2. Introduction
Alpha & Beta adrenergic receptor antagonists prevent
the interaction of the endogenous neurotransmitter
norepinephrine (N.E) or sympathomimetics
(endogenous or synthetic catecholamines, synthetic
noncatecholamines) with the corresponding adrenergic
receptor
Such interference attenuates SNS homeostatic
mechanisms & evokes predictable pharmacologic
responses
3. Alpha Blockers
Interfere with ability of catecholamines or other
sympathomimetics to provoke alpha responses on the
heart & peripheral vasculature
Inhibitory action of epinephrine on insulin secretion is
prevented too (insulin production is not reduced)
Side effects: orthostatic hypotension, baroreceptor
mediated reflex tachycardia, impotence
Absence of Beta blockade allows maximum expression
of cardiac stimulation from N.E.
They are both competitive antagonist of α or β or both.
4. Receptor agonists activate signal transduction pathways
HO
NH3
HO
CH
CH2
NH2
OH
Norepinephrine
a1 adrenergic
receptor
(+) Phospho-
Gq
lipase C
PIP2
COOH
IP3
Diacylglycerol
Increase Ca2+
Activate Protein
Kinase C
Response
7. Pharmacological Effects CVS
•
•
•
•
•
•
Fall in BP (α1 & α2 blockade)
Postural hypotension
Reflex tachycardia
Vasomotor reversal of Dale
Hypovolemia accentuates hypotension
Hypotension- g.f.r reduced
Na & water retention
renin release ↓BP
8. Pharmacological Effects
Nasal stuffiness
Eye – Miosis
Urinary bladder -Decreased tone in sphincter and prostate (α1A
blockade)
Metabolic effects – Increased insulin secretion
Reproductive system
Inhibition of contraction of Vas deference and related organs is blocked
by α1 blockade…..inhibition of ejaculation…impotence
9. Phenoxybenzamine
Alpha blockade develops gradually and lasts for
3-4 days.
Fall in BP by Phenoxy. is mainly due to
venodilatation…postural hypotension.
Shifts blood from pulmonary to systemic
circulation, extravascular to vascular
compartments.
Lipid soluble drug can penetrate CNS may cause
nausea & vomiting on rapid i.v administration
12. Phentolamine
Congener of Tolazoline
Rapidly acting α blocker with short DOA
Many other effects including:
Parasympathomimetic
Increased gastric acid secretion
Cardiac stimulation
Increased secretion from exocrine glands, such
as salivary, sweat, lacrimal, pancreatic
Coronary artery disease and peptic ulcer relative
contraindication to it.
13. Phentolamine : uses
Diagnostic and intraoperative management of
pheochromocytoma
For control of hypertension due to clonidine
withdrawal.
Cheese reaction.
To counteract vasoconstriction due to
extravasation of noradrenaline / Dopamine
given IV.
Dose: 5mg
14. Ergot alkaloids
Interact with serotonin and dopamine receptors
also
Direct smooth muscle contraction
Structure-activity relationships
Coronary vasoconstriction
Toxicity: GI, vascular insufficiency –ergotism
Use in migraine
15. Ergot alkaloids
Ergotoxine, Ergotamine are partial agonist and
antagonist at adrenergic α, 5HT and DA
receptors.
Ergotoxine, dihydroergotoxine are more potent
α blocker and less potent vasoconstrictor than
ergotamine.
USE: Migraine
16. Alpha-1 selective blockers
Prazosin
Highly selective α1 blocker, selectivity ratio 1000: 1
Less cardiac stimulation since it preserves α2 mediated
negative feedback + other mechanisms
Fall in BP with no/ minimal tachycardia.
Used in CHF and in HT but tolerance develops with time,
may be due to fluid retention.
Adverse effects: First dose phenomenon i.e postural
hypotension with initial doses.
Favorable effect on plasma lipids: increase HDL/LDL
ratio
17. Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate
Before and After Prazosin
ADR
(µg/Kg)
0.1
1
10
100
500
1
10
100
500
BP
+PRAZOSIN
HR
19. Tamsulosin
Uroselective α1A/ α1D blocker.
As effective as Terazosin in BPH
α 1A are predominant in bladder base and
prostate. 30 times high affinity for α1A
No effect on BP and heart rate.
Dizziness and retrograde ejaculation are the only
AE.
20. α 2 selective blockers
Yohimbine
Cardiovascular effects – peripheral and central
effects
Blocks other receptors also – 5HT, DA
Increases ADH release
Enhances sexual activity – aphrodisiac
Potential uses: depression, obesity, NIDDM
21. α Blockade—Adverse Effects
Orthostatic hypotension
Reflex tachycardia
Dilates vessels of nasal mucosa
Inhibition of ejaculation
Increase heart rate by stimulating baroreceptor reflex which
causes and increased heart rate to compensate
Nasal Congestion
Reduces blood flow to brain causing dizziness, lightheadedness
and fainting
Due to vasodilation of veins lowering blood flow to brain
α 1, sympathetic reaction needed
Sodium retention
Decreased blood pressure decreases filtering by kidneys and
causes retention of water and salt
25. Beta Blockers
Selective Affinity for Beta-adrenergic receptors
All beta blockers are competitive antagonists
Beta blockade can be reversed by Beta agonist by
displacement from occupied receptors if large amount
of agonist is given
Chronic Beta Blocker use = increased number of betaadrenergic receptors (up regulation)
26. Structure Activity Relationships
Beta Blockers: derived from isoproterenol (beta
agonist)
Substitutions on the benzene ring determines if drug
is antagonist or agonist
Levorotatory forms of beta agonists/antagonists
more potent than Dextrorotatory forms
Example: Dextrorotatory isomer of Propranolol has
<1% of the potency of the Levorotatory form
29. Pharmacological actions
CVS:
Heart: Propranolol ↓ss HR, FOC, COP. ↓ss
cardiac work and oxygen consumption.
Blood vessels: fall in BP both diastolic and
systolic after continuous treatment.
Decrease in COP
Initial increase followed by decrease in TPR
Decreased release of NE from symphathetic neurons
Decrease renin release from kidney
Central action decreasing symphathetic outflow
30. OTHER SYSTEMS
R S: Bronchoconstriction
CNS: ↓ss anxiety, tremors, other actions.
lightheadedness, forgetfulness, nightmares, rarely
hallucinations
Local anesthetic action: Propranolol-membrane
stabilizing action
Metabolic :
increases LDL, triglycerides, ↓ss HDL by inhibiting lipolysis.
Adversely effects recovery from insulin induced
hypoglycemia.
Skeletal muscles : Propranolol inhibits adrenergically
evoked tremors.
Eye : decreases synthesis and releases of aqueous
humour … ↓ iop
35. Atenolol
Selective beta 1 blocker with low lipid solubility.
Longer duration action. OD dosing
Side effects related to CNS are less prominent
No effect on bronchus, carbohydrate
metabolism, lipids
USE: Most commonly used in
Hypertention
angina
36. Acebutolol
Cardioselective with intrinsic symphathomimetic
and membrane stabilizing activity.
Side effect profile is like that of Metoprolol.
Preferred in those prone to severe bradycardia
and low cardiac reserve.
37. Esmolol
Ultra short acting cardioselective beta blocker.
DOA 15-20mins after iv infusion
Rapid onset short lasting fall in BP
USES:
To terminate supraventricular tachycardia
Atrial fibrillation or flutter
Arrythmias during anaesthesias
During cardiac surgery to decrease HR & BP
Early treatment of AMI
42. alpha + beta blocker
Labetalol
β 1 + α1 blocking as well as β2 agonism.
5 times more potent β blocker than α.
Fall in BP is due to decrease in COP and TPR
Uses : pheochromocytoma, clonidine
withdrawl, essential hypertention.
A/E: postural hypotension, impotence.
44. Effect of chronic b-receptor blockade
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
NE
Effector organ
NE
45. Effect of chronic b-receptor blockade:
Receptor up-regulation
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
NE
Effector organ
NE
46. Pharmacologic manipulation of the adrenergic system
Presynaptic neuron
Tyrosine
Na+
1
Dopamine
Tyrosine
2
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
3
NE
Effector organ
NE
b
48. Drugs that reduce storage or release of NE
Tyrosine
Na+
Dopamine
Reserpine
Guanethidine
Tyrosine
Action Potential
H+
NE
NE
NE
Guanethidine,
Bretylium
Effector organ
Guanethidine
b
49. Catecholamine depleters
Reserpine (Serpasil)
Indole alkaloid obtained
from the root of Rauwolfia
serpentina
Block vesicular
monoamine transporters
Deplete vesicular pool of
NE
Slow onset of action
Sustained effect
(weeks)
Used in the treatment
of hypertension
May precipitate
depression
50. Drugs that reduce storage or release of NE
Guanethidine (Ismelin)
Almost completely protonated at physiological pH
“Pharmacologic sympathectomy”
Effects can be blocked by transport blockers
Uses: Hypertension
51. Drugs that reduce storage or release of NE
Tyrosine
Na+
Dopamine
Tyrosine
Guanethidine
Action Potential
H+
NE
NE
NE
Guanethidine,
Effector organ
Guanethidine
b
52. Drugs that reduce storage or release of NE
Bretylium tosylate (Bretylol)
Aromatic quaternary ammonium
Precise mechanism unknown
Displace and release NE and prevent further
release (depletion)
Local anesthetic
Administered: Parenteral
Uses: Antiarrhythmic (ventricular fibrillation)