This document discusses antiadrenergic drugs, also known as sympatholytics, which antagonize the receptor action of adrenaline. It focuses on alpha and beta adrenergic receptor antagonists. Alpha blockers such as prazosin and terazosin are used to treat hypertension and benign prostatic hyperplasia by reducing peripheral resistance. Beta blockers such as propranolol antagonize adrenergic responses mediated through beta receptors, reducing heart rate, contractility and cardiac output. They are used to treat cardiovascular conditions like hypertension, congestive heart failure and arrhythmias. The document provides details on the mechanism of action, pharmacokinetics and clinical uses of various alpha and beta adrenergic
This document discusses antiadrenergic drugs, also known as sympatholytics, which antagonize the receptor action of adrenaline. It focuses on alpha and beta adrenergic receptor antagonists. Alpha blockers such as prazosin and terazosin are used to treat hypertension and benign prostatic hyperplasia by reducing peripheral resistance. Beta blockers such as propranolol antagonize adrenergic responses mediated through beta receptors, reducing heart rate, contractility and cardiac output. They are used to treat cardiovascular conditions like hypertension, congestive heart failure and arrhythmias. The document provides details on the mechanism of action, pharmacokinetics and clinical uses of various alpha and beta adrenergic
This document discusses antiadrenergic drugs, also known as sympatholytics, which antagonize the receptor action of adrenaline. It focuses on alpha and beta adrenergic receptor antagonists. Alpha blockers such as prazosin and terazosin are used to treat hypertension and benign prostatic hyperplasia by reducing peripheral resistance. Beta blockers such as propranolol antagonize adrenergic responses mediated through beta receptors, reducing heart rate, contractility and cardiac output. They are used to treat cardiovascular conditions like hypertension, congestive heart failure and arrhythmias. The document provides details on the mechanism of action, pharmacokinetics and clinical uses of various alpha and beta adrenergic
This document discusses antiadrenergic drugs, also known as sympatholytics, which antagonize the receptor action of adrenaline. It focuses on alpha and beta adrenergic receptor antagonists. Alpha blockers such as prazosin and terazosin are used to treat hypertension and benign prostatic hyperplasia by reducing peripheral resistance. Beta blockers such as propranolol antagonize adrenergic responses mediated through beta receptors, reducing heart rate, contractility and cardiac output. They are used to treat cardiovascular conditions like hypertension, congestive heart failure and arrhythmias. The document provides details on the mechanism of action, pharmacokinetics and clinical uses of various alpha and beta adrenergic
Sympatholytics These are drugs which antagonize the receptor action of adrenaline and related drugs.
They are competitive antagonists at α or β or both
α and β adrenergic receptors α ADRENERGIC BLOCKING DRUGS - I. Nonequilibrium type (i) β-Haloalkylamines—Phenoxybenzamine. II. Equilibrium type (competitive) A. Nonselective (i) Ergot alkaloids—Ergotamine, Ergotoxine (ii) Hydrogenated ergot alkaloids— Dihydroergotamine (DHE), Dihydroergotoxine (iii) Imidazoline—Phentolamine (iv) Miscellaneous–Chlorpromazine Cont… B. α1 selective—Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin C. α2 selective—Yohimbine GENERAL EFFECTS OF α BLOCKERS 1. Blockade of vasoconstrictor α1 (also α2) receptors reduces peripheral resistance
venous return and cardiac output are reduced
fall in BP.
Postural hypotension
dizziness and syncope.
Cont… The α blockers abolish the pressor action of Adr which then produces only fall in BP due to β2 mediated vasodilatation.(vasomotor reversal of Dale). 2. Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA due to blockade of presynaptic α2 receptors. 3. Nasal stuffiness and miosis result from blockade of α receptors. 4. Intestinal motility is increased Cont… 5. Hypotension produced by α blockers can reduce renal blood flow → g.f.r. is reduced 6. Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α1 receptors, urine flow in patients increases. 7. Contractions of vas deferens and related organs which result in ejaculation are coordinated through α receptors—α blockers can inhibit ejaculation. The α blockers have no effect on adrenergic cardiac stimulation, bronchodilatation, vasodilatation Phenoxybenzamine The α blockade is of nonequilibrium (irreversible) type and develops gradually, lasts for 3–4 days till fresh receptors are synthesized. The fall in BP caused by phenoxybenzamine is mainly postural because venodilatation is more prominent than arteriolar dilatation. Pharmacokinetics: Phenoxybenzamine Oral absorption is incomplete; i.m. and s.c. injections are very painful It is lipid soluble, penetrates brain, most of it is excreted in urine in 24 hours,. Chronic administration leads to accumulation in adipose tissue. Adverse effects: Phenoxybenzamine is lipid soluble, penetrates brain and Rapid i.v. injection can produce CNS stimulation, nausea and vomiting on. Oral doses produce depression, tiredness and lethargy. Major side effects are postural hypotension, palpitation, nasal blockage, miosis, inhibition of ejaculation. Dose: 20–60 mg/day oral; Natural and hydrogenated ergot alkaloids Ergot alkaloids are the adrenergic antagonists with which Dale demonstrated the vasomotor reversal phenomenon. The amino acid alkaloids ergotamine and ergotoxine are partial agonists and antagonists at α adrenergic, serotonergic and dopaminergic receptors. Ergometrine has no α blocking activity. The natural ergot alkaloids produce long lasting vasoconstriction —peripheral vascular insufficiency and gangrene of toes and fingers occurs in ergotism. Cont… Ergotoxine is a more potent α blocker and less potent vasoconstrictor than ergotamine. used in migraine Dihydroergotoxine has been used as a cognition enhancer. Phentolamine This is a rapidly acting α blocker with short duration of action(blocks α1 and α2 receptors) It is used as a quick and short acting α blocker for diagnosis and intraoperative management of pheochromocytoma & control of hypertension due to clonidine withdrawal, cheese reaction, etc. Dose: 5 mg i.v. repeated as required; Chlorpromazine Chlorpromazine and some other neuroleptics have significant α adrenergic blocking activity—cause fall in BP, nasal stuffiness and inhibition of ejaculation as side effect. Prazosin It is first of the highly selective α1 blockers having α1 : α2 selectivity ratio 1000:1. All subtypes of α1 receptor (α1A, α1B, α1D) are blocked equally. It blocks sympathetically mediated vasoconstriction and produces fall in BP. Prazosin dilates arterioles more than veins. ADR: Postural hypotension is less marked, may cause dizziness and fainting as ‘first dose effect’. Should start with a low dose and taking it at bedtime. Causes miosis, nasal stuffiness, inhibition of ejaculation Pharmacokinetics: Prazosin is effective orally, highly bound to plasma proteins metabolized in liver and excreted primarily in bile. Its plasma t½ is 2– 3 hours; effect of a single dose lasts for 6–8 hours. Uses: antihypertensive, Raynaud’s disease and benign hypertrophy of prostate Terazosin pharmacologically similar to prazosin; Pharmacokinetics: bioavailability (90%) and longer plasma t½ (~12 hr); a single daily dose lowers BP over 24 hrs. Uses: benign hypertrophy of prostate(apoptosis promoting effect) Dose: usual maintenance dose 2–10 mg OD. Doxazosin Another long acting (t½ 18 hr) congener of prazosin Uses: Has apoptosis promoting effect on prostate. Dose: 1 mg OD initially, increase upto 8 mg BD; Alfuzosin This short acting (t½ 3–5 hours) congener of prazosin. Use: benign hypertrophy of prostate The metabolism of alfuzosin is inhibited by CYP34A inhibitors. Interactions: Concurrent treatment with erythromycin, ketoconazole, ritonavir etc. is to be avoided. Dose: 2.5 mg BD-QID or 10 mg as extended release (ER) tablet. Tamsulosin This relatively uroselective α1A/ α1D blocker. Its plasma t½ is 6–9 hrs. Use: benign hypertrophy of prostate However, it lacks the prostatic apoptosis promoting property. ADR: Postural hypotension is infrequent, dizziness and retrograde ejaculation are the only significant side effects. Dose: DYNAPRES 0.2, 0.4 mg MR cap; Yohimbine An alkaloid from the West African plant Yohimbehe. It is selective α2 blocker with short duration of action. Also blocks 5-HT receptors. Heart rate and BP are generally elevated due to increased central sympathetic outflow as well as enhanced peripheral NA release. ADR: excitation, tremor, ADH release (antidiuresis), nausea and vomiting. may cause congestion in genitals. USES OF α BLOCKERS 1. Pheochromocytoma: It is a tumour of adrenal medullary cells. Excess CAs are secreted which can cause intermittent or persistent hypertension. 2. Hypertension 3. Benign hypertrophy of prostate (BHP) 4. Secondary shock 5. Peripheral vascular diseases 6. Congestive heart failure (CHF) 7. Papaverine/Phentolamine Induced Penile Erection (PIPE) therapy for impotence β-ADRENERGIC BLOCKING DRUGS
through the β receptors. All β blockers are competitive antagonists. Propranolol blocks β1 and β2 receptors, but has weak activity on β3 subtype. β blockers like metoprolol, atenolol, etc. preferentially block β1 receptors CLASSIFICATION Nonselective (β1 and β2) a. Without intrinsic sympathomimetic activity Propranolol, Sotalol, Timolol. b. With intrinsic sympathomimetic activity Pindolol c. With additional α blocking property Labetalol, Carvedilol Cardioselective (β1) Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Betaxolol, Celiprolol, Nebivolol Another system classifies β blockers into 3 generations
First Second Third
generation generation generation
Propranolol Metoprolol Labetalol
Timolol Atenolol Carvedilol Sotalol Acebutolol Celiprolol Pindolol Bisoprolol Nebivolol Esmolol Betaxolol PHARMACOLOGICAL ACTIONS 1. CVS (a) Heart: Propranolol decreases heart rate, force of contraction and cardiac output. BP falls. Cardiac work and oxygen consumption are reduced as the product of heart rate and aortic pressure decreases. Total coronary flow is reduced (blockade of dilator β receptors) The A-V conduction is delayed. Myocardial oxygen requirement is reduced due to reduced cardiac work (b)Blood vessels Propranolol blocks vasodilatation and fall in BP evoked by isoprenaline and enhances the rise in BP caused by Adr. Vasomotor reversal is seen after a blockade. Propranolol has no direct effect on blood vessels & there is little acute change in BP. On prolonged administration BP gradually falls in hypertensive subjects but not in normotensives. Decreased renin release from kidney, Propranolol causes a more marked fall in BP in hypertensives 2. Respiratory tract Propranolol increases bronchial resistance by blocking dilator β2 receptors. Causes asthma. 3. CNS No overt central effects are produced by propranolol. Causes behavioural changes, forgetfulness, increased dreaming and nightmares with long-term use & High doses. 4. Local anaesthetic Propranolol is as potent a local anaesthetic as lidocaine, but is not clinically used for this purpose because it causes irritation at the injected site. 5. Metabolic Propranolol blocks adrenergically induced lipolysis and consequent increase in plasma free fatty acid levels. It also inhibits glycogenolysis in heart, skeletal muscles and in liver 6. Skeletal muscle Propranolol inhibits adrenergically provoked tremor. It tends to reduce exercise capacity by attenuating β2 mediated increase in blood flow to the exercising muscles, & by limiting glycogenolysis and lipolysis 7. Eye Reduces secretion of aqueous humor, i.o.t. is lowered. 8. Uterus Relaxation of uterus in response to isoprenaline. PHARMACOKINETICS Propranolol is well absorbed orally. Has low bioavailability due to high first pass metabolism in liver. Propranolol is lipophilic and penetrates into brain Chronic use of propranolol itself decreases hepatic blood flow: its own oral bioavailability is increased and its t½ is prolonged. hydroxylated product of it has β blocking activity. excreted in urine, mostly as glucuronides. Dose: Oral—10 mg BD to 160 mg QID INTERACTIONS Additive depression of sinus node and A-V conduction with digitalis and verapamil Delays recovery from hypoglycaemia due to insulin and oral antidiabetics. Phenylephrine, ephedrine and other α agonists can cause marked rise in BP. Indomethacin and other NSAIDs reduce the antihypertensive action of β blockers. Cimetidine inhibits propranolol metabolism. ADVERSE EFFECTS Propranolol can accentuate myocardial insufficiency and can precipitate CHF/edema by blocking sympathetic support to the heart. Bradycardia Cold extremities Worsens chronic obstructive lung disease & asthma Carbohydrate tolerance may be impaired in prediabetics. Total triglycerides and LDL-cholesterol tend to increase while HDL-cholesterol falls. Cardioselectivity Cardioselectivity in metoprolol, atenolol, acebutolol, bisoprolol, nebivolol. These drugs are more potent in blocking cardiac (β1) than bronchial (β2) receptors. Contraindications Propranolol is contraindicated in partial and complete heart block. Hypotension Bradycardia Heart block Asthma COPD Membrane stabilizing activity In propranolol, oxprenolol, acebutolol, This activity leads to antiarrhythmic action. Lipid insolubility (atenolol, celiprolol, bisoprolol, sotalol) less likely to produce sleep disturbances and nightmares. They are incompletely absorbed orally, but do not undergo first pass metabolism and are primarily excreted unchanged in urine: are longer acting (t½ 6–20 hours) 1. Sotalol Nonselective β blocker with low lipid solubility. It has K+ channel blocking and class III antiarrhythmic property. 2. Timolol It is topically used in eye for glaucoma. used in hypertension, angina and prophylaxis of myocardial infarction. Betaxolol, Levobunolol, Cartiolol and Metipranolol are β blockers employed exclusively for topical application to the eye 3. Pindolol A potent β blocker with prominent intrinsic sympathomimetic activity. used primarily as antihypertensive Dose: PINADOL 5 mg tab 4. Metoprolol It is the prototype of cardioselective (β1) blockers It is less likely to worsen asthma, but is not entirely safe. Firstpass metabolism of metoprolol is less marked than propranolol, but 90% or more is hydroxylated by CYP2D6. Uses: Hypertension, angina and CHF, Buti.v. injection (5–15 mg) has been used in myocardial infarction provided bradycardia is absent. Dose: 12.5–50 mg OD–BD. 5. Atenolol Selective β1 blocker having low lipid solubility. It is incompletely absorbed orally, but first pass metabolism is not significant. It is one of the most commonly used β blockers for hypertension and angina. Dose: 12.5–50 mg OD; 6. Acebutolol cardioselective agent with significant partial agonistic and membrane stabilizing properties. It is rapidly metabolized to an active metabolite diacetolol which is primarily excreted by kidney and has a longer t½ (8–12 hours). 7. Esmolol It is an ultrashort acting β1 blocker It is inactivated by esterases in blood; plasma t½ is < 10 min; Rapid onset, short lasting fall in BP attends i.v. infusion of esmolol A loading dose of 0.5 mg/kg is given followed by 0.05– 0.2 mg/kg/min infusion Used to terminate supraventricular tachycardia, episodic atrial fibrillation or flutter, arrhythmia during anaesthesia, to reduce HR and BP during and after cardiac surgery, and in early treatment of myocardial infarction. 8. Bisoprolol A cardioselective β blocker lacking intrinsic sympathomimetic activity. Used in hypertension and CHF 9. Celiprolol It is a selective β1 blocker having additional weak β2 agonistic activity which reduces vascular resistance and holds promise of safety in asthmatics. Dose: 200–600 mg OD 10. Nebivolol This highly selective β1 blocker also acts as a NO donor, produces vasodilatation. It has the potential to improve endothelial function, which may delay atherosclerosis. It has been used in hypertension and CHF. Dose: 5 mg (elderly 2.5 mg) OD; USES 1. Hypertension β blockers are relatively mild antihypertensives. 2. Angina pectoris 10. Anxiety 3. Cardiac arrhythmias 11. Essential tremor 4. Myocardial infarction 12. Glaucoma 5. Congestive heart failure 6. Dissecting aortic aneurysm 7. Pheochromocytoma 8. Thyrotoxicosis 13. Hypertrophic 9. Migraine obstructive cardiomyopathy α + β ADRENERGIC BLOCKERS Labetalol It is the first adrenergic antagonist capable of blocking both α and β receptors. There are 4 diastereomers of labetalol, each of which has a distinct profile of action on subtypes of α and β receptors. Commercial preparation has equal parts of each diastereomer and displays β1 + β2 + α1 blocking as well as weak β2 agonistic activity. Labetalol is 5 times more potent in blocking β than α receptors. Cont… High doses reduce both c.o. and t.p.r. Heart rate is unchanged or slightly decreased. It has also been shown to inhibit NA uptake. Pharmacokinetics Labetalol is orally effective but undergoes first pass metabolism. Uses: potent hypotensive and useful in pheochromocytoma ADR postural hypotension, Failure of ejaculation Rashes and liver damage have been reported. Dose: Start with 50 mg BD, increase to 100–200 mg TDS Carvedilol It is a β1 + β2 + α1 adrenoceptor blocker; produces vasodilatation due to α1 blockade as well as calcium channel blockade, It has antioxidant property. It has been used in hypertension, used as as cardioprotective in CHF. PK: Oral bioavailability of carvedilol is 30%. It has a t½ of 6–8 hrs. CHF Dose: Start with 3.125 mg BD for 2 weeks, if well tolerated gradually increase to max. of 25 mg BD. Hypertension/angina: 6.25 mg BD initially, titrate to max. of 25 mg BD. Thank You