2. Catecholamines produce their action
by direct combination with receptors
located on cell membrane
Outcome of this drug receptor
combination is either ↑ or ↓ in tissue
activity
Ahlquist 1948
Alpha & beta receptors
9. Pharmacological actions
Effects of blockade
No marked effect on normal heart in
subject at rest
In presence of ↑ sympathetic tone
• ↓ automaticity and prevents rise in HR
• ↓ Myocardial contractility, cardiac output
and stroke work
• Slows AV conduction
• ↓ myocardial oxygen requirement &
improves exercise tolerance
18. Significance of intrinsic
sympathomimetic action
Less bradycardia & depression of
contractility
Less likely withdrawl symptoms
Lipid profile less worsened
Not effective in migraine prophylaxis
Not suitable for secondary prophylaxis
of MI
23. Cardioselective blockers
Advantages
Lower chances for bronchoconstriction
Less interference with carbohydrate
metabolism and lipid profile
↓ incidence of cold extremities
↓precipitation of raynauds disease
Less impairment of exercise tolerance
Disadvantage
Ineffective in essential tremors
24. Pharmacokinetics of propranolol
Well absorbed , low bioavailability, high first
pass metabolism in liver
Lipophilic
Metabolism dependent on hepatic blood flow
Chronic use of propranolol ↓es hepatic blood flow
Bioavailability and t1/2 ↑ed by 30 % on repeated
administration
Food decreases first pass metabolism
Saturable metabolism at higher doses
Metabolites have blocking action
90% protein bound
Dose oral = 10 mg BD to 160 mg QID
26. Lipid insoluble beta blockers
Atenolol, sotalol, bisoprolol, acebutolol
Less central effects
Incompletely absorbed orally but do not
undergo first pass metabolism, excreted
mostly unchanged in urine
Longer acting 6-20 hrs
Effective in narrow dose range
Propranolol is the most lipid soluble beta
blocker
27. Adverse effects & contraindications
1. Can accenuate myocardial insufficiency &
precipitate CHF by blocking sympathetic
support to heart in CVS stress
2. Bradycardia
3. COPD, Bronchial asthma
4. Exacerbates variant, prinzmetal angina
5. Impairment of carbohydrate tolerance in
prediabetics
6. Increase TG & LDL/HDL ratio
7. Rebound hypertension, angina on withdrawl
28. Adverse effects & contraindication
8. Contraindicated in partial & complete heart
block – arrest may occur
9. Tiredness , decreased exercise capacity
10. Cold hands & feet – worsening of PVD due
to blockade of vasodilator Beta 2
11. Adverse events not due to beta blockade:
GIT upset, lack of drive, night mares, forgetfulness,
rarely hallucination , sexual distress
31. Salient features
Sotalol:
Non selective, lower lipid solubility, class 3
antiarrhythmic
Timolol:
Topical preferred in glaucoma
Betaxolol, carteolol, levobunolol (Local
acting)
Pindolol:
Non selective, intrinsic sympathomimetic
action
Metoprolol:
Cardioselective , less first pass metabolism
32. Salient features
Atenolol:
Cardioselective
Low lipid solubility
No significant first pass metabolism
Longer DOA 6-9 Hrs
No deleterious effect on lipid profile
Effective in narrow dose range
Most commonly used beta blocker for
angina & hypertension
35. Hypertension:
First line drugs
• Absence of postural hypotension
• Low adverse events
• Once daily dose
• Low cost
• Cardioprotective potential
Angina pectoris:
Decrease work load and Oxygen
requirement by heart
Favourable redistribution of blood
36. Myocardial infarction:
Catecholamines released during MI
More useful if ongoing pain, tachycardia,
hypertension , ventricular rhythm instability
Secondary prophylaxis;
• Prevent reinfarction
• Prevent sudden ventricular fibrillation
Myocardial salvage during evolution of MI:
• Limit infarct size by decreasing oxygen consumption
• Marginal tissue which is partly ischemic may survive
• May prevent arrhythmias VF
37. Cardiac arrhythmias
Supress tachycardias & extrasystoles
mediated by adrenergic system
Control ventricular rate in Atrial fibrillation &
flutter
Esmolol alternative drug for paroxysmal
supraventricular tachycardia
Dissecting aortic aneurysm:
Decrease contractile force & aortic pulsation
Hypertrophic obstructive cardiomyopathy
Decrease LV outflow obstruction
38. Congestive cardiac failure:
Negative ionotropic effect? Worsen
ventricular function
1970 waagstein & associates found improved
exercise tolerance & improvement in several
measures of ventricular function.
Immediately after starting beta blockers
• Decrease in systolic function as reflected by
decrease in ejection fraction however continued
treatment over 2-4 months systolic function
gradually improves
This is due to prevention of adverse
effects of NA on myocardium that are
mediated by beta adrenergic receptors
40. Alpha + beta blocker
Labetolol:
5 times more potent for beta receptors
Has weak beta 2 agonist action also
Decrease blood pressure by 3 mechanisms
Orally effective but extensive first pass
metabolism
Uses: hypertension, pheochromocytoma,
clonidine withdrawl,
Side effects: postural hypotension, failure of
ejaculation, other side effects of alpha & beta
blockers
NON equilibrium type: phenoxybenzamine
Equilibrium type (competitive)
Non selective- ergotamine, ergotoxine, dihydroergotamine and dihydroergotoxine , tolazoline, phentolamine
Alpha1 selective: prazosin, terazosin, doxazosin, Tamsulosin
Alpha2 selective- Yohimbine
Uses of alpha blockers:
pheochromocytoma
hypertension
benign hypertrophy of prostrate
secondary shock
peripheral vascular disease
congestive cardiac failure
papaverine / phentolamine induced penile erection therapy for impotence
Powell & slater - Dichloro-isoproterenol 1958 first beta blocker having agonistic action
Pronethalol first pure beta blocker but caused thymic tumors in mice by sir james black
Propranolol has equal affinity for beta1 and beta2 receptors it is a pure antagonist
Local anaesthetics like procaine prevent the increase in permeability of cell membrane to sodium ion which is the first event in depolarization (sodium channel block) thus an action potential is not generated. This action affecting the process of depolarization leading to failure of propogation of impulse without affecting resting potential is known as membrane stabilizing effect.
Cardiac response to exercise and to other situations in which sympathetic activity is increased is attenuated
Total coronary blood flow is decreased which is largely restricted to subepicardial region , while subendocardial area which is site for ishemia in angina patients is not affected over all effect in angina is
Some beta blockers have additional actional through NO production (celiprolol, carteolol), calcium channel blocking- carvedilol , potassium channel opening tilisolol
Increase the bronchial muscle tone in asthamatics in normal persons no effect because sympathetic bronchodilator tone is minimal. In asthamatics condition is consistently worsened and severe attack may be precipitated
No overt central effects are produced
Propranolol is a potent local anaesthetic agent but cannot be used because of its irritant activity
Inhibits adrenergically mediated tremor
Decrease exercise capacity by attenuating the blood supply to muscles and by limiting glycogenolysis and lipolysis, which provide fuel to working muscles.
No consistent effect on pupillary size or accomodation
Oral : parenteral dose ratio 40:1
Metabolite of propranolol hydroxypropranolol makes frequency of administration BD possible
Plasma half life of drugs mostly metabolized by liver is short 2-3 Hrs whereas drugs excreted unchanged by kidneys have long 8 to 12 hrs half life
The plasma half life does not corelate well with duration of therapeutic effects of beta blockers which is relatively long lasting. This is because plasma levels decline exponentially following forst order kinetics while effect decreases linearly following zero order kinetics. Hence ,ost peparations can be given orally at much longer intervals than suggested by their plasma half lives
Chlorpromazine increased bioavailability by retarding metabolism