full lecture of Adrenal receptors antagonist pharmacologicaly

1. Adrenal Antagonist
By Dr. Sara Sami
Yuzuncu Yil University
2015

2. Adrenoceptor Antagonist Drugs
Classification
– Alpha Antagonists
• Non Selective
• α1 Selective
• α2 Selective
– Beta Antagonists
• Non Selective
• β1 Selective
• β2 Selective
• Toxicity

3. Classification of adrenergic receptor antagonist.

4. Wording
• Adrenoceptor Blocker
• Adrenergic Antagonist
• Subgroups in Sympathoplegic drugs
• Alpha Blocker, Alpha Antagonist
• Beta Blocker, Beta Antagonist

5. General effects of α blockers
Blood vessels
• α1-blockade reduces peripheral resistance
Fall in BP
Postural hypotension
• α2-blockade in brain se vasomotor tone.
• Block pressor action of adrenaline, fall in BP due
toβ2.
action- “vasomotor reversal of Dale”
• Actions of selective α-agonists supressed.

6. Heart
• Reflex tachycardia due to:-
 fall in mean arterial pressure
Blockade of presynaptic α2 receptors- ↑ NA release.
Nose: nasal stuffiness
Eye: miosis
GIT: intestinal motility se
Kidney: Hypotension
se GFR
NA+ & H2O reabsorption

7. Urinary bladder
• α1A blockade- se tone of smooth muscle in trigone,
sphincter & prostrate.
• Improved urine flow, used in BPH.
Reproductive system
• Contraction of vas deferens result in ejaculation
through α receptors.
• Blockade results in impotence.

8. Alpha-Blocking Drugs
A. Classification
–based on: selective affinity for alpha
receptors, reversibility
1. Irreversible, long-acting alpha
blockers
2. Reversible, short-acting alpha
blockers
3. a1-selective blockers
4. a2-selective blockers

9. Classification
1. Irreversible alpha blockers :
Phenoxybenzamine
–slightly a 1 -selective, long-acting
2. Reversible alpha blockers:
Phentolamine (nonselective), tolazoline
(slightly a 2 -selective)
3. a 1 blockers: Prazosin, Doxazosin,
Terazosin
4. a 2 blockers: Yohimbine
used primarily in researches

10. Pharmacokinetics
• All active orally as well as
parenterally
• Phenoxybenzamine: short t1/2 but long
duration-48 hr (covalent bond)
• Phentolamine, tolazoline: parenteral,
duration 20-40 min by parenteral
route
• Prazosin: oral, duration 8-10 hr

11. Irreversible non-selective α- blockers
Phenoxybenzamine
• Cyclizes spontaneously to highly reactive
ethyleniminium intermediate.
• Binds covalently to α-receptors- irreversible or non-
equilibrium competitive block.
• Blockade is slow onset & longer duration (3-4 days).
• Also inhibits reuptake of NE.
• Shifts blood from pulmonary to systemic circuit.
• Shift fluid from extravascular to vascular compartment-
relaxation of postcapillary vessels.

12. Reversible alpha blockers
Yohimbine
• Natural alkaloid from Pausinystalia yohimbe.
• No established clinical role.
Idazoxan
• Has membrane stabilizing action.
Ergot alkaloids
• Ergotamine & Dihydroergotamine
• Competitive α-receptor blockers.
• Principal use is migraine.

14. Reversible, selective α1- blockers
Prazosin
• Highly selective α1-blocker , α1: α2 selectivity 1000:1
• Fall in BP with only mild tachycardia.
• Dilates arterioles more than veins
• Postural hypotension occurs as 1st dose effect,
minimized by starting with low doses at bed time.
• Also inhibits PDE- se cAMP in smooth muscle.
PK
• Effective orally, BA- 60%.
• Highly bound to plasma proteins (α1 acid
glycoprotein).

15. • Metabolized in liver, 1o excreted in bile.
• t1/2 – 2-3hrs, effect lasts for 6-8hrs.
Uses
• Primarily as antihypertensive.
• LVF not controlled by diuretics & digitalis.
• Raynaud’s disease
• BPH
• Scorpion sting

16. PK
• Preferred ROA- i.v.
• Lipid soluble penetrates brain.
• Mainly excreted through urine in 24 hrs.
• Accumulates in adipose tissue on ch. Administration.
Dose
20-60 mg/d oral
1mg/kg/1hr slow i.v infusion.
Uses
Pheochromocytoma, occasionally 2oshock, PVD.

17. Reversible non-selective α-blockers
Tolazoline
• Block is modest & short lasting.
• Direct vasodilator & stimulates the heart.
• Also blocks 5-HT receptors, histamine like gastric
secretagouge & Ach like motor action on intestine.
SE
• N, V, cramps, diarrhoea, nervousness, chills
• Tachycardia, Exacerbation of MI, peptic ulcer.
Use
• PVD
• Pulmonary HT of newborn.

18. • Cause reflex tachycardia (due to decreased
MAP)
• Tachycardia may be exaggerated because a 2
receptors are also blocked.
• e.g. phenoxybenzamine, phentolamine,
tolazoline
Effects of Alpha Blockers
1. Nonselective alpha blockers (cont)

19. Clinical Uses
1. Nonselective alpha-blockers
Presurgery of pheochromocytoma: phenoxybenzamine
During surgery: phentolamine (sometimes)
Carcinoid tumor: phenoxybenzamine (5-HT blocking)
Mastocytosis: phenoxybenzamine (H1 antihistamine)
 Accidental local infiltration of alpha agonist:
phentolamine
Overdose of sympathomimetics (amphetamine,
cocaine, phenylpropranolamine)
Raynaud’ s phenomenon, erectile dysfunction
(phentolamine)

20. 2. Selective a 1 blockers
• The same effects as nonselective alpha
blockers
• But cause much less tachycardia than
nonselective blocker
• e.g. Prazosin, Doxazosin, Terazosin
Effects of Alpha Blockers

21. Clinical Uses
2. Selective a 1 -blockers
 Prazosin and others
 Essential Hypertension
 Urinary hesitancy
 Prevention of urinary retention in
benign prostatic hyperplasia (BPH)

22. Terazosin &Doxazosin
• Long acting( t1/212 & 18hr) congener of prazosin.
• Used in HTN & BPH as single daily dose.
Tamsulosin & Silodosin
• Uroselective α1A blocker
• α1A –bladder base, prostrate. α1B- blood vessels.
• Don't cause significant changes in BP & HR.
• t1/2- 6-9hr, MR cap(0.2-0.4 mg) can be taken OD.
• Efficacious in Rx of BPH.
• SE: retrograde ejaculation, dizziness,, floppy iris syd.
• Silodosin weaker(4-8mg/d) but longer acting.

23. Phentolamine
• More potent α-blocker than tolazoline.
• Other actions are less marked.
• Duration of action is shorter (min).
• Equally blocks α1 & α2 receptors- NA release sed.
Uses
• ∆sis & intraop.management of pheochromocytoma. 5mg
i.v- B.P falls by 25(D)or35(S)mmHg.
• HTN due to clonidine withdrawl, cheese reaction.
• Dermal necrosis due to extravasated i.v NA/DA. Given
S.C as local infiltration.

24. Bunazosin & Alfuzosin
• Orally effective α1 blockers similar to prazosin.
• Alfuzosin t1/2 4hrs (2.5mgTDS or 10mg SR OD).
• CI in hepatic impairment, metabolized in liver.
• Bunazosin slightly longer t1/2.
• Primarily used in BPH.

25. F Adverse effects of Alpha blockers
 Orthostatic hypotension (venodilatation)
 Reflex tachycardia (nonselective >
selective)
 First dose hypotension (take before going
to bed)
 Nausea/vomiting
 Caution in patients with coronary artery
disease (CAD or CHD): angina

26. Side effects of α-blockers
• Palpitation
• Postural hypotension
• Nasal blockade
• Diarrhea
• Fluid retention
• Inhibition of ejaculation & impotence.

27. Receptor Type a1 a2
Selective Agonist Phenylephrine
Oxymetazoline
Clonidine
Clenbuterol
Selective Antagonist Doxazosin
Prazosin
Yohimbine
Idazoxan
Agonist Potency
Order
A=NA>>ISO A=NA>>ISO
Second Messengers
and Effectors
PLC activation via
Gp/q causes inc.
[Ca2+]i
dec. cAMP via Gi/o
causes dec. [Ca2+]i
Physiological Effect Smooth muscle
contraction
Inhibition of
transmitter release
Hypotension,
anaesthesia,
Vasoconstriction

28. Beta-Blocking Drugs
A. Classification and Mechanisms
All are competitive antagonists
Propranolol is prototype
Classification is based on
 Beta subtypes selectivity
 Partial agonist activity
 Lipid solubility
 Local anesthetic action

29. 3. Propranolol is contraindicated in
one of the following diseases:
a) Hypertension
b) Tachycardia
c) Hyperthyroidism
d) Angina pectoris
e) Bronchial asthma

30. 4. Propranolol produces its
antihypertensive action by:
a) Vasodilatation
b) Ganglionic blockade
c) Decreased cardiac output
d) A diuretic action
e) Blockade of 1 receptors

31. Classification and Mechanisms
1. Receptor selectivity
– b 1 -selective: metoprolol, atenolol
– b 2 -selective: butoxamine (research
only)
– Nonselective: propranolol
–Combined beta- and alpha-
blocking: labetalol

32. A. Classification and Mechanisms
Partial agonist activity
–Intrinsic sympathomimetic
activity, ISA
–eg, pindolol, acebutolol
–may be useful in patients
with asthma

33. Classification and Mechanisms
3. Local anesthetic activity
(membrane-stabilizing activity):
–disadvantage when used topically
in the eye
–timolol: no this activity
4. Lipid solubility
–responsible for CNS adverse
effects: propranolol

34. Pharmacokinetics of
Beta blockers
• For systemic effects, developed for
chronic oral use
• Esmolol: short-acting--only used
parenterally
• Nadolol: longest-acting
• Atenolol, acebutolol are less lipid-
soluble

35. Effects and Clinical Uses
• Predict from beta blockade
–decreased HR, force of contraction
–decreased A-V conduction
–slow firing rate of SA node
• Cardiovascular and ophthalmic
applications are extremly important

36. Clinical Uses
• CVS: hypertension, angina pectoris,
arrhythmia prophylaxis after MI,
supraventricular tachycardias,
hypertrophic cardiomyopathy,
congestive heart failure*
• Glaucoma: reduce aqueous humor
secretion (timolol)

38. Clinical Uses
• Migraine: propranolol
• Thyroid storm, thyrotoxicosis:
propranolol
• Famillial tremor, other types of
tremor, “stage fright” :
propranolol

40. Adverse effects
• CVS: bradycardia, A-V blockade,
congestive heart failure
• Patients with airway disease:
asthmatic attack
• Mask sign of hypoglycemia in
diabetic patients: tachycardia,
tremor, anxiety
• CNS effects: sedation, fatigue,
sleep alterations

41. Receptor
Type
b1 b2 b3 b4
Selective
Agonist
Dobutamine
xamoterol
Salbutamol
salmeterol
BRL 37344 none
Selective
Antagonists
Atenolol
metoprolol
Butoxamine SR59230A Bupranolol
Agonist
Potency
Order
ISO>A=NA ISO>A>>NA ISO=NA>A
Second
Messengers
and Effectors
Inc cAMP via
Gs
Inc cAMP via
Gs
Inc cAMP via
Gs
Inc cAMP via
Gs
Physiological
Effect
Inc heart rate
and force
Vasodilatation
and broncho-
dilation
Lipolysis and
thermogenesis
Inc heart rate
and force

42. SUMMARY

43. Selectivity
Partial
Agonist
Activity
Local
Anesthetic
Action
Elimination Half-
Life
Approximate
Bioavailability
Acebutolol β1 Yes Yes 3-4 hours 50
Atenolol β1 No No 6-9 hours 40
Betaxolol β1 No Slight 14-22 hours 90
Bisoprolol β1 No No 9-12 hours 80
Carteolol None Yes No 6 hours 85
Carvedilol None No No 7-10 hours 25-35
Celiprolol β1 Yes No 4-5 hours 70
Esmolol β1 No No 10 minutes 0
Labetalol None Yes Yes 5 hours 30
Metoprolol β1 No Yes 3-4 hours 50
Nadolol None No No 14-24 hours 33
Penbutolol None Yes No 5 hours >90
Pindolol None Yes Yes 3-4 hours 90
Propranolol None No Yes 3.5-6 hours 30
Sotalol None No No 12 hours 90
Timolol None No No 4-5 hours 50