adrenergic blockers

NOTE: Some drugs possess membrane stabilizing action (local anesthetic action) and / or intrinsic sympathomimetic activity of their own on beta receptors.

CLASSIFICATION Non selective blockers: Nadolol, Propranolol, Pindolol, Timolol 1 selective blockers: Atenolol, Acebutolol, Bisoprolol, Esmolol, Metoprolol blockers with additional blocking property: Labetalol, Carvedilol, Celiprolol

Note: Pindolol, Acebutolol, Labetalol, Celiprolol, Carteolol have intrinsic sympathomimetic activity (Partial agonist) ; stimulate receptors partially in the absence of catecholamines Propranolol, Acebutalol, Carvedilol, Labetolol, Metoprolol, Pindolol - have membrane stabilizing activity (Local anaesthetic activity)

PROPRANOLOL (prototype drug) MAO: blockers competitively block the mediated actions of catecholamines and other adrenergic drugs PHARMACOLOGICAL ACTIONS: Heart: 1 heart rate (negative chronotropic) contractility (negative inotropic) Depress SA and AV nodal activity

in conduction velocity (negative dromotropic) in cardiac output in automaticity cardiac work & oxygen requirement In high doses membrane stabilizing effect Blood vessels: Initially PVR due to unopposed 1 action Continued use, resistant vessels adapt to chronically reduced CO (because of effect BP on heart) so that TPR decreases

Respiratory tract: Blockade of 2 receptor

severe bronchospasm Selective 1 blockers are less likely to cause bronchospasm Skeletal muscles: Chronic use skeletal muscle weakness, tiredness ; this is due to blockade of 2 receptors of sk. muscle and the blood vessels supplying it

Metabolic effects: Inhibit glycogenolysis in heart, skeletal muscle and liver (inconsistently) ** Inhibit lipolysis Long term use total TG and LDLcholesterol tend to increase while HDLcholesterol falls Eye: On topical application IOP

PHARMACOKINETICS Propranolol is well absorbed from GIT Bioavailability is low because of extensive first pass effect, hence for better BA propranolol is given with meals 90% bound to plasma proteins Highly lipid soluble, hence cross the BBB Metabolites excreted in urine, mostly as glucuronides Chronic use BA increases HOW?

ADVERSE EFFECTS
CVS: bradycardia, heart block & may precipitate CCF in patients with low cardiac reserve Aggravation of peripheral vascular diseases Exacerbates Prinzmetals angina Respiratory tract: bronchospasm, hence CI in COPD & Asthmatics

 CNS: sleep disturbances, hallucinations, fatigue & depression Metabolic: - hypoglycemia especially in diabetics; may mask the warning symptoms of hypoglycemia - muscular weakness & tiredness Abrupt withdrawal of blockers after chronic use is dangerous, WHY?

Adverse Effects and Contraindications  Precipitates heart failure.  Bradycardia- Heart block.  Worsening of COPD and precipitates asthma.  Precipitates variant angina.  Fatal hypoglycemia in DM.  Increased risk of CAD - o in triglycerides.  Sudden withdrawal- rebound hypertension

DRUG INTERACTIONS
PROPANOLOL X VERAPAMIL - additive cardiac depressant effects PHENYTOIN, RIFAMPIN, PHENOBARBITONE X BLOCKERS - metabolism of blockers PROPRANOLOL X LIGNOCAINE - hepatic blood flow, hence clearance of lignocaine CHOLESTYRAMINE, COLESTIPOL X BLOCKERS - bind to blockers & interfere with their absorption

INSULIN X PROPRANOLOL

Insulin/sufonylureas blood glucose (hypoglycemia) SYMPATHETIC STIMULATION LIVER glycogenolysis HEART tachycardia, palpitation SKELETAL MUSCLE tremors BLOOD VESSEL vasodilatation

 Propranolol and other blockers cause - delayed recovery from hypoglycemia - mask the warning symptoms of hypoglycemia - vasoconstriction and rise in BP due to unopposed 1 action

THERAPEUTIC USES
HYPERTENSION: Useful in all types of HT Preferred in pts. associated with angina, MI, arrhythmias Mechanism Heart ? CNS ? JG cells in the kidney ? Advantages less sodium and water retention, cheaper, long duration of action, well tolerated

ANGINAL PROPHYLAXIS & MI: myocardial oxygen demand how? Improve exercise tolerance & the frequency of anginal episodes Use of blockers early in acute phase of MI may limit the infarct size Long term use - mortality and reinfarction CARDIAC ARRHYTHMIAS: Mainly for atrial arrhythmias

CCF: Benefit results from antagonism of damaging effects of cardiac 1 receptor overactivity which promotes unfavorable remodelling of the myocardium Carvedilol, metoprolol, bisoprolol PHEOCHROMOCYTOMA: Given to control cardiac manifestations Should not be given alone. WHY ? GLAUCOMA: Advantages of using

blockers ?

PROPHYLAXIS OF MIGRAINE: Mechanism of action is not clear

HYPERTHYROIDISM: signs and symptoms of hyperthyroidism Propranolol inhibits the conversion of T4 to T3 ESSENTIAL TREMORS: Propranolol oral ACUTE ANXIETY STATES: Control symptoms

Cardioselectivity:
Selectivity - relative Block cardiac 1 than bronchial 2 Cause less bronchoconstriction Less interference with carbohydrate metabolism and less inhibition of glycogenolysis during hypoglycemia Lipid profile is less worsened, compared to propranolol. Lower incidence of PVD. DISADVANTAGES?

Partial agonistic (intrinsic sympathomimetic) action:

Lesser bradycardia and myocardial depression may be preferred in those prone to severe bradycardia or with low cardiac reserve. Rebound hypertension after withdrawal is less likely as continued agonistic action on receptors (of the drug itself) prevents develop-ment of supersensitivity Lipid profile is less worsened DISADVANTAGES?

ATENOLOL: Selective 1 blocker Has no membrane stabilizing property No central effects because of poor lipid solubility (doesnt cross the BBB) Has longer duration of action hence once daily dosing More potent than propranolol Lipid profile not altered much Uses : HT and angina

ESMOLOL: Administered Intravenously t is about I0 minutes O Has nO Membrane stabilizing property Selective 1 blocker and has a short duration of action Rapidly destroyed by Esterases Used for rapid control of ventricular rate in supraventricular arrhythmias, to reduce BP and Hr during and after cardiac surgery.

e s m=o I0 I

Mixed ( & ) antagonists

LABETOLOL: Competitive blocker at 1 + 2 + weak 2 agonistic activity (ISA) Administered orally or IV

1 with

Inhibits neuronal uptake of NE

 Undergoes extensive first pass metabolism Orally essential hypertension Pheochromocytoma and controlling rebound HT after clonidine withdrawal. Side effects: Postural hypotension and hepatotoxicity

CARVEDILOL: Like labetolol, blocks 1 + 2 + 1 Has antioxidant, antiproliferative, membrane stabilizing (independent action) and vasodilatory properties Has cardio protective effect ; long term use reduces mortality in pts. with CCF Also used in essential HTN

CELIPROLOL: Selective 1 blocker with weak 2 agonistic activity (ISA) Has direct vasodilatory property Bronchodilating property Effective in the treatment of HTN (in asthmatics) and angina