1. Adrenoceptor Blockers
Dumrongsak Pekthong
M.Sc.(Pharmacology)

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

3. 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.

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

5. Outline II. Alpha-Blocking Drugs (cont’d) III. Beta-Blocking Drugs
E. Clinical Uses
F. Adverse Effects
III. Beta-Blocking Drugs
A. Classification and Mechanisms
B. Effects and Clinical Uses
C. Adverse Effects

6. I. Concepts Classification is based on receptor selectivity.
These drugs differ markedly in their effects and clinical applications.

7. 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

8. 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
used primarily in researches

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

10. C. Mechanism of Action
Phenoxybenzamine: binds covalently--irreversible (insurmountable) blockade (slightly a 1 -selective)
Other agents: competitive antagonists--the effects can be overcome by increased concn of agonist

11. D. Effects of Alpha Blockers
1. Nonselective alpha blockers
block alpha-mediated sympathetic responses and exogenous sympathomimetics
Most important effects: CVS effects
vasodilation --reduce arterial and venous pressure (a 1 )
no significant direct cardiac effects

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

13. D. Effects of Alpha Blockers
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

14. 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 )

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

16. 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)

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

18. 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

19. 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

20. 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

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

22. 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

23. 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

24. 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

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

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

27. 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, tremor, anxiety
CNS effects: sedation, fatigue, sleep alterations

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

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

30. The End