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Adrenergic antagonists
1.
2.
3.
4. Gs and Gi produce stimulation and inhibition of the enzyme adenylate cyclase
respectively, whilst Gq interacts with phospholipase C.
H. Zhong, K.P. Minneman European Journal of Pharmacology 375 (1999) 261-276
7. Objectives
1. Describe the effects of E and NE in the
presence and in the absence of Alpha
Blocker.
2. Compare the effects among Beta Blockers
3. Compare the pharmacokinetics among
Beta Blockers
4. Describe the clinical applications and
toxicity of typical Alpha- and Beta
Blockers.
9. Outline
II. Alpha-Blocking Drugs (cont’d)
E. Clinical Uses
F. Adverse Effects
III. Beta-Blocking Drugs
A. Classification and Mechanisms
B. Effects and Clinical Uses
C. Adverse Effects
10. I. Concepts
• Classification is based on
receptor selectivity.
• These drugs differ markedly
in their effects and clinical ap
plications.
11. II. 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. Alpha1-selective blockers
4. Alpha2-selective blockers
12. A. 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, rauwolscine
•
13. B. 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 rout
e
• Prazosin: oral, duration 8-10 hr
14. C. Mechanism of Action
• Phenoxybenzamine: binds
covalently--irreversible (insurmount
able) blockade (slightly a 1 -selective)
• Other agents: competitive
antagonists--the effects can be overc
ome by increased concn
of agonist
16. D. Effects of Alpha Blockers
1. Nonselective alpha blockers
–block alpha-mediated sympathetic
responses and exogenous sympathomi
metics
–Most important effects: CVS effects
•vasodilation --reduce arterial and
venous pressure (a 1 )
•no significant direct cardiac effects
17.
18. • Cause reflex tachycardia (due to
decreased MAP)
• Tachycardia may be exaggerated
because a 2 receptors are also blocked.
• e.g. phenoxybenzamine, phentolamine,
tolazoline
D. Effects of Alpha Blockers
1. Nonselective alpha blockers (cont)
19. Selective a1 blockers cause less reflex tachycardia than
Phenoxybenzamine and 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
D. Effects of Alpha Blockers
21. Epinephrine Reversal
occur when alpha blockers are given before Epi
---> Epi produce the opposite effects : decreased
BP resulting from b 2 effect
(a 1 ,a 2,b 1,b 2 )
23. E. 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)
24. Disorders of the Autonomic Nervous System:
Raynaud’s Disease
• Raynaud’s disease – characterized by constriction of blood vessels
– Provoked by exposure to cold or by emotional stress
25. Disorders of the
Autonomic Nervous
System:
Hypertension
• Hypertension – high
blood pressure
– Can result from
overactive
sympathetic
vasoconstriction
26. E. Clinical Uses
2. Selective a 1 -blockers
Prazosin and others
Essential Hypertension
Urinary hesitancy
Prevention of urinary retention in
benign prostatic hyperplasia (BPH)
27.
28. 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
29. 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
31. 1. An α adrenergic receptor blocker
which is more effective in the
management of benign prostate
hypertrophy:
a) Tamsulosin
b) Phenoxybenzamine
c) Doxazosin
d) Phentolamine
e) Terazosin
32. 2. A non selective α adrenergic
receptor blocking agent:
a) Phenoxybenzamine
b) Prazosin
c) Doxazosin
d) Tamsulosin
e) Terazosin
33. 3. A drug useful in the treatment of a
patient with a slightly enlarged
prostate and suffering from
hypertension:
a) Prazosin
b) Labetalol
c) Phentolamine
d) Propranolol
e) Isoproterenol
34. 4. The reversal of the hypertensive
effect of epinephrine (adrenaline) is
produced by the blockade of:
α)α1 receptors
β) α2 receptors
χ) β1 receptors
δ) β2 receptors
e) M1 receptors
35. Practice Questions
• Blockade of which receptors is responsible for
the therapeutic and adverse effects of
adrenergic receptor agonists?
• Therapeutic: a1, b1
• Adverse: a2, b2
36. • Which type of drugs causes chemical
sympathectomy? Give an example?
• Non-Competitive a blocker
• phenoxybenzamine
37. III. 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
38. A. 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
39. A. Classification and
Mechanisms
2. Partial agonist activity
–Intrinsic sympathomimetic
activity, ISA
–eg, pindolol, acebutolol
–may be useful in patients
with asthma
40. A. 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
41. 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
42. B. 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
57. 1. A non selective β receptor
antagonist:
a) Timolol
b) Acebutalol
c) Atenolol
d) Esmolol
e) Metoprolol
58. 2. A β receptor antagonist which also
acts as a partial agonist:
a) Pindolol
b) Propranolol
c) Esmolol
d) Timolol
e) Metoprolol
59. 3. Propranolol is contraindicated in
one of the following diseases:
a) Hypertension
b) Tachycardia
c) Hyperthyroidism
d) Angina pectoris
e) Bronchial asthma
60. 4. Propranolol produces its
antihypertensive action by:
a) Vasodilatation
b) Ganglionic blockade
c) Decreased cardiac output
d) A diuretic action
e) Blockade of α1 receptors