Non- selective β-adrenoceptor antagonists

Non- selective β-adrenoceptor antagonists

Propranolol (Inderal®)
About The drug	- Propranolol is a non-selective beta blocker drug. - It blocks both β1 and β2 receptors with equal affinity. - James W. Black (British scientist) successfully developed propranolol in the   1960s. In 1988, he was awarded the Nobel Prize for this discovery.
Pharmaco- kinetics	- It is a highly lipophilic à readily crosses the blood-brain barrier (BBB) and the   placenta and is distributed into breast milk. - It is almost completely absorbed after oral administration. - First-pass effect: only about 25% of an orally administered dose reaches the   circulation. - Volume of distribution (Vd) of propranolol is quite large = 4 L/kg. - It is extensively metabolized, most metabolites are excreted in the urine.
Pharmacological action	Heart	- (-ve) Inotropic (Force) & (-ve) Chronotropic (HR). - slow SA (sinoatrial) and AV (atrioventricular) nodal conduction. - Decrease cardiac work and O2 consuming à useful in treatment of   angina.
	Blood Vessels	- Blocking B2-receptors on the skeletal muscle block vasodilation    effect. - Reflex peripheral vasoconstriction: decrease CO à decrease BP,   which triggers a reflex peripheral VC, but, chronic drug administration   lead to returns to normal or decreases total peripheral resistance.
	Lung	- Bronchoconstriction: blocking β2 receptors in the lungs of susceptible   patients causes contraction of the bronchiolar smooth muscle. - Non-selective B-blockers, are contraindicated in patients with COPD   or asthma.
	Eyes	- β-blocking agents reduce intraocular pressure (IOP) especially in   glaucoma due to decrease aqueous humour formation.
	Metabolic effects	- Block B-receptors in the adipose tissues à decrease Lipolysis. - Block B2-receptors in the liverà decrease Glycogenolysis. - Block B2- receptors in the pancreas à decrease Glucagon.   N.B: Glucagon hormone used to combat hypoglycemia effects, So; non-    selective B-blockers used with caution in insulin-dependent diabetic   patients. -Block β2-receptors in skeletal muscles hyperkalemia. - Chronic use à ↑ VLDL (very low density lipoprotein) and decrease   HDL (high density lipoprotein; good cholesterol) - ↑ risk for coronary artery disease. - Propranolol may cause sodium and water retention.
Therapeutic Uses	- Hypertension:    B-blocking agents (especially Propranolol) do not usually cause hypotension in    healthy individuals with normal blood pressure.    Propranolol lowers blood pressure in hypertension by several different    mechanisms of action: 1) Decrease cardiac output (primary mechanism).                              2) Inhibition of renin release from the kidney.                                3) Decrease in total peripheral resistance. 4) Decrease sympathetic outflow from the CNS. - Angina Pectoris (Ischemic Heart Disease):      - Decrease cardiac work and decrease O2 requirement of heart muscle.      - Useful in chronic management of stable angina (not variant angina). - Myocardial Infarction: (due to decrease O2 consuming)    - As a protected against a second heart attack (prophylactic).    -Reduce infarct size and hastens recovery.    - Reduce the incidence of sudden death after myocardial infarction. - Cardiac Arrhythmias:     Effective in the treatment of both supraventricular and ventricular arrhythmias. - Hypertrophic Subaortic Stenosis:    Propranolol improve NYHA (New York Heart Association) functional class in    symptomatic patients with hypertrophic subaortic stenosis. - Hyperthyroidism:     Protective against sympathetic stimulation that occurs in hyperthyroidism.     Propranolol inhibits the peripheral conversion of T4 (thyroxine; less potent) to     T3 (triiodothyronine; more potent). - Migraine:   used as prophylaxis of migraine headache. - Anxiety status:    control sympathetic symptoms (tachycardia/tremor).
Side Effects	- Hypotension (common). - Bronchospasm (uncommon):          Propranolol is C/I in COPD or asthma. - Arrhythmias (uncommon):         Bradycardia or heart failure. - Metabolic disturbances (uncommon):          decrease glycogenolysis and decrease glucagon secretion à increase          incidence of hypoglycaemic episodes in type I diabetics (fasting          hypoglycemia).          increase LDL (low density lipoprotein; bad cholesterol) à ↑ risk for coronary          artery disease. - Cold extremities (Raynaud's phenomenon) (common): -        May due to reflex peripheral vasoconstriction. - Male impotence (uncommon): Mechanism is unclear. - CNS effects (severity depends on lipophilicity) (common):    Sleep disturbances (insomnia and vivid dreams and nightmares), fatigue and    irritability.
FDA Warning	The B-blockers must be tapered off gradually. - Long-term treatment with a B-blocker à up-regulation of the B-receptors. - Sudden stop of B-blocker therapy à increased receptors sensitivity and can   worsen angina or hypertension.

 

 

 

Nadolol (Corgard®)		Timolol (Timogel®)
- Nadolol and Timolol  are a non-selective B-blocker drugs. - Nadolol and Timolol are more potent than Propranolol. - Nadolol has a very long duration of action with low lipid solubility and used in hypertension, angina   pectoris, migraine prophylaxis and anxiety symptoms. - Nadolol (non-selective) widely used in esophageal varices to prevent (prophylaxis) bleeding in   people with portal hypertension caused by cirrhosis (decrease both cardiac output by β1-blockade   and splanchnic blood flow by blocking vasodilating B2-receptors at splanchnic vasculature. - Timolol used topically in the treatment of chronic open-angle glaucoma due to it reduces the    production of aqueous humour in the eye.
Carteolol (Ocupress®)	Metipranolol (Betanol®)		Levobunolol (Betagan)
- Carteolol, Levobunolol and Metipranolol are a non-selective drugs used to treatment of chronic   open-angle glaucoma.
Sotalol (Betacor®)
- Sotalol is a non-selective β-blocker drug. - It is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac - action potential duration prolongation; inhibit of potassium channels) properties.

 

 

 

Drugs Used in Open Angle Glaucoma
Cholinomimetics	Pilocarpine, Carbachol, Physostigmine, Echothiophate, Demecarium	Opining trabecular meshwork; Increased outflow
a-Agonists	Non-selective;  Epinephrine, Dipivefrin	Increased outflow
	Selective α2 ; Apraclonidine,Brimonidine	Decreased aqueous secretion
B-blockers	Timolol, Betaxolol, Carteolol, Levobunolol, Metipranolol	Decreased aqueous secretion
Carbonic anhydrase inhibitors	Dorzolamide, Brinzolamide, Acetazolamide, Dichlorphenamide, methazolamide	Decreased aqueous secretion
Prostaglandins	Latanoprost, Bimatoprost, Travoprost, Unoprost	increased outflow

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