Yogesh

Adrenoreceptors Adrenoreceptors or Adrenergic receptors are membrane receptors

bound which

G-protein

function

coupled

primarily

by

increasing or decreasing the intracellular production of second messenger cAMP/IP3 DAG.

Classification and Location of adrenoreceptor There are main two types of adrenoreceptors α & β. In this classification there again two types of α & three types of β-receptors. Subtypes of α receptors are α1 & α2 while subtypes of β receptors are β1, β2, β3,. α1 is located in vein pupil bladder sphincter, pilometor & α2 in arterioles, CNS, kidney & platelets. β1 receptors are those in the myocardium and kidney, β2 are those in the smooth muscles & most other sites like

Effects mediated by receptors α1 receptors: Vasoconstriction, relaxation of gastrointestinal smooth muscles, salivary muscles, salivary secretion & hepatic glucogenolysis.  α 2 receptors: Inhibition of transmitter release (including NA & Ach release from autonomic nerves), platelet aggregation, contraction of vascular smooth muscles, CNS neurons. β 1 receptors: Increased cardiac rate & force, relaxation of gastrointestinal smooth muscles. β 2 receptors: Bronchodialation, vasodialation, relaxation of visceral smooth muscle, hepatic glycogenolysis & muscle tremors. β 3 receptors: Lipoloysis All β-receptors are involved in the action of nor-epinephrine on the heart, pulmonary

Some adrenergic receptors function in human tissue  

Location

Function

β1

Heart

Lontrophy & chronotrophy

 

Kidney

rennin release

β2

Arterioles

Dilation

 

Heart

Ionotrophy & Chronotrophy

 

Islets cells

Insulin release

 

Bronchi

Dilation

   

Presynaptic terminal Various cells

 

Uterus

Relaxation

 

Leucocytes

Demargination

β3

Adipocytes

Lipolysis

Noradrenergic

Enhancement epinephrine K+ entry

[Pg – 175, 60]

of

nor

–

Beta Blockers Introduction All beta adrenoceptors blocking agents are synthetic

compounds

and

competitively

inhibit the action of adrenergic agonist on beta receptors. Beta blockers are competitive inhibitor of the effect of catecholamine at beta adrenergic

CLASSIFICATION Division 1 (NON-CARDIOSELECTIVE) Group1 i.e. Oxprenolol

Agents with both MSA & ISA Alprenolol and

Group2 i.e.

Agents with MSA but no ISA Propranolol

Group3 ISA i.e.

Agents with out MSA but with Pindolol

Group4 ISA i.e.

Agents without both MSA and Sotalol and Timolol

Division 2 (CARDIOSELECTIVE) Group1 - Agents with both MSA & ISA i.e. Acebutolol Group 2- Agents with MSA but no ISA agents (NOT AVAILABLE) Group 3- Agents without MSA but with ISA (NOT AVAILABLE) Group 4- Agents without both MSA and ISA i.e. Atenolol & Metoprolol

Division 3 (Beta + Alpha blockers) Group1 - Nonselective Propranolol, Oxprenolol, Sotalol, Alprenolol, Penbutolol

β-blockers i.e. Nadolol, Pindolol, Timolol,

Group2 - Cardioselective i.e.Metoprolol, Atenolol, Betaxolol, Esmolol, Tolamolol Group 3- β Carvedilol

+α

Group4 - Agents

Blockers with

i.e.

direct

P-blockers Acebutolol, Celiprolol, Labetalol, vasodilator

MECHANISM OF ACTION Beta

blockers

combines

reversibly

with

these

receptors to block the response to the sympathetic nerve stimulation. Beta adrenergic blocking agents competitively

antagonizes

catecholeamine

at

β

the

adrenergic

effect

of

receptors.

Beta

adrenoceptors are located predominantly in heart (β1) In arteries and arterioles of skeletal muscles (β2) and in addition bronchi (β2) where there stimulation induces cardiac excitation, peripheral vasodilatation &

Blockade of cardiac (β1) receptors reduces heart rate, mayocardial contractility and cardiac output. The artioventricular

conduction

time

is

slowed

and

automaticity is suppressed. Due to this blood pressure falls. Studies shows that cardiac output falls by 1520%. Renin release is reduced by 60%. It is believed that partly Propranolol exert its antihypertensive effect by inhibiting the secretion of renin from juxtaglomerular apparatus of kidney by inducing β receptor blockade. The peripheral β2 blockade allows α adrenergic mediated vasoconstriction to be opposed and peripheral vascular resistance increases initially.

Blockade of non-cardiac β2 receptors increases airway resistance inhibit catecholamine induced glycogeno lysis and lipolysis & inhibit the vasodilating effect of catecholamine on peripheral circulation. These noncardiac action are responsible for some of adverse effect

of

beta

hypoglycemia.

blockers

[Pg. – 212]

like

bronchospasm

and

Pharmacology of Propranolol and other drugs Propranolol is the most extensively investigated β blockers. It was introduces in therapeutics in 1964. It is considered to be prototype drug. Quantitatively all β blockers produces similar effects but quantitative differences

exist

sympathomimetic

depending activity

and

upon local

action (membrane stabilizing action).

intrinsic

anaesthetic

1. Action on cardiovascular system Stimulation of cardiac β1 receptors leads to increase in rate

and

force

of

contraction

of

heart,

prior

administration can completely block this action of β agonist and clinical effects are bradicardia, decreased myocardial contractility, and reduced stroke volume, decreased automaticity, increased exercise tolerance with reduced oxygen consumption. ECG shows slow AV

conduction

intervals.

characterized

by

increased

PR

2. Action on blood vessels Stimulation of β2 receptors causes dilatation of skeletal blood vessels, which is counteracted by Propranolol. It has no direct effect on other blood vessels. Since there is decrease in cardiac output simultaneously with skeletal vasoconstriction. There is a very little acute change in B.P. as a result of these opposite action.

When

Propranolol

is given

to a

normal

individual in therapeutic doses there is a no change in blood pressure, but in patient of hypertension it lowers the blood pressure.

3. Action on respiratory system Stimulation β2 receptors evokes relaxation of smooth muscles of bronchi, which is blocked by Propranolol. The increase in resistance of air way is more marked in patients of bronchial asthma, chronic bronchitis and in other form of respiratory insufficiency than in normal individual and Propranolol may precipitate an acute attack of bronchial asthma in asthmatics.

4. Action on eye There is a reduction in intraocular pressure which may be due to decrease formation of aqueous humour. Timolol is a β blocker with MSA used in Glaucoma.

5. Action on C.N.S. Inhibition

of

central

β2

adrenoceptor

mediated

sympathetic stimulation by Propranolol contributes to its hypotensive effects over and above its direct effect on cardiac outputs. Due to central action it also produces

sedation,

lethargy,

depression,

and

disturbances of sleep.

6. Action on skeletal muscles Propranolol

antagonizes

the

adrenaline

induced

tremor due to its peripheral action on β2 receptors on

7. Uterus Relaxation of uterus in response to selective β2 agonist is blocked by Propranolol. However normal uterine activity is not significantly affected.

  8. Local anaesthetic Propranolol is a potent local anaesthetic as a Lidocaine but it not clinically used for this purpose because of its irritant properties.

9. Metabolic effects In a normal person Propranolol has a very little effect on normal blood glucose, even after 24 hours fast but it inhibit adrenaline induced glycogenolysis occurs during hypoglycemia and should be used with a caution in a patient treated with insulin. Propranolol is associated with increased VLDL and decreased HDL level which are unfavorable effect. This action is also shared by all selective and non-selective β blockers but not by those with intrinsic sympathomimetic activity.

[Pg. – 119]

Pharmacology of other drugs 1. Selective β 1 blockers (Atenolol, Esmolol, Metoprolol, Acebutolol) These drugs are more potent β1 blockers in a low and therapeutic doses and act on β2  receptors in larger doses, thus a. They may be relatively safer in asthmatics who experiences

broncho-constriction

with

Propranolol but they are not completely safe. b. These may be proffered in patient with diabetes

c. These agents do not worsen the symptom of patient with

peripheral vascular

disease as there is a less muscular vasoconstriction. d. They are ineffective in suppression of adrenaline induced

tremors.

e. Atenolol has a long duration of action and may be given as a

single daily dose orally. It doesn't

cross blood brain barrier not have central effects. f. They produce less adverse lipid changes.

and so

2. Beta blockers with intrinsic sympathomimetic activity (Pindolol, Oxprenolol, Alprenolol, Acebutolol) a. They produce less myocardial depression and bradycardia hence they are preferred in patient with low cardiac reserves. b. They block exercise induced tachycardia and produce less abnormality in plasma lipid profile. c. There is no rebound hypertension and no super sensitivity of the receptors when drugs are withdrawn suddenly.

3. Non-selective pure β blockers (without ISA + MSA) i.e. Nadolol, Sotalol, Timolol They do not crosses blood brain barrier (except Timolol) therefore expected to cause less C.N.S. effect. Hence proffered in the patients who can not tolerate the central side effect of Propranolol. Nadolol has a longer half life, is excreted unchanged in urine and can be given as single dose. Sotalol is similar. Timolol is given as an eye drop in the treatment of wide angle of Glaucoma. It may be absorbed if given in excess and may produce systemic effects.

[Pg. – 119]

Pharmacokinetics A. Absorption Most of drugs in this class are well absorbed after oral

administration,

within

1-3

hrs

peak

after

concentration

ingestion.

occurs

Hydrophilic

β

blockers like Atenolol, Nadolol, Sotalol are not as readily absorbed from gut as lipophilic agents like Propranolol, Metoprolol, Oxprenolol. Propranolol is almost completely absorbed from gut.

B. Bioavailability Beta blockers undergoes extensive hepatic (first pass) metabolism. Its bioavailability is relatively low. The proportion of drug reaching the systemic circulation increases as the dose is increased.

C. Distribution and clearance The β antagonist are rapidly distributed and have large volume of distribution. Propranolol and Penbutolol are quite lipophilic and readily crosses the blood brain barrier. Most β antagonists have half life in the range of 2-5 hrs. Propranolol and Metoprolol are extensively metabolized in liver with little unchanged drug apperaring in urine. Atenolot, Celiprolol &

Clinical uses 1. Hypertension All beta blockers appear to be equally effective antihypertensive

agents.

Propranolol

is

useful

in

treatment of all degree of hypertension. When used alone, the anti hypertensive effect of Propranolol is equivalent to that of thiazide diuretics.

2. Angina Pectoris Propranolol or Nadolol may be used for long term management of a patient with angina pectoris. The frequency of anginal attacks is reduced and also the nitroglycerine requirement in patient is reduced.

3. Cardiac arrhythmias Beta blockers suppresses extra systole and tachycardia, specially those mediated adrenergically (during anaesthesia digitalis induced) may be used I.V. for this purpose. They control ventricular rate in atrial fibrillation and flutter but only occasionally restores sinus rhythm. Esmolol is an alternative drug for supraventricular tachycardia.

4. For Myocardial Infarction In relation to myocardial infarction, β blockers have been used for two purposes. a. Secondary prophylaxis of MI: There is a now a firm of evidence of benefits. Long term use after recovery from MI has been found to decrease subsequent mortality by 20%. 1. By preventing reinfarction

b. Myocardial

salvage

administered

during

evaluation

of

MI:

I.V. within 4-6 hrs

of an attack followed by continued oral therapy β blockers 1. May limit infarct size by reducing oxygen consumption

marginal

tissue which is partially ischemic may survive. 2. May prevent arrhythmias including ventricular fibrillation. However β blockers can be given to only to those

patients not

5. Pheochromocytoma Beta blockers may be used to control tachycardia and arrhythmias, but should not be administered unless an α blocker has been given before otherwise dangerous rise in B.P. occurs. They suppresses cardio myopathy caused by excess CAS.

6. Migraine Propranolol is used for the prophylaxis of migraine headache specialty in the patient who can not take ergot preparations due to associated diseases like hypertension, pectoris,

cerebrovascular

several

peripheral

disease,

vascular

angina

disease

or

7. Hyperthyroidism Propranolol rapidly controls tachycardia, tremors and anxiety in the patient of thyrotoxicosis. It is useful as an adjutant to other appropriate therapy for thyrotoxic crisis & neonatal thyrotoxicosis. Propranolol may be used with anti thyroid drugs pre-operatively in the patients undergoing sub-total thyroidectomy. Regarding the mode of action, it has been suggested that Propranotol reduces the peripheral conversion of thyroxine (T4) to triiodothyronine (T3).

8. Parkinson's Tremors

disease

&.

Essential

Propranolol combined with Levodopa may benefits a patient of Parkinson's disease. There is a definite

9. Glaucoma Timolol is used as an eye drop (0.25, 0.5 %) for the treatment of an wide angle Glaucoma. It is a pure non-selective β antagonist with no local anaesthetic action. It act by reducing the secretion of aqueous humour. If given in large amounts, it may be absorbed from eye and may produce toxic effects.

10.Anxiety Propranolol and other β blockers suppress objective sign of anxiety like diarrhea, palpitation, tachycardia and tremors. The anti-anxiety action of β blockers is more peripheral than central. There is a increase in

11. Hypertrophic Cardiomyopathy The

subaortic

contraction

of

region this

is

hypertrophic.

region

under

Forceful

sympathetic

stimulation (exercise), emotions increases out flow resistance which has in capacitating haemodynamic consequence. Beta blockers improves cardiac output in this patient during exercise though they have little effect while at rest.

12. Essential tremors Nonselective β blockers have now an established place in treating essential tremors. However they do not

DRUG INTERACTIONS 1. Additive depression of sinus node and A-V conduction with digitalis and verapamil cardiac arrest can occur. However, Propranolol can be used safely with Nifedippine. 2. Propranolol delays recovery from hypoglycemia due to insulin and oral antidiabitics. Warning signs of hypoglycemia mediated through sympathetic stimulation (tachycardia, tremor) are suppressed. In some cases B.P. raises due to unopposed α action of released adrenaline. 3. Phenylephrine, epheridine and other α agonists present in cold remedies can

5. Cimetidine inhibits Propranolol metabolism. However, the dose range of propranolol is wide and this may not be clinically significant. 6. Propranolol reduces lidnocaine metabolism by reducing hepatic blood flow. 7. Propranolol increases chlorpromazine by its first pass metabolism.

bioavailability of decreasing

8. β- blockers furthur adds to the anti hypertensive effect of Captopril but overall response is less than additive. 9. The bronchodilating and cardio stimulating action of sympathomimetics are antagonized. [Pg. – 127]

Contraindication Beta

blockers

are

contraindicated

bradycardia, greater than 1st

degree

in

sinus

heart block.

Congestive heart failure, cardiogenic shock overt cardiac failure and hypersensitivity to β blockers. Propranolol,

Nadolol,

Timplol

and

Pindolol

are

contraindicated in the patient with bronchial asthma or severe chronic obstructive pulmonary disease. Beta blockers are contraindicated in the management ofmyocardial infarction patient with heart rate below 45 beats per minute's heart block greater than 1st degree systolic B.P. less than 100mmHg or moderate

Adverse reaction and Precautions 1. Gastromtestinaldisturbances: (anorexia, nausea, vomiting, diarrhea, abdominal pain)

are

the

most

common

adverse

effects

reported. Other less frequently reported adverse effects are: (in descending order) cold extremities and

exacerbation

of

Raynaud's

phenomenon;

congestive heart failure; sleep disturbances including vivid dreams; dizziness, fatigue and bronchospasm. Reported

adverse

effects,

systems are recorded below.

according

to

organ

2. Cardiovascular: Congestive heart failure; secondary effects of decreased cardiac output which could include: syncope, vertigo, lightheadedness, decreased renal perfusion and rarely, postural hypotension; intensification of AV block and hypotension; severe bradycardia; claudication and cold extremities, Raynaud's phenomenon; dyspnea; palpitations; precordial pain.

3. CNS Dizziness, lethargy, weakness, drowsiness, headache, insomnia, fatigue, anorexia, anxiety, mental depression, poor concentration, reversible amnesia and catatonia, vivid dreams with or without

4. Respiratory Propranolol induces bronchoconstriction and may provoke asthmatic attack. If severe bronchospasm develops, β2 agonist (terbutaline) and aminophylline should be administered.  

5. Metabolic Propranolol impairs the sympathetically medicated rebound response to hypoglycemia and may mask some hypoglycemic symptoms like tachycardia in a patient on insulin therapy. Although Propranolol can be given safely to most diabetics, it may prolong the duration of hypoglycemia in a patient on insulin. Beta blockers are reported to reduce HDL, Cholesterol and

6. Neurologic Fatigue and lethargy are common central side effects. Vivid dreams or nightmares with or with out insomnia occurs frequently. Depression and memory loss are not uncommon, hallucination; psychotic reactions have also been reported.

 7. Pregnancy & Lactation Propranolol crosses the placenta and may cause bradycardia, hypotension and hypoglycemia in neonates bom to mothers on a Propranolol therapy. It is also excreted in breast milk.

8. Miscellaneous Propranolol may cause sexual dysfunction (impotence) or decrease libido, fever, rash, myopathy, alopecia. Thrombocytopenia and agranulocytosis may occur rarely. Propranolol mask the sign and symptoms ofhyperthyroidism. Indomethacin antagonizes the antihypertensive activity of Propranolol. [Pg. – 214, 127]

BETA BLOCKERS CHEMICAL NAME

BRAND NAME (S)

ATENOLOL

TENORMIN, *TENORETIC

BETAXOLOL

KERLONE

BISOPROLOL

ZEBETA, *ZIAC

CARTEOLOL

CARTROL

CARVEDILOL**

COREG

ESMOLOL

BREVIBLOC (Only available for intravenous use)

LABETOLOL***

NORMODYNE, TRANDATE

METOPROLOL

LOPRESSOR, *LOPRESSOR HCT, TOPROL

NADOLOL

CORGARD, *CORZIDE

PENBUTOLOL

LEVATOL

PINDOLOL

VISKEN

PROPRANOLOL

INDERAL, *INDERIDE, INNOPRAN

TIMOLOL

BLOCADREN, *TIMOLIDE, TIMOPTIC (eye drops)

*These are a combination of the beta blocker with a diuretic for the control of blood pressure. **This is also an alpha blocker and a free radical scavenger. It has been specifically developed as treatment for heart failure. This is a combined alpha and beta blocker and also dilates arteries.

Newer drugs and combination 1. Atenolol + Amiodipme Beta blockers + calcium channel blockers, anti hypertensive   Action : Atenolol is a cardioselective p blocker which reduces heart rate and blood pressure. Amiodipine, a dihydropyridine which is a calcium channel blockers causes peripheral vasodilatation, reduces peripheral resistance and after load. There is a no reflex tachycardia. Amiodipine dilates the coronary vessel in normal and ischemic areas and blunts the vasoconstrictor stimuli. Pulse pressure product is reduced and exercise tolerance

Indication & Dosage Oral: Hypertension, Adult: (Atenolol 50 mg + Amiodipine as a besylate 5mg) one tablet OD.   Safety alerts   Contraindication: Hypotension, sinus bradycardia 2nd and 3rd degree block, cardiogenic shock, CCF, poor LV functions, hypersensitivity to either component, pregnancy. Special precaution: Excessive fall of blood pressure may occur in elderly patients, should be used with caution in a patient with thyrotoxicosis, CCF, Vasospastic angina,

Interaction: No significant interaction for Amiodipine have been reported. Additive anti hypertensive effects with other antihypertensive may occur.   Adverse reaction: Headache, hypotension dizziness, breathlessness, fatigue, muscle cramp, bradycardia, drowsiness, chest pain and impotence rarely.   Preparation : Arnlong A (Amiodipine 5 mg + Atenolol 50 mg tablet)

2.Metoprolol + Hvdrochlorthiazide  

Category: Beta blocker + Diuretic

Action: Metoprolol is a cardio selective beta blocker causing reduction in heart rate, cardiac output and B.P. Hydrochlorthiazide increases renal excretion of sodium and chloride. Thus reduces cardiac load. The two drugs exert a additive effect in hypertension. Indication and Dosage: Oral: Hypertension: Adult: Metoprolol (tartarate) 100 mg + Hydrochlorthiazide 12.5 mg 1-2 tablets daily

Safety alerts Contraindication: 2nd or 3rd degree AV blocks, sinus bradycardia, cardiogenic shock, CCF, anuria, hypersensitivity, bronchial asthma.   Special Precautions: Renal or hepatic impairment, diabetes, hyperlipidemia, LVH, and ventricular ectopics. Interaction : Risk of arrhythmias with digitalis, alter response to quinidine, amiodarone and possibly other antiarrythmics. Glycemic controls may be altered in diabetic patients. Hydrochlorthiazide may increases nephrotoxicity of aminoglycosides and lithium

Adverse reaction: Fluid and electrolyte imbalance, dizziness, headache, tiredness, depression, bradycardia, cold extremities, Raynaud's phenomenon, bronchospasm, hypokalemia, oedema. Absorption and bioavailability of both Metoprolol and hydrochlorthiazide are increased when taken with food. Brand: BetaIoc-H