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

5. SympathSympatholyolytic Drugstic Drugs

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

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.

8. Outline
I. Concepts
II. Alpha-Blocking Drugs
A. Classification
B. Pharmacokinetics
C. Mechanism of Action
D. Effects

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

15. Chemical
sympathectomy
Hypertensive
Episodes
- decreases vascular
resistance
- lowers BP
- smooth
muscle relaxation in
the bladder
Used to treat
hypertensive episodes
of
Pheochromocytoma

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

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 )

22. Antagonistic effect of alpha blocker
on pretreatment with alpha agonist

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)

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

30. QUESTIONS

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

43. α1-antagonist _____
β1-antagonists --------

44. B. Clinical Uses
• CVS: hypertension, angina pectoris,
arrhythmia prophylaxis after MI, sup
raventricular tachycardias, hypertrop
hic cardiomyopathy, congestive heart
failure*
• Glaucoma: reduce aqueous humor
secretion (timolol)

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

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

50. Drug List
Alpha-blockers
–Nonselective:
phenoxybenzamine*,
phentolamine*
– a 1 -selective: prazosin*,
terazosin, doxazosin
– a 2 -selective: yohimbine

51. Drug List
Beta-blockers
–Nonselective: propranolol*, timolol,
nadolol
–Combined a - and b - blocking:
carvedilol, labetalol
– b 1 -selective: metoprolol, atenolol
– b 2 -selective: butoxamine

52. α1- Contract vascular
smooth muscle, iris,
bladder sphincter
muscle
α2-Inhibits NE
release
β2- Relaxes
bronchial,
uterine, and
vascular
smooth
muscle
α2-mediates platelet
aggregation;decrease insulin
secretion; decreases secretion
of aqueous humor
β2-inhibits platelet aggregation;
promotes glycogenolysis

53. 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

54. SUMMARY

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

61. The EndThe End