Lecture on beta blockers their classification, therapeutic uses, adverse effects , contraindications.

1. Beta blockers

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

3. Classification of Beta blockers
 Non selective
• Propranolol
• Pindolol
• Sotalol
• Timolol
 + β Blocker
• Labetolol
• Carvedilol
 Cardio Selective
(β1)
• Atenolol
• Acebutolol
• Betaxolol
• Bisoprolol
• Esmolol
• Metoprolol
• Nebivolol

4.  Without intrinsic sympathomimetic
action:
 Propranolol
 Timolol
 Sotalol
 With intrinsic sympathomimetic action:
 Pindolol
 Acebutolol
 With membrane stabilizing action:
 Propranolol, oxprenolol, acebutolol

8. Propranolol
Non selective beta blocker also
an inverse agonist

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

10. Heart

11.  Blood vessels:
 Reduce BP
• ↓ COP
• ↓ renin levels
• ↓ central sympathetic outflow
• ↓ NA release from sympathetic terminal
 Respiratory tract:

12.  CNS:
 Subtle behavioral changes
 Forgetfulness, nightmares , ↑ dreaming
 Supresses anxiety in short term stressful
situation
 Local anaesthetic:

13.  Metabolic:
 blocks lipolysis & subsequent ↑ FFA
 ↑ TG, ↑ LDL/HDL ratio
 Inhibit glycogenolysis in heart, muscle, liver
 No effect on normal BGL but ↓ carbohydrate
tolerance by ↓ insulin release
 Skeletal muscle:
 Inhibit tremors
 Decrease exercise capacity
 Eye : ↓ secretion of aqueous humor
 Uterus : relaxation of uterus in response to
selective 2 agonistis blocked

15. To summarize the
pharmacological actions

16.  Heart
 Respiratory
 CNS
 Local anaesthetic
 Metabolic
 Skeletal muscle
 Eye
 Uterus

17. Important actions
 Membrane stabilizing action:
• Propranolol, oxprenolol, acebutolol
 Intrinsic sympathomimetic action:
• Pindolol, acebutolol

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

22.  Cardioselectivity:
 Metoprolol, acebutolol, atenolol,bisoprolol
 More potent Beta 1 blockade than beta2

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

25. Uses of betablockers
 Cardiac :
 Hypertension
 Angina pectoris
 Myocardial infarction
 Cardiac arrhythmias
 CCF
 Hypertrophic
obstructive
cardiomyopathy
 Dissecting aortic
aneurysm
 Non cardiac:
 Pheochromocytoma
 Thyrotoxicosis
 Migraine prophylaxis
 Anxiety
 Essential tremors
 Glaucoma
 Portal hypertension

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

30.  Doses of beta blockers
Drug Dose in mg
Propranolol 80 – 240 mg 6-12
hrly
Metoprolol 100 – 200 mg BD
Atenolol 25 – 100 mg daily
Timolol 10 – 60 mg daily
Pindolol 10 – 45 mg 6 hrly
Labetolol 200 – 600 mg BD
Bisoprolol 5 – 10 mg OD

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

33. Salient features
 Acebutolol:
 Cardioselective
 Partial agonist & membrane stabilising action
 Bisoprolol:
 OD administration in angina , hypertension, CHF
 Esmolol:
 Ultrashortacting
 Celiprolol, nebivolol:
 vasodilatory release nitric oxide

34. Uses of betablockers
 Cardiac :
 Hypertension
 Angina pectoris
 Myocardial infarction
 Cardiac arrhythmias
 CCF
 Hypertrophic
obstructive
cardiomyopathy
 Dissecting aortic
aneurysm
 Non cardiac:
 Pheochromocytoma
 Thyrotoxicosis
 Migraine prophylaxis
 Anxiety
 Essential tremors
 Glaucoma
 Portal 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

39.  Thyrotoxicosis:
 Migraine prophylaxis:
 Anxiety:
 Pheochromocytoma:
 Essential tremor:
 Glaucoma
 Portal hypertension:

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

41.  Carvedilol:
 1, β1, β2 blocker
 Vasodilation: alpha 1 + calcium channel
blockade
 Antioxidant property
 Use:
• Hypertension
• Cardioprotective in congestive heart failure
 Oral bioavailabilty – 30%
 T1/2 = 6-8 Hrs