receptors - Causes NA release and venodilatation more than arteriolar Cardiac stimulation: Enhanced NA release due to alpha-2 blockade Inhibits serotonin release – muscarinic agonist (?) Uses: Pheochromocytoma, clonidine withdrawal, cheese reaction and in extravasations of NA and Adr injection Dose: 5 mg IV injection

Prazosin:

Prazosin Highly selective alpha-1 blocker Non-specific blockade of all subtypes - α1A, α1B and α1D Blockade of sympathetic vasoconstriction NA is not released as α2 is not blocked Dilates arterioles more than veins – Postural hypotension is less – only 1 st dose effect Also inhibits PDE – rise in cAMP - vasodilatation Kinetics: effective orally (70%), metabolized in liver and half life is 6-8 Hrs Uses: Hypertension Raynaud`s disease BHP Dose: start with 0.5 mg bed time and then 1-4 mg tds.

Other alpha Blockers:

Other alpha Blockers Terazosin: Similar to Prazosin but better bioavailability (90%) Duration of action is longer – 24 Hrs Preferred in BHP – single dose and apoptosis Similar is Doxazosin Tamsulosin: Uroselective - α1A and α1D but not α1B No change in BP and HR at therapeutic doses Preferred drug in BHP Only once dosing regime (MR caps) ADRs: Retrograde ejaculation and dizziness

Comparison of alpha blockers:

Comparison of alpha blockers Receptor affinity

Uses of α-blockers:

Uses of α-blockers Pheochromocytoma: Tumor of medullary cells of Adrenals VMA estimation is diagnostic Phentolamine test: Injection of 5mg IV over 1 minute 35 mm (Systolic) and 25 mm (Diastolic) of Hg Treatment: Surgery Phenoxybenzamine in preoperatively and intra-operative because: To Normalize blood volume: Excess CA shifts blood from vascular to extra vascular To prevent outpouring of CA during surgery To prevent unwanted hypotension due to dilatation of blood vessels following removal of tumor (Previously - Clonidine suppression test – Measurement of plasma CA levels)

Uses of α-blockers – contd.:

Uses of α-blockers – contd. Hypertension: Not useful except Prazosin due to Compensated cardiac stimulation Postural hypotension, Impotence, nasal blockage etc. Phentolamine and Phenoxybenzamine – in clonidine withdrawal and cheese reaction BHP: Static component: Tone of Prostate and bladder neck (alpha-1 mediated) Dynamic component: Size of prostate (5-alpha reductase) Converts testosterone to active dihydrotestosterone) Effects of alpha blocking – relaxation of neck and prostate structures – reduction in obstruction 5-alpha reductase inhibitors like Finesteride decreases size of the prostate – better voiding Alpha blockers – 2 weeks and 5-alpha reductase inhibitors – 6 months Remember – BHP is a progressive disease

BHP Images:

BHP Images

Beta Adrenergic Blockers:

Beta Adrenergic Blockers Cardioselective: Metoprolol, atenolol, acebutalol, bisoprolol, esmolol, betaxolol, celiprolol, nebivolol Nonselective (beta-1 and beta-2): Without intrinsic sympathomimetic activity: Propranolol (membrane stabilizing action), Sotalol, Timolol With intrinsic sympathomimetic activity: Pindolol Additional alpha blocking property: Labetolol, Carvedilol and Celiprolol

Intrinsic sympathomimetic activity?:

Intrinsic sympathomimetic activity? Some beta-blockers posses beta-receptor stimulating property – partial agonist Likely to cause less myocardial depression and less precipitation of CCF in damaged heart – preferred in severe bradycardia and elderly patients Favourable withdrawal Pindolol and oxprenolol may not impair A-V conduction Pharmacological actions of beta blocking effects are at lower concentrations – others are at higher doses

Pharmacokinetics (Propranolol as prototype) - absorption:

Pharmacokinetics (Propranolol as prototype) - absorption Most of the drugs are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion including propranolol Sustained-release preparations of propranolol and metoprolol are available Propranolol undergoes extensive hepatic (first-pass) metabolism But, proportion of drug reaching the systemic circulation increases as the dose is increased – saturation of hepatic extraction mechanism High oral : Parenteral route bioavailability difference Interindividiual and equieffective dose bioavailability variation

Pharmacokinetics - Distribution:

Pharmacokinetics - Distribution All are rapidly distributed and have large volumes of distribution Propranolol is lipophillic and crosses BBB Half life ranges from 3-10 Hrs (esmolol 10 min) Propranolol and metoprolol are extensively metabolized in the liver – little unchanged excretion Cytochrome P450 2D6 (CYP2D6) genotype is a major determinant of interindividual differences in metoprolol plasma clearance Atenolol, celiprolol, and pindolol are less completely metabolized Nadolol is excreted unchanged in the urine and has the longest half-life of any available antagonist (up to 24 hours) Propranolol elimination may vary in liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition Pharmacodynamic effects often prolonged beyond half-life

Actions - Propranolol:

Actions - Propranolol Heart: Decrease in Heart rate, Decrease in cardiac output, Decrease in force of contraction Prolongs systole Not prominent in Normal persons, but in presence of sympathetic over activity (exercise, emotion) Decreased ventricular size Cardiac work and oxygen consumption are reduced Total coronary flow reduction – subepicardial region but not subendocardial region – benefit in angina Abbreviate Refractory period, reduces automaticity, delayed AV conduction At high doses membrane stabilizing and direct depressant action

Propranolol – contd.:

Propranolol – contd. Blood Pressure: No direct and acute action on Blood Pressure But beneficial in hypertensives on prolonged administration Normally, propranolol would block CA induced vasodilatation and cause increase in TPR and decrease in cardiac output – but negligible change in BP ADAPTATION: But chronic exposure will lead the resistance vessels to adapt to chronically low CO – TPR falls (Most possible explanation of antihypertensive effect) Other explanations may be: Decreased Renin release (beta-1) Central reduction of sympathetic outflow

Re-reversal of Vasomotor reversal:

Re-reversal of Vasomotor reversal

Actions - Propranolol:

Actions - Propranolol Respiratory: Bronchoconstriction due to blockade of dilator beta-2 receptors Not considerable in normal individual - May be dangerous in presence of asthma (avoid) Beta-1 selective drugs are preferred Contrary: COPD patients tolerate Eye: Decreases IOP by reducing production of aqueous humor – glaucoma CNS: No considerable CNS effect except – behavioural, forgetfulness and nightmare etc. Skeletal Muscle: Reduction of Tremor Reduction of exercise capacity: reduction in blood flow, glycogenolysis and lipolysis

Propranolol Actions – contd. :

Propranolol Actions – contd. Propranolol inhibits sympathetic nervous system stimulation of lipolysis Inhibition of glycogenolysis – beta-2 mediated Uncertain response to hypoglycaemia But, Glucagon is the main hormone that responses to hypoglycaemia Still, beta blockers should be used in caution in patients with diabetes and low glucagon reserve patients and in pancreatectomized patients Beta-1 selective are much safer Increased plasma concentrations of VLDL and decreased concentrations of HDL cholesterol – unfavourable in terms of risk in hypertension

Propranolol Actions – unrelated to beta blockade:

Propranolol Actions – unrelated to beta blockade Intrinsic sympathomimetic activity: May be useful in asthma to prevent precipitation of attack To prevent excess bradycardia Membrane stabilizing effect: like lidocaine Local anaesthetic action Typically blocks Na+ channel

Drug Interactions:

Drug Interactions Propranolol and insulin: Belayed recovery of hypoglycemia by insulin Warning signs are supressed Propranolol + alpha agonists: Rise in BP NSAIDs + Propranolol: Attenuation of antihypertensive action of beta-blockers

Propranolol - ADRs:

Propranolol - ADRs Precipitation of CCF/Oedema Bradycardia Risk of Coronary Heart Disease (VLDL and HDL) Respiratory: Precipitation of asthma and COPD Variant angina exacerbation – unopposed coraonary constriction by alpha receptor Tiredness and reduced exercise capacity Col hands and feet – worsening of Peripheral vascular disease Others: GIT upset, nightmare, forgetfulness and sexual distress

Uses of Beta Blockers:

Uses of Beta Blockers Hypertension: 1 st line of agent (JNC7) Angina pectoris Myocardia infarction: Prevent reinfarction Prevent ventricular fibrillation Myocardial salvage: reduction in infarct size Cardiac arrhythmias: Class II type of agent Congestive Heart failure Hyperthyroidism Migraine Anxiety: social phobia Essential Tremor Glaucoma

Other Beta Blockers:

Other Beta Blockers Metoprolol: Prototype of cardioselective blockers Safe in patients with bronchoconstriction after propranolol Less first pass metabolism Slow and fast hydroxylators Used: In Diabetics and OPHs cold hands and feets with Propranolol Also in MI Patients Available as tab – 25/50/100/ mg and IV injection Atenolol: Selective beta-1 and low lipid solubility Longer duration of action – once daily dosing No lipid profile adverse effects

Other Beta Blockers:

Other Beta Blockers Partial beta-agonist: Pindolol, acebutalol, celiprolol, carteolol, bopindolol, oxprenolol, and penbutolol: Major CVS applications – less plasma lipid action and bradycardia Intrinsic sympathomimetic activity However, doubtful clinical benefit Esmolol: Ultra short acting (less than 10 minutes) Steady dose can be maintained Given as IV infusion in SVT, AF, Atrial flutter, arrhythmia during anaesthesia etc. Available as injections IV: 100 – 500 mg/10 ml inj.

Other Beta Blockers:

Other Beta Blockers Celiprolol: Selective beta-1 with additional beta-2 agonistic activity Safe in asthmatics Causes vasodilatation by NO producation Dose: 200-600 mg Nebivolol: Highly selective beta-1 blocker Acts as NO donor Improves endothelial function and delay of atheroschlerosis In CHF Dose: 2.5/5 mg Carvedilol: Beta-1, beta-2 and alpha-1 blocker and also Ca+ channel block Specially preferred in CHF as cardioprotective

Summary:

Summary Drugs acting as antagonist of Adrenergic receptors are very important class of Drugs in clinical practice Beta adrenergic antagonists are very much clinically relevant and used in day to day life, particularly in Cardiovascular Diseases Understanding of basic mechanism of these drugs in these diseases is of utmost importance Usefulness and actions of Beta blockers shall be discussed again in relation to their use when we discuss individual CVS diseases Presently, please remember: Name of some beta blockers as per classification given Pharmacological actions and MOA of Propranolol as discussed Overall therapeutic uses of beta-blockers

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