7. General effects of α-blockers
Fall in BP & postural hypotension: dizziness &
syncope
Blockade of vasoconstrictor α receptors
⇩Peripheral resistance
Pooling of blood in capacitance vessels
⇩ Venous return & COP
↓BP
8. • Hypovolemia accentuates hypotension
• Block the pressor action of adrenaline →↓BP
due to β2 mediated vasodilatation:
• “vasomotor reversal of Dale”
• Reflex tachycardia-
– ⇩Mean arterial pressure & ⇧release of NA due to
blockade of presynaptic α2 receptors
9. Cont.
• Nasal stuffiness, miosis
– Blockade of α receptors in nasal blood
vessels & radial muscles of iris
• Increased intestinal motility⇛
Diarrhoea
– Loss of relaxant sympathetic
influences
• Reduce renal blood flow →↓GFR
→ Na+ retention
10. Cont.
• Improves urine outflow in Benign prostatic hypertrophy
– Blockade of α1receptors in smooth muscles of bladder
trigone, sphincter & prostate
• Inhibit ejaculation ⇛impotence
– Inhibit contractions of vasdeference & ejaculatory duct
11. Phenoxybenzamine
• Non-selective irreversible α-blocker
• Covalently block-both receptor
• ⇧NA release (α2 blockade) auto receptor (Prominent reflex
tachycardia)
• Higher doses: partial blockade of 5-HT,histaminergic &
cholinergic receptors
• Postural hypotension
• Venodilatation is more prominent than arteriolar dilatation
α1, α2 receptor Phenoxybenzamine
NA
(Antagonist)
(Agonist)
Non-competitive antagonism
12. • Uses:-
– Phaeochromocytoma-DOC (To control BP before
surgery /Inoperable tumor)
– Secondary shock
– Peripheral vascular diseases
– To prevent dermal necrosis after incidental
extravasations of NE from IV infusion
• Adverse effects:-
– IV:CNS stimulation, nausea & vomiting
– ORAL: Depression, tiredness & lethargy
– Postural hypotension, palpitation, nasal blockage,
miosis & inhibits ejaculation
13. Phentolamine
• Non selective Reversible type of α- blockers
• Congener of Tolazoline
• Rapid action-short duration
• USES:-
• Diagnosis-(Phentolamine test) 5mg i.v.-rapid fall in bp
(35/25mmHg) in1min
• Pheochromocytoma- DOC (Intra-operative BP control)
• Control of hypertension during clonidine withdrawal, cheese reaction
etc.
• Most suitable α blocker for local infiltration to counteract
vasoconstriction due to extravasated NA/DA IV infusion
• Used to reverse the action of dental anesthesia (lignocaine+
Adrenaline )
14. Tolazoline
• Imidazoline compound
• Modest, short lasting alpha blockade
• Direct vasodilator & stimulates heart
• Blocks 5-HT receptors, histamine like gastric
secretagogue and ACH like action on intestines
• Uses:-
– Peripheral vascular diseases
– Pulmonary hypertension of new born
15. Ergot alkaloids
• Ergotamine & ergotoxin- Partial agonists & antagonists at ά
adrenergic, serotonergic & dopaminergic receptors
• Ergometrine:- No ά blocking action
Side effect- Long lasting vasoconstriction → peripheral
vascular insufficiency & gangrene of toes & fingers
• Ergotoxine is a more potent α blocker and less potent
vasoconstrictor than ergotamine
• Principle use in migraine
• Dihydroergotoxine-used as cognition enhancer
16. Prazosin
• Selective α1 blocker
• Blocks sympathetically mediated vasoconstriction ⇛⇩BP
(causes less tachycardia than non selective )
– No NA release due to absence of α2 blockade
– ↑HDL & ↓LDL & TG
• First dose phenomenon::-
Postural hypotension (Dilates arterioles more than veins)
leading to transient loss of consciousness (syncopal
attacks) Within 30–90 min of first oral dose of prazosin.
Minimized by
– starting with low dose(0.5-1mg)
– Take at bedtime/in supine position
17. Uses:-
• Hypertension-(given bed time to prevent postural
hypotension)
• Raynaud’s disease- recurrent vasospasm
of the finger & toes occurs in response
to stress or cold exposure due to vasoconstriction of small
arteries.
• but lesser oral BA(30%)
• undergoes first pass metabolism & short t1/2-4hr
• Prostatic hypertrophy
– Blocks α1 receptors in bladder trigone & prostate
– Improves urine outflow
– Relax smooth muscle in bladder neck, prostatic capsule, urethra
– Reduces residual urine in bladder
18. Terazosin
• Analogue of prazosin
• Chemically + Pharmacologically similar =Prazosin
• Higher (90%) bioavailability
• Longer plasma half life: 12 hrs
• Single daily dose
• Also has apoptosis promoting effect on prostate-
more popular for the treatment of BPH
• Long acting (t1/2 = 18hr) Prazosin congener
• Used in hypertension and BHP
Doxazosin
19. Tamsulosin
• Uroselective α1A/α1D blocker
• No effect in BP or HR
– No cardiovascular events (Postural hypotension)
• Side effects: Dizziness,
retrograde ejaculation
• Used for BHP-It has been shown that it may ↓
Prostatic volume by apoptosis
• Preferred for BPH in normotensive pt
Bladder base Prostate
20. Trimazosine
• Less potent congener of Prazosin
• Subtype non-selective
• Used in BHP
• α1blockers
• Used in hypertension
Alfuzosin
Indoramine & Urapidil
21. Yohimbine
• Alkaloid from West African plant
Pausinystalia yohimbehe & Raouwlfina serpentina
• α2blocker; short duration of action
• ⇧HR & BP
– ⇧Central sympathetic outflow + ⇧Peripheral NA release
• CNS effects: excitation, tremors, ADH release, nausea &
vomiting
• Claimed to be an aphrodisiac;
used in case of Psychogenic erectile dysfunction- replaced by
sildenafil(PD-5 inhibitor)
• No valid indications for clinical use
23. 1.Phaeochromocytoma
• Tumor of adrenal medullary cells
• Excess catecholamines release
⇛persistent hypertension
Excess catecholamines⇛ low blood volume (fluid shift from
vascular to extravascular compartment
Symptoms:-
Sudden & paroxysmal raise in BP
Headache, palpitation, Excessive sweating
• Diagnostic:- VMA in urine, CT scans, MRI-scans
• Pharmacological test-Phentolamine test-I.v.
• Treatment- Surgery
24. • Pre-operatively given:-
Phenoxybenzamine-control BP due to α-blocked
Advantage-
Normalizes blood volume and distribution of blood
Prevents rise in BP
In-operatively:-
Metyrosine (tyrosine hydroxylase
inhibitor)+Phenoxybenzamine(slow iv)-malignant pheochromocytoma
(α-blockers should be given prior to β-blockers-propranolol)-
control cardiac manifestation-tachycardia, arrhythmias due to excess
catecholamine
i.v. phentolamine-control BP during handling of tumor
25. 2.Hypertension:-
• Essential hypertension(mild-moderate)-
Selective α1 blockers like Prazosin can be used over non
selective blockers in mild-moderate hypertension.
Advantage-
No reflex tachycardia-Unacceptable side effects
Favorable effects on lipid profile
• Hypertensive emergencies:-
• Phentolamine(i.v.) due to rapid onset of action
To control hypertensive episodes intraoperatively during surgery of
pheochromocytoma
To control hypertensive crisis due to clonidine withdrawal
To control hypertensive crisis due to cheese reaction-in patients on
MAO inhibitors
26. 3.Benign prostate hypertrophy
Urinary obstruction-due to ↑tone of capsular SM of prostate
Static component:- Increase in size
Dynamic component- Increased tone of bladder neck/prostate
smooth muscle
27. Benign hypertrophy of prostate
Ultimate treatment is surgical resection of prostate-Trans-urethral
resection
28. Rationale for Combination
Therapy
• Alpha blockers:- relax the smooth muscle(α1A)of bladder
neck and prostatic capsule/adenoma
– Improve symptoms and flow rates, relieving obstruction
– Minimal cardiovascular side effect (α1B)-hypotension
BPH+hypertension-Prazosin, doxazosin, terazosin,alfuzosin
• Uroselective Drugs- Tamsulosin, Silodosin(BPH in normotensive pt)
• 5-α Reductase Inhibitors:-(finasteride) reduce size/arrest growth
5ARIs
Arrest disease progression
1-adrenergic
blockers
Rapidly relieve symptoms
?
29. Secondary shock
• Hypovolemic Shock due to fluid or blood loss
⇛fluid replacement
If it fails
Alpha Blockers:- (i.v. phenoxybenzamine)
– Counteracts vasoconstriction
– Shifts blood from pulmonary to systemic circuit
– Returns fluid from extravascular to vascular
compartment
Dopamine –preferred
30. Other uses
• Peripheral vascular diseases (PVD)- tolazoline to
relieves vasoconstriction
• Congestive heart failure-prazosin-↓after load
• Male sextual dysfunction- Papaverine with
Phentolamine use.
• As Aphrodisiac-Yohimbine increases sexual desire
36. 36
Mechanism of action:-
Propranolol is the prototype drug.
Blockers competitively block the -mediated actions of
catecholamines and other adrenergic agonists.
β-receptor
Propranolol
and other
β-blockers
(antagonists)
Catecholamines
and other
adrenergic
agonists
38. Cardio-selectivity
Nebivolol-Most cardio selective
Selectively inhibit β1-receptor on Heart
Low propensity to cause bronchoconstriction-preferred in
asthma (most useful -celiprolol-due to β2 agonist activity)
Less interference with carbohydrate metabolism-preferred
in DM
No deleterious effect on blood lipid profile-due to blocked
of β2 receptor-↓HDL ↑TG
preferred in hyperlipidemia-
Less liable to impair exercise capacity
Disadvantages:- ineffective in suppressing essential
tremor- β2 mediated effect
39. Intrinsic sympathomimetic activity(partial agonist)
• These drugs themselves activate (agonist) β1 & β2 receptors
submaximally.
Advantages:- safer in
• Elderly pt prone to develop bradycardia
• Pt with sick sinus syndrome with
Disadvantages:-
In Angina pt-they might precipitate MI due to stimulate of heart
Not effective for prophylaxis of Migraine-dilate cerebral blood
vessels
Drugs include-
carteolol,celiprolol,pindolol,Acebutolol,Penbutalol,oxprenolol.
Most potent partial agonist-pindolol
40. Vasodilator property
• It contributes to ↓BP-effective for the treatment of
hypertension & CHF
This property may possible due to-
Direct action-celiprolol
α-blocking action-labetalol, carvedilol
Partial agonist at-β2-celiprolol,labetalol
Production of Nitric oxide-celiprolol, nebivolol
Ca++ blocking action-carvedilol, betaxolol
K+channel opening action-tilisolol
Antioxidant-carvedilol
41. PHARMACOLOGICAL PROPERTIES (PROPRANOLOL)
Heart:
↓HR, ↓ FOC, ↓ COP
↓ cardiac work and oxygen consumption of the
myocardium
↓conductance in atria & av node
Blood vessels:
Decreases blood pressure in hypertensive patients,
negligible effect in normotensives.
Decreased TPR due to decreased CO
Block release of renin from kidney ( β1 receptor)
Reduced NA release, reducing sympathetic out flow 41
42. Respiratory tract:-
Non selective β- blockers - bronchospasm (β₂)
Cardio selective β1 blockers are safe.
Metabolic:-
Lipid:- Inhibits lipolysis-in prolong use
↑LDL cholesterol & triglycerides
↓HDL cholesterol levels
Carbohydrate:-
Inhibits Glycogenolysis
Augments hypoglycemia delay recovery from hypoglycemia due to
blocked of β2 receptor in the liver (mask the symptoms of
hypoglycemia)
Eye:-
Lowers intraocular pressure(topical application)- Glaucoma by
↓secretion of aqueous humor
42
43. Skeletal muscle:-
↓adrenergically (stress induced) mediated tremors
Reduces exercise capability -decreasing blood flow
CNS:- Prolong use-sedation, sleep disturbances
Other effect:-
1.Local anesthetic effect- LA effect of propranolol is equal to
lignocaine but not used clinically due to irritant action
2.Neuroprotective effect:-
Betaxolol, levobetaxolol, timolol have been shown to produce
neuroprotective effect on retinal neurons possible by inhibiting
neuronal Ca++ & Na+ influx.
This may block ganglionic cell death in glaucoma 43
44. PHARMACOKINETICS
Absorption-
well absorbed from GI tract,
poor oral BA due to high first pass metabolism
Distribution:-
Highly lipid soluble-cross BBB
High bound to Plasma protein(>90%) – ↓volume of
distribution
Metabolism:-
Hydroxylations-produce 4-hydroxy propranolol(↑duration)
Metabolism dependent on hepatic blood flow- chronic use
increases its bioavailability and T1/2 due to ↓hepatic BF
Excretion-urine 44
45. ADVERSE EFFECTS
A. Due to blocked of β-receptor:-
1.Bradycardia- due to negative chronotropic effect
2.Hypotension- due to ↓renin release & ↓COP
3.Worsening of COPD & asthma- due to β2 blocked
4.AV-Block-due to negative dromotropic effect
5.Alter plasma lipid profile- ↓HDL ↑TG
6.Exacerbation of variant angina-blocked of β2 mediated
vasodilatation leads to unopposed α mediated coronary
constriction
7.Hypoglycemia-recovery from antidiabetic drug induced
hypoglycemia is delayed. mask the warning symptoms of
hypoglycemia
45
46. 8.Impired exercise capacity-because β2 mediated
vasodilatation in skeletal muscle is blocked.
9.Worsening of peripheral vascular disease- due to blocked
of β2 mediated vasodilatation
10.Rebound hypertension on withdrawal:-
Common-selective β1 blocker
least common- β blocker +partial agonist action
Due to up regulation(super sensitivity) of β-receptor in
response to prolong blocked
B.Not due to blocked of β-receptor:-
CNS-Depression, confusion, drowsiness, forgetfulness
GI upset-diarrhoea, nausea
Decrease in libido-not preferred in adults
Skin rashes
48. CONTRAINDICATIONS
Bronchial asthma- blocking β2 mediated
bronchodilatation
Variant angina-unopposed α mediated action
Partial & complete heart Block- β blockers decrease
conduction by reducing sympathetic drive on β1 receptor
Bradycardia-they ↓HR by ↓sympathetic tone on β1
receptor worsening of bradycardia
Hypoglycemia-
48
49. NAME β1-selective α- blockade ISA Lipophilic Metabolism Uses
Propanolol No No No Yes Liver Angina, HTN
Timolol No No No Mod Liver Glaucoma
Sotalol No No No Weak Kidney Arrhythmias
Metoprolol Yes No Yes Yes Liver Angina , CHF
Esmolol Yes No No No Kidney Arrhythmias
Atenolol Yes No No No Kidney hypertension
Acebutolol Yes No Yes No Kidney Arrhythmias
Bisoprolol Yes No No Weak Kidney Heart failure
Carvedilol No Yes No Yes Liver Heart failure
celiprolol Yes No Yes No/less Unchanged Angina, HTN
Nebivolol Yes No No Heart failure
49
50. Important Factors about β-
blockers
• Nadolol-longest acting drug
• Esmolol-shortest acting drug(t1/2-10 min)
• Acebutolol-process all activities i.e. cardioselectivity, partial agonist,
membrane stabilizing action, lipid insolubility
• Sotalol,penbutalol,pindolol-100% BA
• Carvedilol-maximum PPB
• Celiprolol-Minimum PPB
• β blockers which are primarily excreted by kidney should not be given
in renal failure are-Atenolol, Nadolol, Sotalol
• Sotalol-type-III anti-arrhythmic action-prolong action potential(β-
blockers are type-II anti-arrhythmic)
• Celiprolol-additional β2 agonistic action-can be used in asthma
51. Interactions
1.Propranolol × verapamil- They produce additive cardiac
depressant effects and may cause CCF, bradyarrhythmias, heart block
or even cardiac arrest
2. Propranolol × lignocaine: Propranolol reduces the clearance of
lignocaine by decreasing hepatic blood flow
3. Propranolol × Cholestyramine & chlestipol- interfere the
absorption of β-blockers
4. Propranolol × Insulin/sulfonylureas- Nonselective -blockers
inhibit glycogenolysis and delay recovery from hypoglycaemia
5. Propranolol ×NSAIDS- NSAIDs by inhibiting prostaglandin
synthesis, promote Na+ and water retention on chronic use. Thus, they
decrease antihypertensive effect of -blockers.
54. 1.Cardiovascular Uses:-
Hypertension:-
Has antihypertensive activity.
Mechanisms…
Blockade of β1-receptor in heart ↓CO.
↓ renin secretion due to blockade of β1 receptors in
juxtaglomerular apparatus.
↓ central sympathetic outflow by blocking presynaptic β
receptors centrally.(atinolol,sotalol poor penetrability also
use)
Release of nitric oxide e.g Nebivolol, Carvedilol.
Blocked of peripheral facilitator presynaptic β2 receptors to
reduce NE release
55. Increase natriuretic peptide secretion
Produces peripheral vasodilatation by
α adrenergic blockade e.g.:-Labetolol
β2 ISA which causes arterioles to relax e.g.:-Pindolol,
Acebutolol, Bopindolol, Celiprolol
Blockade of Ca²⁺ entry e.g.:-Carvedilol, Bevantolol
By opening of K⁺ channels e.g.:- Tilisolol
Advantages
low cost
once daily dosing
absence of postural hypotension
no salt and fluid retention
# Hypertensive emergencies
Esmolol (I.V)
labetalol (I.V)
dose:o.1-o.2 mg/kg/min infusion
56. Angina pectoris
In case of stable angina:-
Blockers improve exercise tolerance,
↓Ventricular volume.
Used in long-term prophylaxis
of stable Angina.(combined with nitrates).
β-blockers also Reduces frequency
of angina episodes.
β-blockers
Blocks β1-receptors of heart
↓Myocardial work load
↓ Heart rate
↓ force of myocardial
contraction
↓ Myocardial oxygen
demand
Drugs: Atenolol
Metoprolol
Timolol
Bisoprolol
Propranolol.
Variant angina- β-blockers are contraindicated
57. exert antiarrhythmic effect.
↓ HR
↓ automaticity in SA node and purkinje fibers.
↓ the slope of phase-4 depolarization.
Depress AV conduction by prolonging the RP of AV-node.
↓ myocardial contractility
Membrane stabilizing activity(at higher dose)
Reducing sympathetic activity, increasing vagal tone
in atrial flutter, fibrillation – control ventricular rate
Drugs:- Atenolol, Metoprolol-treatment and prevention of paroxysmal
supraventricular tachycardia.(PSVT)
Esmolol-(IV)use to treat arrhythmias during surgery. Use alone or
{esmolol+digitalis}
Sotalol-Additional class-III Anti-arrhythmic property-equally effect as Na+ channel blockers
Cardiac arrhythmias
58. Mild to moderate case
Ventricular wall stress enhancing
Inhibit apoptosis &ventricular remodeling
Decrease After load
reduce effect of excess sympathetic activity
Anti-oxidant effect of carvedilol also contribute to its beneficial effect
Drugs: Metoprolol, Bisoprolol,
carvedilol – along with others drugs
Congestive Cardiac Failure
59. In acute phase beta blockers
prevent arrhythmias
long term use decrease mortality, recurrence
prevents reinfarction.
Prevention of platelet aggregation and promotion of
fibrinolysis.
Decrease myocardial oxygen demand,
Drugs- Metoprolol, propranolol, timolol.
Dose:-40-80 mg TDS orally.
Myocardial
infarction
60. Progressive dilation of aorta.
Beta blockers reduce the force of myocardial
contraction and decrease systolic pressure.
↓ left ventricular ejection force
DISSECTING AORTIC ANEURYSMS
Drugs:-
Esmolol, Propranolol,
Metoprolol, Labetalol
61. Autosomal disease characterized by Thickening of
myocardium
Sub-aortic region hypertrophic
contracts on sympathetic stimulation obstructs left
ventricular outflow
↓outflow resistance
β-blockers help during exercise
Drug-Propranolol
HYPERTROPHIC CARDIOMYOPATHY (HCM)
62. Advantages of β-blockers:-
lower blood pressure,
slow heart rate,
Reduce force of contraction by blocking the nerve
signals within the heart that control the heart
rhythm.
improve blood flow, which helps decrease
symptoms
delay the progression of heart failure
63. • Uneven closure of the valve during each
heartbeat.
Drugs:-
Atenolol, Metoprolol, Propranolol
Advantage of using β blockers:-
increasing the size of the
left ventricle, thereby reducing
the degree of prolapse.
They slow down the heartbeat
and reduce blood pressure.
relieve chest discomfort,
Absolute treatment- mitral valvotomy
MITRAL VALVE PROLAPSE
64. • Neuroendocrine tumor of the medulla of the glands
to increase catecholamine.
Results in hyper-secretion of the catecholamine.
PHAEOCHROMOCYTOMA
β- blockers used to control cardiac manifestations due to excess of
catecholamine.
Drugs:-
Propranolol -α-blockers should be given prior to propranolol.
Propranolol use to control cardiac manifestation. tachycardia,
palpitation
α-blockers :- to control BP
Drug having both α & β blocking action can also be used – like
labetalol, Carvedilol
65. • Morbid condition caused by excess of thyroid
hormones in the blood
Drugs: Propranolol, carteolol, labetolol, celiprolol
Advantage:-
• β- blockers Decrease peripheral conversion of T4 to
T3(mainly propranolol )
• Relieves tachycardia, tremors(β2 blocked), anxiety,
palpitations
Thyrotoxicosis/Hyperthyroidism
66. GLAUCOMA
Drugs:- Timolol(T-0.5%)-most frequently use
Betaxolol,
carteolol ,
levobunolol.
Act by blocking β2 receptor in ciliary body - ↓Aqueous humor
secretion (Wide Angle glaucoma)
(betaxolol, Levobetaxolol, metiprolol,timolol) having neuroprotective
action by blocking Na+/ Ca2+ influx.
• Advantages over miotics
No change in pupil size – no ↓ in vision in dim light
no headache
no fluctuations in i.o.p
once / twice daily administration
67. • Used prophylactically
• Propranolol block the 5-HT receptor in CNS
• Drugs:-
• Propranolol (20 mgTDS,orally), timolol ,Metoprolol,
atenolol
• Reduces frequency & severity of attacks in 70%
patients
MIGRAINE
68. Decreases sympathetic activity
Blocks peripheral manifestation of anxiety Decreases
tremors, tachycardia
Propranolol used to reduce anxiety under condition which
provoke nervousness. eg-interview
#Drugs:- Non selective beta blockers – Propranolol(10-20
mg,TDS orally), nadolol.
ANXIETY & ESSENTIAL TREMORS
69. Alcohol/opioid dependence:-
produces beneficial effect by reducing central
sympathetic over activity during the phase of withdrawal.
Drugs-propranolol.
Portal hypertension:-In variceal re-bleeding,
Propranolol and nadolol, which are non-selective beta
blockers,
reduce portal pressure and bleeding .
Mechanisms-
1) COP by blocking β1 adrenergic receptors,
2) Splanchnic vasoconstriction by blocking β2
receptors .dose:- 10-20mg BD orally.
70. Explain Why question:-
1.Why timolol not propranolol is used in the treatment of
glaucoma
2.Clonidine is used as moderately potent antihypertensive
drug
3.Why beta blockers are preferred over miotics for glaucoma
4.Why propranolol should not be used in vasospastic angina
5.Why propranolol should be administered with caution in
patients receiving insulin
6.Why oral dose of propranolol must be higher than
intravenous dose
7.Why propranolol but not atenolol is used for treatment of
tremors
