6.adrenergic blockers

ADRENERGIC BLOCKERS
Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Department of Pharmacology and Medical Sciences, Faculty of
Pharmacy- Al azhar University 1

Adrenergic blocker
(antagonists/sympatholytics)
 Drug that bind to adrenoceptor but do not trigger
the usual receptor-mediated intracellular effect.
 Have the opposite effect of adrenergic agents
 Also known as adrenergic antagonists or
adrenergic Blocking Agents
 Block alpha & beta receptor sites(nonselective)
 direct or indirect acting on the release of
norepinephrine and epinephrine.
2

Major effects mediated by α and β adrenoceptor
3

Classification
 Classified by the type of adrenergic receptor they
block
 Alpha1 and alpha2 receptors
 Beta1 and beta2 and beta 3 receptors
4

1- -Adrenergic blocking agents
6

A- Non Selective Alpha Blocker
1- Phenoxybenzamine 1 > 2
 Irreversible
 Covalent binding with receptor
 Long duration of action (14 - 48 hrs)
 Also blocks 5-HT, ACh & H1 receptors
 Inhibits neuronal & extra-neuronal uptake of NE
 Absorbed from GIT, low bioavailability
7

 CVS effect
• Vasodilatation – arteriolar and venous  BP
• Magnitude dependent on sympathatic activity at that
time
• postural hypotension
• More marked if hypovolaemia is present
• Baroreceptor reflex activation
• reflex tachycardia
• tends to oppose the fall by  HR and CO
 Epinephrine reversl: All -adrenergic blockers
reverse -agonist action of epinephrine.
8

 Other Effects
 ↓contraction of trigone and sphincterin blood
vessels
  urine flow
 insulin secretion from islet cells(2 blockers)
 Miosis
 Nasal stuffiness
  adrenergic sweating
9

 Clinical use:
 Phaeochromocytoma
 Control of BP
 Prior to surgery
 Adverse effects:
 Postural hypotension
 Tachycardia
 Nausea & Vomiting
 Nasal stuffiness
  ejaculation
 Contraindication: in patient with decrease
coronary infusion.
10

2- Phentolamine : 1 = 2
 Actions
  PVR –  blockade + direct (non adrenergic)
  HR – Reflex + 2 presynaptic on cardiacsympathetic
Terminals.
 Poorly absorbed orally
 Clinical use:
 Phaeochromocytoma
 Local vasoconstrictor excess
 Adverse effects:
 Cardiac stimulation : tachycardia, arrhythmia, angina
 GIT Stimulation :diarrhea;  gastric acid secretion
11

3- Tolazoline
 Similar to phentolamine
 Slightly less potent
 Better absorption from GIT
 Rapidly excreted in urine
 Limited clinical application
 peripheral vasospastic disease
12

B- 1 Selective Agents
Prazosin & Terazosin 1 >>>> 2
 Effective in management of hypertension
 Low affinity for 2
 Relative absence of tachycardia
 ↓ Triglycerides & LDL, ↑ HDL (favourable)
 Both are extensively metabolized by liver
 Prazosin shows high 1st Pass effect (50%)
 Oral absorption – good
 Terazosin :Bioavailability >90%; >18 h action
 Uses:
• Hypertension
• BPH
 Adverse effects
 First dose effect
 Postural hypotension
 Salt & water retention ( long term use) 13

Doxazosin:
 Similar to Prazosin but longer t ½ (22 Hr) and
inactive product excreated in feces not in urine.
Alfuzosin :
 similar to prazosin
Tamsulosin
 Selective α1 anatgonist
 Has greater selectivity for α1A subtype
 Has greater efficacy for BPH
 Relatively smaller effects on blood vessels
14

Clinical Uses Of  Blockers
 Pheochromocytoma
 Hypertensive emergencies
 Chronic hypertension – non selective blockers are not
used
 Peripheral vascular diaease
 spastic (Raynauds), not morphological
 Local vasoconstrictor excess– phentolamine useful-
local infiltration
 Urinary obstruction – BPH-prazosin, terazosin,
tamsulosin
 CHF
 α2- selective antagonists do not have any recognised
clinical use. 15

Adverse effects α1 – blockers
 Postural hypotension( less with α1 selective-
vasodilatation is less)
 Reflex tachycardia ( less with α1 selective)
 Salt and water retention
 Nasal stuffiness
 Miosis
 Failure of ejaculation
16

β-Adrenergic blocking agents
17

Beta blocker
Classification:
 Non selective beta1 & beta2:
(Propranolol, Timolol, nadolol,)
 Cardioselective beta1 receptor:
(Acebutolol, atenolol,, bisoprolol,, and esmolol)
 Antagoinst for both alpha & beta adrenoceptor
(Labetolol, carvedilol)
18

1- Propranolol
 Propranolol is the prototype of β-adrenergic
antagonist and block both β1 &β2 receptor with
equal affinity.
 Actions:
• decrease cardiac output
• Bronchoconstricton
• Reflux preipheral vasoconstriction
• Increase sodium retention.
• decrease glycogenolysis & decrease glucagon
secretion.
20

 Therapeutic use:
• Hypertension.
• Migraine.
• Hyperthyroidism.
• Angina pectoris.
• myocardial infarction
 Adverse effect:
• Bronchoconstriction.
• Arrhythmias.
• Sexual impairment.
• Metabolic disturbance.
• CNS effect: depression, dizziness, lethargy, fatigue,
weakness, visiual disturbance, hallucination, short-term
memory loss, and emotional lability
 Contraindication: patient with COPD or asthma. 21

Timolol and Nadolol
 Block β1 & β2 adrenoceptor and are more potent
than propranolol.
 Nadolol has a very long duration of action.
 Timolol reduces the production of aqueous humor
in the eye. It is used topically in the treatment of
chronic open-angle glaucoma and, occasionally, for
systemic treatment of hypertension.
22

 Symptoms of overdose include:
 abdominal irritation
 central nervous system depression
 coma
 extremely slow heartbeat
 heart failure
 lethargy
 low blood pressure
 wheezing
23

Selective β1 antagonists
Acebutolol, atenolol, betaxolol, bisoprolol, esmolol,
metoprolol, and nebivolol
 Drugs that preferentially block the β1 receptors minimize
the unwanted bronchoconstriction (β2 effect) seen with
propranolol use in asthma patients.
 Actions:
 lower blood pressure in hypertension
 and increase exercise tolerance in angina
 Therapeutic use:
 In hypertensive patients with impaired pulmonary function.
 first-line therapy for chronic stable angina
 Because these drugs have less effect on peripheral vascular
β2 receptors, coldness of extremities (Raynaud
phenomenon), a common side effect of β-blockers, is less
frequent. 24

 Symptoms of overdose include:
 extreme bradycardia
 Advanced atrioventricular block
 intraventricular conduction defects
 hypotension
 severe congestive heart failure
 seizures
 angina susceptible patients
 bronchospasm
 hypoglycemia
25

Antagonists with partial agonist ctivity
Acebutolol and pindolol
 Acebutolol (β1-selective antagonist)
 pindolol (nonselective β-blocker) are not pure
antagonists.
 These drugs also have the ability to weakly stimulate
both β1 and β2 receptors.
 Used in hypertensive patient with moderate bradycardia.
26

Antagonists of both α and β adrenoceptors
Labetalol and carvedilol
Labetalol and carvedilol are nonselective β-blockers
with concurrent α1-blocking actions that produce
peripheral vasodilation, thereby reducing blood
pressure.
 They contrast with the other β-blockers that
produce initial peripheral vasoconstriction, and
these agents are therefore, useful in treating
hypertensive patients for whom increased
peripheral vascular resistance is undesirable.
 Carvedilol also decreases lipid peroxidation and
vascular wall thickening, effects that have benefit in
heart failure. 27

 Therapeutic use in hypertension and heart failure
 Adverse effect:
 Orthostatic hypotension.
 Dizziness.
28

Dr. Mahmoud H. Taleb 29
IV. DRUGS AFFECTING NEUROTRANSMITTER
RELEASE OR UPTAKE
A. Reserpine
Reserpine a plant alkaloid, blocks the Mg2+/adenosine triphosphate
dependent transport of biogenic amines, norepinephrine, dopamine,
and serotonin from the cytoplasm into storage vesicles in the
adrenergic nerves of all body tissues. This causes the ultimate
depletion of biogenic amines. Sympathetic function, in general, is
impaired because of decreased release of norepinephrine. The drug
has a slow onset, a long duration of action, and effects that persist
for many days after discontinuation.

B. GUANETHIDINE
Guanethidine blocks the release of stored norepinephrine
as well as displaces norepinephrine from storage
vesicles (thus producing a transient increase in blood
pressure). This leads to gradual depletion of
norepinephrine in nerve endings except for those in the
CNS. Guanethidine commonly causes orthostatic
hypotension and interferes with male sexual function.
30

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