ppt antiadrenergics ppt for mbbs bds class

antiadrenergics ppt for mbbs bds class

1. ALPHA-RECEPTOR
ANTAGONIST DRUGS
Dr.Ramnarayanreddy

2. ADRENERGIC TRANSMISSION
Adrenergic receptors are G protein coupled receptors
which acts by increasing or decreasing the
production of cAMP

ADRENERGIC RECEPTORS
ALPHA – 1 -- A , B , D
ALPHA – 2 -- A , B , C

3. ADRENERGIC TRANSMISSION
ALPHA 1 :
Acts by activating PLC – production of IP3 and DAG
IP3 promotes the release of calcium from the intracellular
stores --- increase cytoplasm calcium

4. Adrenergic System
ALHA 1 receptors
EYE – radial fibers – contraction –mydriasis
Arteries and veins – contraction – can
increase peripheral resistance.
Bladder trigone and sphincter – contraction
– urinary retention
Liver – Glycogenolysis.
Vas deferens – ejaculation.

5. Adrenergic System
ALPHA 2 : acts by inhibiting adenylyl cyclase –
cAMP
Platelets - aggregation
Prejunctional receptors – decrease release of transmitter
(NE)
Pancreas -- decrease insulin release (predominant)

6. MoA
Reversible antagonists—Phentolamine, prazosin
and several ergot derivatives.
Phenoxybenzamine irreversible blockade.

7. Pharmacologic Effects
A. CARDIOVASCULAR EFFECTS
↓PR & ↓BP. Selective α-receptor antagonism may convert a
pressor to a depressor response, called epinephrine
reversal; Alpha-receptor antagonists often cause Postural
hypotension (due to antagonism of sympathetic nervous
system stimulation of α
1 receptors in venous smooth muscle)
& Tachycardia (block of α
2-presynaptic receptors augmented
release of NE further stimulate β- receptors in the heart.
B. OTHER EFFECTS
Minor - miosis, nasal stuffiness and ↓ resistance to the flow
of urine.

8. Dale's vasomotor reversal: Epinephrine Reversal
: when alpha-1 receptors are blocked , epinephrine will
produce hypotension because of uninhibited beta 2 receptors.

9. SPECIFIC AGENTS
Phentolamine causes ↓PR(α
1
) and possibly α
2
receptors on
vascular smooth muscle. The cardiac stimulation resulting
from baroreflex mechanisms. Antagonism of presynaptic α
2

receptors may lead to enhanced release of NE from
sympathetic nerves.
limited absorption after oral administration and half-life of 5-
7 hours.
ADR: cardiac stimulation, severe tachycardia, arrhythmias,
and MI, especially after IV administration.
Use: pheochromocytoma intraoperatively & male ED -
intracavernosally.
Tolazoline similar to phentolamine.

10. Phenoxybenzamine
Irreversible blockade of long duration (14-48 hours or
longer). Also inhibits reuptake of released NE by
presynaptic adrenergic nerve terminals.
PBA attenuates catecholamine-induced vasoconstriction.
PBA is absorbed after oral administration, BA is low and its
kinetic properties are not well known.
orally starting with low doses of 10-20 mg/d and
progressively increasing the dose until the desired effect is
achieved.
The major use is in pheochromocytoma .
ADR: Postural hypotension, tachycardia, Nasal stuffiness
and inhibition of ejaculation. CNS effects fatigue, sedation
and nausea.

11. Ergotamine, DHE reversible α- blockade.
Prazosin: highly selective for α
1
receptors and typically
1000-fold less potent at α
2
receptors. Prazosin leads to
relaxation of both arterial and venous vascular smooth
muscle, in the prostate. BA (degradation by the liver) only
about 50% after oral administration. t
1/2 about 3 hours.
Terazosin is another reversible a
1-selective antagonist that
is effective in HTN, BPH. has high BA. t
1/2 is 9-12 hours.
Doxazosin is efficacious in HTN and BPH. longer t
1/2 - 22
hours.

12. Tamsulosin is a competitive α
1
antagonist, has high BA and
a long t
1/2
of 9-15 hours. Metabolized extensively in the liver.
The drug's efficacy in BPH suggests that the α
1A subtype
mediating. Has less effect on standing blood pressure in
patients.
OTHERS: Alfuzosin is an a
1
-selective for use in BPH. BA
about 60%.
Indoramin is another a
1-selective antagonist as an
antihypertensive.

13. Labetalol has both a
1
-selective and b-antagonistic effects.

Neuroleptic drugs such as chlorpromazine and
haloperidol are potent dopamine receptor antagonists
but are also antagonists at alfa receptors. Their antagonism
of a receptors probably contributes to some of their adverse
effects, particularly hypotension.
Similarly, the antidepressant trazodone has the capacity to
block a
1 receptors.

14. USES:
Pheochromocytoma : catecholamine excess, including
intermittent or sustained hypertension, headaches,
palpitations, and increased sweating.
Unavoidable release of stored catecholamines sometimes
occurs during operative manipulation of pheochromocytoma;
the resulting hypertension may be controlled with
phentolamine or nitroprusside.
Phenoxybenzamine preoperatively help to control
hypertension Oral doses of 10-20 mg/d can be increased at
intervals, very useful in the chronic treatment of inoperable
or metastatic pheochromocytoma.

15. Hypertensive Emergencies: labetalol used.
When increased BP reflects excess circulating
concentrations of a agonists,
eg: in pheochromocytoma, overdosage of
sympathomimetic drugs or clonidine withdrawal.
Chronic Hypertension: Members of the
prazosin family of α
1
-selective antagonists are
efficacious drugs in the treatment of mild to
moderate systemic hypertension, but postural
changes in blood pressure should be checked
routinely in any patient being treated for
hypertension.

16. Peripheral Vascular Disease: Raynaud's
phenomenon and other conditions involving
excessive reversible vasospasm in the
peripheral circulation do benefit from
phentolamine, prazosin, or PBA, although
CCBs may be preferable for many patients.
Local Vasoconstrictor Excess:
Phentolamine used to reverse the intense local
vasoconstriction caused by inadvertent
infiltration of a agonists (eg:NE) into
subcutaneous tissue.

17. Urinary Obstruction: several α
1
- antagonists in
BPH. Prazosin, doxazosin and terazosin are
efficacious. subtype-selective α
1A
- antagonists might
lead to improved efficacy & safety in treating this
disease.
Erectile Dysfunction: A combination of
phentolamine with the nonspecific smooth muscle
relaxant papaverine, when injected directly into the
penis, may cause erections in men with sexual
dysfunction. Fibrotic reactions may occur, especially
with long-term administration. -- orthostatic
hypotension.

20. Beta blockers

21. Beta blockers
Enormous clinical attention because of utility in variety of CVS
disorders
Propranolol- prototype

22. Receptor
Name
Locations Ligand Binding
β1 Heart, lipocytes, brain,
presynaptic
adrenergic and cholinergic
nerve terminals
Stimulation of
adenylyl cyclase,
increased cAMP
β2 Smooth muscle (uterine,
vascular, bronchial) and
cardiac muscle
Stimulation of
adenylyl cyclase
and
increased cAMP.
β3 Lipocytes Stimulation of
adenylyl cyclase
and
increased cAMP

23. -ve Inotropic
-ve Chronotropic
-ve Dromotropic
 COP
 Cardiac work & O2 consumption
 Excitability &  Automaticity
Pharmacodynamic
s:
1- Heart (1):

24. 2- Blood vessels (2):
 V.D.  Unopposed   V.C.

3- Anti-hypertensive:
 Sympathetic outflow from CNS
 COP
 Renin
 Noradrenaline release
Reset Baroreceptors

25. 4-  I.O.P.:

5- Bronchi (
2
)  Bronchodilatation
6- Metabolism: 2   Glycogenolysis
 2   Hypokalemia
 1 & 3   Lipolysis

26. 7- I.S.A. (Some -Blockers) = Dualist
8- C.N.S. (Lipophilic -Blockers)
 Anxiety  Tremors
9- Local anesthetic action: (Some -Blockers)
Na+ Channel Block
→Membrane stabilizer
Direct Myocardial Depressant

27. Classification based on
selectivity to receptor
1.Selective beta blockers:
Cardioselective: selective beta1 blockers- Atenolol,
metoprolol, acebutalol, bisoprolol, esmolol
2.Nonselective beta blockers: Propranolol, timolol, sotalol,
nadolol, pindolol
3.Beta blockers with additional alpha blocking property:
Carvedilol, labetalol, carteolol

28. Classification….
4. β-blockers with ISA: Pindolol, acebutolol, labetalol,
carteolol, celiprolol.
5. β-blockers with membrane stabilising action: Propranolol,
pindolol, acebutalol, labetalol, carvedilol, betaxolol.

29. Additional CVS actions
Alpha blockade: labetalol, carvedilol, bucindolol
Releasing nitric oxide: Celiprolol, nebivolol,
carteolol
Calcium entry blockade: Carvedilol, betaxolol
Anti-oxidant action: Carvedilol
Antiproliferative action: Carvedilol

30. Pharmacological actions
Effect of beta blockade:
When sympathetic tone is high:
Attenuate expected increase in heart rate,
cardiac output.
Decreases myocardial contraction

31. Actions of beta blockers…
Inhibition of automaticity.
Slows AV conduction
Decreases BP.
Decreases myocardial oxygen requirement
Nonselective blockers increases bronchial resistance
Inhibits adrenaline induced glycogenolysis
Inhibits release of free fatty acids from adipose tissue

32. Actions…
Membrane stabilising action:
Unrelated to beta blocking potency
Seen in high concentrations only
Intrinsic sympathomimetic activity:
Partial agonistic activity- less myocardial
suppression, less chances of CCF

33. Actions…
Effect on CNS:
Propranolol- highly lipid soluble, large volume of
distribution- readily crosses BBB -
alters mood- useful in anxiety
Atenolol- hydrophilic- does not cross BBB
Intraocular pressure:
Decreases secretion of aqueous humor - decrease
intraocular pressure

34. Pharmacokinetics
Rapid oral absorption.
High first pass metabolism (BA of propranolol is
30%, on prolonged use increases BA)
Plasma half-lives:
Propranolol- 3 to 6 hours
Atenolol- 6 to 8 hours
Esmolol- 8 minutes(shortest acting, given IV)
Nadolol- 20-24 hours (longest acting)

35. Adverse effects
Due to extended cardiac actions:
Hypotension
Bradycardia that can progress to life threatening heart
blocks
Precipitation of CCF
Aggravation of AV conduction defects
Abrupt withdrawal: exacerbate angina/ precipitation of MI
(due to enhanced sensitivity to beta agonists). Hence taper
and stop.

36. Adverse effects….
Noncardiac:
CNS: sleep disturbances, depression
Fatigue: probably due to reduced cardiac output and reduced
muscle perfusion in exercise
Cold extremities, worsening of peripheral vascular disease
due to loss of beta mediated cutaneous vessels.
Bronchospasm
Hypoglycemia unawareness

37. Therapeutic uses
Cardiovascular uses:
1.Hypertension- decreases CO, decreases renin release
2.Angina pectoris -decreases O2 requirement, HR, BP. CI in
Prinzmetal angina
3.Myocardial infarction- decreases O2 requirement,
redistribution of myocardial blood flow, antiarrhythmic actions
4. Cardiac arrhythmias:
5. Hypertropic obstructive cardiomyopathy
6. CCF- acutely worsen, long term treatment may be beneficial

38. Noncardiovascular uses
1.Hyperthyroidism, thyrotoxicosis
2.Migraine prophylaxis- propranolol
3.Open angle glaucoma- timolol, betaxolol
4.Portal hypertension- propranolol, nadolol
5.Pheochromocytoma (after alpha blockade)
6.Essential tremor- propranolol
7.Anxiety- propranolol
8.Alcohol withdrawal syndrome

39. Drug interactions
Pharmacokinetic:
Aluminium salts, cholestyramine, colestipol decrease
the absorption of beta blockers.
Phenytoin, rifampicin, smoking decrease plasma
concentration of beta blockers (Enzyme induction)
Cimetidine, hydralazine increases bioavailability of
beta blockers.
Beta blockers decrease clearance of lidocaine

40. Drug interactions
Pharmacodynamic
Beta blockers with calcium channel blockers- additive effects
on heart.
Beta blockers with other antihypertensives- additive effect
on BP
NSAIDs decreases the antihypertensive efficacy of beta
blockers

41. Selection of a beta blocker
Pharmacokinetic/dynamic differences/cost
Do not assume all members of the class
interchangeable
Select appropriate drug with documented efficacy
For patients with bronchial asthma, diabetes,
peripheral vascular diseases:
Select beta1 selective blockers
CCF: Combined beta and alpha blockers preferred

42. Describe the th.uses, adverse effects and
contraindications of propranolol.
Cardioselective beta blockers
Adverse effects beta blockers
Noncardiovascular uses