Pharmacology of Antiadrenergic drugs

1. ANTIADRENERGIC
DRUGS
By: Darya Osman Hussein Daoud
Manal Bala Saeed

2. The
Adrenergic
Neuron
• Synthesis and release of
norepinephrine from the
adrenergic neuron
• MOA – Monoamine
Oxidase
• SNRI – Serotonin
norepinephrine
reuptake inhibitor

3. α Adrenergic Receptors
(α Adrenoreceptors):
Equally responsive to
naturally occurring
catecholamines (i.e. EP and
NE)
Classified as α1 and α2

4. α1 Receptors:
Present on postsynaptic membrane
Constrict smooth muscle
Activation initiates series of reaction through G protein
activation or phospholipase C
Ultimately results in generation of 2nd messengers IP3 (initiates
release of Ca2+ from ER into cytosol) and DAG (turns on other
proteins within the cell)

5. Present on sympathetic presynaptic nerve endings and
parasympathetic presynaptic neurons
Controls release of NE via feedback inhibition
Also inhibits Ach release
Binding is mediated by inhibition of adenyl cyclase and fall in
intracellular cAMP levels
α2 Receptors:

6. α Receptors
• DAG – diacylglycerol
• IP3 – Inositol 3
triphosphate
• ATP – Adenosine
triphosphate
• cAMP – cyclic adenosine
monophosphate

7. • Vasoconstriction
• Increased peripheral resistance
• Increase BP
• Mydriasis
• Increased closure of internal
sphincter of the bladder
α1
• Inhibition of NE release
• Inhibition of Ach release
• Inhibition of insulin release
α2

8. β Adrenergic Receptors
(β Adrenoreceptors):
Equally responsive to
naturally occurring
catecholamines (i.e. EP and
NE)
Classified as β1, β2 and β3

9. β Adrenergic Receptors
(β Adrenoreceptors):
β1 have equal affinities to EP and NE
β2 have higher affinity for EP than for NE
β3 are responsible for lipolysis and have effects on detrusor
muscle of the bladder
Binding results in activation of adenylyl cyclase and increased
cAMP concentration

10. • Tachycardia
• Increased lipolysis
• Increased myocardial contractility
• Increased release of renin
β1
• Vasodilation
• Decreased peripheral resistance
• Bronchodilation
• Increased muscle and liver
glycogenolysis
• Relaxed uterine smooth muscle
β2

11. Regulation:
Desensitization of receptors can occur after prolonged exposure to
catecholamines
Occurs via 1 of the following mechanisms:
1. Sequestration of receptors – become unavailable for interaction with ligand
2. Downregulation – disappearance of receptors by destruction or decreased
synthesis
3. Phosphorylation - an inability to couple to G protein because of
phosphorylation on cytoplasmic side

12. What are adrenergic antagonists?
Drugs which antagonize the action of EP and NE at the
receptor level
They occupy adrenergic receptors (α and β ) but do not
produce signal transduction.
Can be reversible or irreversible
Classified according to relative affinity for α or β receptors

14. α adrenergic blockers
PHENOXYBENZAMINE, PHENTOLAMINE, PRAZOSIN,
TERAZOSIN AND DOXAZOSIN

15. Phenoxybenzamine & Phentolamine

16. Non-selective α blockers
Actions:
 Block of α1 receptor
 vasodilation and postural hypotension.
 Block of α2 receptor
 reduced NE action on α2 receptors on the varicosity
 increases release of NE from varicosity which can cause
tachycardia and increased CO
Phenoxybenzamine & Phentolamine

17. Mechanism of action:
Binds covalently (and therefore
irreversibly) to α receptor and blocks
NA action.
Action is reversible in the case of
phentolamine.
Phenoxybenzamine & Phentolamine

18. Pharmacokinetics
Given orally, IV and SC injection.
T ½ for Phenoxybenzamine = 12 hours (because of irreversible binding
to receptor).
T ½ for Phentolamine = 3 hours.
Phenoxybenzamine & Phentolamine

19. Clinical Use:
Used in treatment of phaeochromocytoma
Adverse effects:
Postural hypotension
Tachycardia
Dizziness and headache
Sexual disfunction
Phenoxybenzamine & Phentolamine

20. Prazosin, terazosin and doxazosin

21. Selective α1 antagonist
Action:
Vasodilatation and reduction in BP.
Increase HR (a reflex β1 receptor resonse to the decrease in BP)
Decrease bladder sphincter tone.
Inhibition of hypertrophy on smooth muscle of bladder neck and prostate
capsule.
Prazosin, terazosin and doxazosin

22. Mechanism of Action:
Block the action of endogenous and exogenous agonists on the α1
receptor.
Decrease peripheral vascular resistance
Relaxes arterial and venous smooth muscle
Causes minimal changes in CO, renal blood flow and GFR
Prazosin, terazosin and doxazosin

23. Pharmacokinetics:
Prazosin and Terazosin
absorbed orally
T ½ = 3 – 4 hours
Metabolised by liver
Extensive 1st pass metabolism
Doxazosin
T ½ = 22 hours
Prazosin, terazosin and doxazosin

24. Examples of uses of α1 selective blocker

25. Clinical use:
◦ Severe hypertension.
◦ Benign prostatic hypertrophy.
Adverse effects:
◦ Orthostatic hypotension
◦ Dizziness
◦ Hypersensitivity reactions
◦ Insomnia
◦ Priapism
Prazosin, terazosin and doxazosin

26. Caution -
Syncope
First dose of α1 receptor
blocker may produce an
orthostatic hypotensive
response and result in
fainting

27. β adrenergic blockers
PROPRANOLOL, TIMOLOL, NADOLOL,
ACEBUTOLOL, ATENOLOL, METOPROLOL AND
ESMOLOL

28. NON SELECTIVE
Propranolol
Timolol
Nadolol
Β1 SELECTIVE
(CARDIOSELECTIVE)
Acebutolol
Atenolol
Metoprolol
Esmolol
β adrenergic blockers

29. Propranolol
Non – Selective β blocker
Action:
CVS
decreases CO (-ve inotropic and chronotropic effects)
Decreased SA and AV node activity
Peripheral vasoconstriction via increased peripheral resistance
Bronchoconstriction
Reduces renin release
Decreased glycogenolysis and glucagon secretion

30. Mechanism of Action:
Block sympathetic drive
Reducing pacemaker activity and increases AV conduction time
Reduces the slow inward Ca2+ current
Propranolol

31. Pharmacokinetics:
Orally administered
Almost completely absorbed
Extensive 1st pass metabolism (only 0.25 bioavailability)
Large volume of distribution
Readily crosses blood-brain barrier
Metabolites excreted in urine
Propranolol

32. Therapeutic uses:
Class II antiarrhythmic
Hypertension
Angina pectoris
Migraine
Hyperthyroidism
Prevention of death by dysrhythima following myocardial infarction
Paroxymal atrial fibrillation
Propranolol

33. Propranolol
Adverse effects:
Bronchoconstriction
Arrhythmias (if stopped abruptly)
Sexual impairment
Metabolic disturbances (fasting
hypoglycemia)
CNS effects
Dissiness
Lethargy
Fatigue
Weakness
Visual disturbances
Hallucinations
Short term memory loss
Emotiaonal lability
Vivide dreams
Depression

34. Nadolol and Timolol
Non selective beta antagonists
Nadolol has very long duration of action
Action:
Drecrease intraocular pressure
More potent than propranolol

35. Nadolol and Timolol
Mechanism of action:
Reduce production of aqueous humor in the eye
Decrease secretion of aqueous humor by ciliary body
Do not cause cycloplesia

36. Nadolol and Timolol
Pharmacokinetics:
Onset is about 30 minutes when administered intraocularly
D.O.A. = 12 to 24 hrs
Clinical Use:
Chronic management of glaucoma

37. Acebutolol, Atenolol, Bisoprolol,
Esmolol, and Metoprolol
Slective beta blockers – known as cardioselective
Selectivity is lost at high doses
Action:
Decrease BP in hypertension
Inrease exorcise tolerane in angina

38. Pharmacokinetics:
Orally administered
T ½
Atenolol = 6 hours
Esmolol = 10 hours
Acebutolol, Atenolol, Bisoprolol,
Esmolol, and Metoprolol

39. Clinical Use:
Emergency treatment of supraventricular dysrhythmias (Esmolol)
Antianginal
Antihypertensive in diabetic patients reviecing insulin or oral
hypoglycemic agents
Acebutolol, Atenolol, Bisoprolol,
Esmolol, and Metoprolol