1. ADRENERGIC
BLOCKERS

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

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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

5. Receptor antagonists block agonist binding to the receptor
Antagonist
NH3
Gq
COOH
Phospholipase C

6. CLASSIFICATION
Non selective


Reversible: Phentolamine , Tolazoline
Irreversible : Phenoxybenzamine
Selective
Alpha 1 selective Prazosin , terazosin , Doxazosin , Tamsulosin , Alfuzosin
Alpha 2 selective Yohimbine, Idoxamin
Miscellaneous

Ergot alkaloids: Ergotoxine , Ergotamine

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

10. Adverse effects

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Postural hypotension
Tachycardia
Sedation
Nasal stuffiness
Miosis
Impotence (inhibits ejaculation)
Exercise care in hypovolemic patients

11. USES

Diagnostic and intraoperative management of
pheochromocytoma.

Secondary shock (occasionally)

Peripheral vascular diseases.

12. Phentolamine

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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

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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
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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
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
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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
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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

18. Prazosin : uses


Antihypertensive
DOC: Benign prostatic hyperplasia ( BPH)
Blocks α1 in bladder trigone & prostate
 Decreases tone
 Improves urine flow
 Decreases residual urine



Dose :1-4 mg BD/ TDS
Terazosin : longer t1/2 , OD dosing

19. Tamsulosin

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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
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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

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
Reflex tachycardia


Dilates vessels of nasal mucosa
Inhibition of ejaculation

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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

22. α Blockade—Uses

Therapeutic Applications

Essential hypertension

Benign prostatic hyperplasia

Pheochromocytoma

Raynaud’s disease

Overdose of α1 agonist

23. Therapeutic Uses of
Alpha-Adrenergic Blockers
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Hypertension - α1 selective
Conditions associated with increased sympathetic
activity – e.g. pheochromocytoma
Hemodynamic shock
Peripheral vascular disease – Raynaud’s
CHF
Benign prostatic hyperplasia-prazosin
Pulmonary hypertension – tolazoline
Yohimbine or intracavernous
phentolamine+papaverine for impotence

24. THANK YOU

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

27. Classification

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.
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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
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R S: Bronchoconstriction
CNS: ↓ss anxiety, tremors, other actions.
lightheadedness, forgetfulness, nightmares, rarely
hallucinations
Local anesthetic action: Propranolol-membrane
stabilizing action
Metabolic :
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
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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

31. Contraindication
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CHF
Bradycardia
COPD
Bronchial asthma
Diabetis mellitus
Hypertriglygeridemia
Partial –complete heart block

32. Adverse effects
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Adverse Effects of beta1 blockade
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Bradycardia
Reduced cardiac output
Heart failure
AV block
Long-term use can sensitize heart to catecholamines. If withdrawn abruptly,
angina pain and/or ventricular dysrhythmias can develop= rebound excitation.
Withdraw drug gradually
COPD, Bronchial asthma
Tiredness , reduced exercise capacity.
Rebound hypertension on abrupt withdrawal.
Cold hands and feets
hypoglycemia
Others: gi upset, lack of drive, lightheadedness, forgetfulness,
nightmares, rarely hallucinations

33. CARDIOSELECTIVE (BETA 1 )
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Metoprolol
Atenolol
Acebutolol
Bisoprolol
Esmolol
No effect on bronchus, carbohydrate metabolism,
lipids.
Lower incidences of Cold hands and feets.
Less liable to impair exercise tolerance and essential
tremors.

34. Metoprolol


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Cardioselective
Preferred in diabetics on insulin or oral
hypoglycemics.
Less likely to worsen asthma
Side effects are milder.
USE: AMI without bradycardia

35. Atenolol



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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



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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


38. Celiprolol & Nebivolol



Beta 1 blocker + beta 2 agonism
Acts as NO donor …vasodilatation
Uses:
Hypertension
 CHF


39. Intrinsic symphathomimetic activity
Pindolol


Used primarily as antihypertensive, Preferred in
those prone to severe bradycardia and low
cardiac reserve.
Chances of rebound hypertention are less.

40. Without intrinsic symphathomimetic
activity


Sotalol : Class III antiarrhythmic
Timolol : topical use in eye

41. Uses of Beta blockers
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Hypertension
Angina pectoris
Cardiac arryhythmias
AMI
CHF
Dissecting aortic aneurysm
Pheochromocytoma
Thyrotoxicosis
Migraine
Essential tremors.
Glaucoma
Anxiety

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.

43. Carvedilol



β 1 + β2+ α1 blocker, calcium channel blocker.
Antioxidant property.
Use:
Hypertension
 CHF
 Angina.


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

47. Tyrosine
Inhibition of
norepinephrine
synthesis
X
tyrosine hydroxylase
Metyrosine
DOPA
aromatic L-amino acid decarboxylase
Dopamine
dopamine b -hydroxylase
Norepinephrine
phenylethanolamineN-methyltransferase
Epinephrine

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)

53. THANK YOU