Pharmacology PPT

1. Pharmacotherapy
with
α-Receptor
Antagonists
Dr. Chintan Doshi

2. Classification
α receptor
Antagonists
Non-
Equilibrium Equilibrium

3.  NON-equilibrium
1) β-Haloalkylamines- Phenoxybenzamine
 Equilibrium type
A) Non selective
1) Ergot alkaloids – Ergotamine,Ergotoxine
2) Hydrogenated Ergot alkaloids – Dihydroergotamine,
Dihydroergotoxine
3) Imidazoline- Tolazoline, Phentolamine
4) Miscellaneous- chlorpromazine
B) α1 selective
Prazosin ,Terazosin, Doxazosin , Alfuzosin, Tamsulosin,
silodosin
C ) α2 selective
Yohimbine, idazoxan

4. Non-selective α1- Selective α2 -Selective
• Yohimbine
• Prazosin
• Terazosin
• Doxazosin
• Alfuzosin
• Tamsulosin
• Phenoxybenzami
ne
• Phentolamine

5. Pharmacological Actions
1) Cardiovascular system
a) Blood vessels
α receptor
Decrease peripheral resistance
Pooling of blood in capacitance vessels
↓ venous return and cardiac output
Fall in blood pressure
Blockade of
vasoconstrictor
α receptor

6. b) Heart
- Blockade of presynaptic α2 receptor
↓ in mean arterial pressure
↑ release of NA: Reflex Tachycardia

7. 2) Gastrointestinal system (GIT)
Inhibition of relaxant sympathetic influences
↑ Intestinal motility
Loose motion

8. 3) Genitourinary system (GUT)
α1 receptor blockers
↓ tone of smooth muscle in bladder trigone
and sphincter, Prostate
↑Urine flow (BPH)

9. α receptors
Contraction of vas deferens
Ejaculation
Inhibit Ejaculation
Impotence
α blocker

10. 4) Metabolic
- Facilitate insulin release(α2 pancreatic receptor blockade)
5) Eye
•Miosis

11. 6) Nose
- Nasal stuffiness
Blockade of α receptor in nasal blood vessels
Vasodilatation
Congestion of nasal mucosa

12. Phenoxybenzamine
 Pro drug
 Metabolism –liver
to active Ethyliniminium
↓
React with α receptor by
Covalent bond
↓
Nonequilibrium
Phentolamine
Not a prodrug
Bind with α receptor
↓
By simple bond
↓
Equilibrium

13. Phenoxybenzamine
 Nonequilibrium
 The blockade -gradually
 longer acting → 3-4 days
 Oral, i.v.
 Dose:20-40 mg/day, 1 mg/kg
by slow iv infusion - hour
 lipid soluble, penetrates
brain → CNS stimulation
Phentolamine
 Equilibrium
 Rapidly acting a blocker
 short duration (min)
 i.v
 Dose: 5 mg i.v. repeated as
required

14. Use - Pheochromocytoma
Use
 Pheochromocytoma
 Hypertensive emergencies

15. Tolazoline
 Similar to phentolamine
 Less potent
 Better absorbed – GIT
 Rarely used now a days

16. α1 Blockers
Prazosin
 Introduction – α1 : α2 selectivity ratio 1000:1
 Subtypes of α1 receptor (α1A, α1B, α1D ) blocked equally.
Pharmacological action
- Fall in BP
- Inhibits phosphodiesterase rise in cAMP (SM)
Vasodilatation

17. serum lipid- ↓ LDL , Triglycerides
-↑ HDL
Pharmacokinetics
 Effective -orally (bioavailability -60%),
 Metabolized - liver
 Excreted - bile
 Plasma t ½ - 2-3 hours (single dose lasts for 6-8
hours )
Dose – start with 0.5 -1 mg at bed time
- 1-4 mg BD

18. Terazosin
 less potent than prazosin ,high specificity –α 1
Bioavailability (90%)
 longer plasma t ½ - 12 hours
 Single daily dose lowers BP over 24 hours
 Single daily dose
 Probable apoptosis promoting effect on prostate.

19. Doxazocin
Plasma t ½ - 20 hours
Longer acting
Apoptosis promoting effect on prostate
Dose – 1 mg OD

20. Tamsulosin
 Uroselective
α 1A /α 1D (α 1A : α1B affinity 7-38 fold)
Does not cause significant changes in BP or HR
 No increase in adverse cardiovascular events
 Lacks the prostatic apoptosis promoting property
of terazosin and doxazosin

21. During cataract surgery - Floppy iris
Plasma t ½ - 5-10 hours
 Modified release (MR) cap. needs only once daily
dosing.
Better tolerated
 No CVS side effect

22. Silodosin
 Selectively α 1A
Approved for - BPH
 Lesser effects on blood pressure
 Silodosin - 4 mg and 8 mg capsules.

23. 1.Benign Hypertrophy Of Prostate (BHP)
Introduction
-Nonmalignant enlargement of the prostate gland.
Pathophysiology
- stromal and glandular epithelial hyperplasia the
periurethral transition zone of the prostate that surrounds
the urethra
-overgrowth of smooth muscle tissue and glandular epithelial
tissue (aging, late activation of cell growth, genetic factors,
and hormonal changes.)

25. - increase in smooth muscle mass
- the α 1 receptor–mediated increase in smooth muscle
tone in the prostate and neck of the bladder
mechanical pressure on the urethra
symptomatic urethral obstruction
weak stream, hesitancy, urinary frequency and nocturia

26. • increased size of
prostate
Static
component
• due to increased tone
of bladder
neck/prostate smooth
muscle(α1)
Dynamic
component

27. Pharmacological bases
Bladder trigone , prostate and prostatic urethra increases
smooth muscle tone,
Relaxes these structures, decrease tone of
prostatic/bladder neck muscles
Reducing dynamic obstruction,
↑urinary flow rate and causing more complete emptying of
bladder
Blockade

28. Voiding symptoms- Relieved better than irritative symptoms
Advantages Disadvantages
Faster symptomatic relief
Within 2 weeks
Greater symptomatic
relief than finasteride
Do not affect prostate size
Effects last only till the
drug is given
Even with continued
therapy, benefit may decline
after several years due to
disease progression

29. Finasteride – Static component
- delayed onset taking nearly 6 months for
clinical improvement.
Pharmacological agents
Prazosin, Terazosin, doxazosin , alfuzosin and tamsulosin
once daily dosing.
Tamsulosin drug of choice
- No increase in adverse cardiovascular events
Combination therapy with α1 blocker and finasteride reduces
the risk of overall clinical progression of BPH significantly
more than treatment with either drug alone

31. 2. Pheochromocytoma

32. The name pheochromocytoma the black-coloured
staining caused by chromaffin oxidation of
catecholamines
Catecholamine- producing tumors derived from the
sympathetic or parasympathetic nervous system
Pheochromocytomas - adrenal medullary cell

33. Secrete excessive quantities of catecholamines into
the circulation.
Intermittent or persistent hypertension , Sweating
Palpitations and tachycardia, Anxiety and panic
attacks, Pallor

34. Diagnostic
Phentolamine test
Inject phentolamine 5 mg i. v. over 1 min in recumbent
subject
A fall in BP > 35mm Hg systolic and/ or > 25 mm Hg diastolic
is indicative of pheochromocytoma.
-Both false positive and false negative results are obtained.

35.  Provocative tests
injecting histamine, methacholine or glucagon
provoke release of CAs
cause marked rise in BP
pheochromocytoma.
These tests are dangerous - phentolamine must be available
to counteract excessive rise in BP

36.  Therapeutic
- Therapeutic Phenoxybenzamine can be used as definitive
therapy for inoperable and malignant tumours
- When surgical removal
phenoxybenzamine - orally for 1-2 weeks preoperatively
i.v. during surgery

37. Shift fluid from vascular to
extravascular compartment
Blood volume is low
α blocker normalizes blood volume
and distribution of body water.
Pre-operative

38. phenoxybenzamine given pre and intra operatively.
phentolamine drip - during operation.
marked rise in BP
surgery
outpouring of CAs in blood

39. Removal of the tumour
Marked fall in BP as blood vessels
dilate and the blood volume is low.
Initially give α -blocker
Post-operative

40. 3. Hypertension
Phentolamine/Phenoxybenzamine are of great value in
controlling episodes of rise in BP during clonidine
withdrawal and cheese reaction in patients on MAO
inhibitors

41. Drawback
- vasodilatation is compensated by cardiac stimulation
α blockers (except α1 selective blockers) have been Failure
in the management of essential hypertension
- postural hypotension , impotence, nasal blockage and other
side effects produced by nonselective α blockers are
unacceptable

42. 4. Congestive Heart Failure
 The short-term effects of prazosin
due to dilation of both arteries and veins,
Resulting in a reduction of preload and afterload,
which increases cardiac output and reduces pulmonary
congestion.
 Symptomatic relief

43. 5.Secondary shock
Shock
blood and fluid loss
accompanied by reflex vasoconstriction.
- If volume replacement fails to reverse this
extremities remain pale and cold,
pulse pressure does not improve

44. Pharmacological bases
Phenoxybenzamine
(i) Counteracting vasoconstriction
(ii) Shifting blood from pulmonary to systemic
circuit
(iii) Returning fluid from extravascular to the
vascular compartment so that cardiac output
improves

45. 6. Peripheral vascular diseases
 Raynaud's phenomenon,
vasoconstriction prominent feature
- good symptomatic relief is afforded by prazosin
or phenoxybenzamine

46. 7.PIPE
( Papaverine/phentolamine induced penile erection therapy
for impotence.)
In patients unable to achieve erection

47. Adverse drug reaction
First does effect
Prazosin dilates arterioles more than vein
 Postural hypotension, dizziness and fainting ,
syncope - 30-90 minutes
Minimized - starting with a low does and taking it
at bedtime. Subsequently tolerance develops to this
side effect

48.  Orthostatic hypotension
-Phenoxybenzamine
- Problem during long term treatment with prazosin
 Miosis
 Nasal stiffness
 Inhibition of ejaculation
 Dizziness
 Retrograde ejaculation

49.  All of the following are therapeutic uses of
prazosin, except:
 (a) Peripheral vascular disease
 (b) Phaeochromocytoma
 (c) Lupus Erythematosus
 (d) Hypertension

50.  A drug ‘X’ is an α adrenergic blocker but
paradoxically produces vasoconstriction. ‘X’ is:
 (a) Phenoxybenzamine
 (b) Ergotamine
 (c) Prazosin
 (d) Tolazoline

51.  Which of the following effects of adrenaline
would be blocked by phentolamine but not by
propanolol?
 (a) Cardiac stimulation
 (b) Relaxation of bronchial smooth muscle
 (c) Relaxation of the uterus
 (d) Contraction of the radial smooth muscle in the
iris

52.  An old man Baba comes to you and is diagnosed
to be having benign hypertrophy of prostate. The
drug which provides faster and greater
symptomatic relief to this patient will be:
 (a) Tamsulosin
 (b) Desmopressin
 (c) Finasteride
 (d) Sildenafil

53.  Tamsulosin, a competitive αadrenoceptor
antagonist has affinity for which of the following
receptors?
 (a) α1A
 (b) α1D
 None of the above
 (d) Both (a) and (b)

54.  Ideal drug employed in the preoperative
preparation for surgical excision of
pheochromocytoma is:
 (a) Atenolol
 (b) Phenoxybenzamine
 (c) Reserpine
 (d) Clonidine

55.  An example of covalent drug receptor interaction is:
 (a) Noradrenaline binding to b1 adrenergic receptor
 (b) Acetylcholine binding to muscarinic receptor
 (c) Prazosin binding to a1 adrenergic receptor
 (d) Phenoxybenzamine binding to alpha adrenergic
receptor.

56. Contd.
 Nicotinic receptor sites include all of the
following except:
 (a) Bronchial smooth muscle
 (b) Adrenal medulla
 (c) Skeletal muscle
 (d) Sympathetic ganglia

57.  Alpha I blocker without any effect on blood
pressure is:
 (a) Tamsulosin
 (b) Prazosin
 (c) Doxazosin
 (d) Terazosin

58.  Which of the following is an selective alpha 2
 antagonist?
 (a) Prazosin
 (b) Labetalol
 (c) Yohimbine
 (d) Butoxamine

59.  Drug of choice for bradycardia due to beta
blocker overdose is:
 (a) Atropine
 (b) Dopamine
 (c) Adrenaline
 (d) Isoprenaline

60.  Tachyphylaxis is seen after use of:
 (a) Tamoxifen
 (b) Ephedrine
 (c) Morphine
 (d) Chlorpromazine

61.  Fenoldopam is used in
 (a) Hypertensive emergencies
 (b) CHF
 (c) Migraine
 (d) Tachyarrythmia

62. THANK YOU