Adrenergic Antagonists DSA and lecture Flashcards
Nonselective alpha blockers
phenoxybenzamine
phentolamine
They start with ph. al-PH-a blockers
Alpha-one selective blockers
prazosin
tamsulosin (alpha 1A)
Nonselective beta blockers
propanalol
Cardioselective beta blockers
cardioselective? Think Beta 1
atenolol
acebutolol
metoprolol
betaxolol
alpha and beta blockers
labetalol
carvedilol
Phenoxybenzamine
IRREVERSIBLE alpha 1 and alpha 2 blocker
noncompetitive
Mechanism. Binds covalently to alpha-1 and alpha-2 adrenergic receptors. i.e. non-selective, irreversible, alpha blocker. Onset is slow requiring 10-20 minutes for formation of covalent linkages. Offset is even slower with a t1/2 of 24 hours. Terminated by metabolism and new receptor synthesis. Called non-equilibrium or non-competitive blocker.
New receptors must be synthesized to overcome the blockade
Several (2-5) days to regenerate
“Dirty” drug - also blocks histamine, acetylcholine, & serotonin receptors
Phentolamine
prototype reversible alpha 1 and alpha 2 blocker
competitive
prazosin
selective alpha 1 A blocker
Tamsulosin basic action
selective alpha 1A blocker
Alpha Adrenergic Blockers in general
Non-selective blockers- block both alpha-one and alpha-two adrenergic receptors.
Alpha blockers are antagonists
they have no intrinsic activity but do produce pharmacological changes).
They block the effects of endogenous agonists (epinephrine; norepinephrine)
Phenoxybenzamine:Pharmacological Effects.
Vascular. Dependent on the degree of sympathetic tone. i.e., blocks the effects of endogenous NE. Reduces blood pressure. Significant side effect is Orthostatic hypotension.
- Cardiac. Reflex tachycardia from reducing BP, which enhances NE release. Because alpha-2 receptors on adrenergic nerves are also blocked, this further increases NE release at the heart, where it can act on beta-1 receptors.
Phenoxybenzamine: Other effects
- CNS. lipophilic agent which can cross the blood brain barrier. Nausea, vomiting and weakness may be signs of non-specific effects.
- Others: miosis, inhibition of ejaculation, stuffy nose (all alpha1 blockade).
Phenoxybenzamine: Clin. Uses
Pheochromocytoma: Pre-operative management to treat vascular effects of high circulating catecholamines. Always in combination with a beta blocker.
Peripheral Vascular Disease. Raynaud’s syndrome where sympathetic tone to peripheral vasculature is high. Acrocyanosis from frost bite.
Reversible Alpha Blockers
Competitive blockers. Rapid onset of blockade. Surmountable by high concentrations of alpha-1 agonists.
Phentolamine and Tolazoline (Imidazoline derivatives). Non-selective for alpha-1 and alpha-2 receptors. Duration of several hours. They also activate histamine receptors (adverse effect).
Phentolamine: Clinical Uses
- Pheochromocytoma. Acute hypertensive crisis.
- Clonidine withdrawal
- Treat necrosis due to vasoconstrictors such as NE and phenylephrine.
- For erectile dysfunction (ED) – has been replaced by drugs with less severe side-effects.
Side effects: tachycardia, nausea, diarrhea, orthostatic hypotension ***.
Alpha-1 Selective Blockers: side effects, agents, uses
Block alpha-1 but not alpha-2 adrenergic receptors.
Generally reflex tachycardia is less prevalent than with non-selective alpha blockers.
Syncope is noted when first administered in a large group of patients. Caution patients to avoid sudden postural changes.
Agents: ***prazosin (Minipress), terazosin (Hytrin), doxazosin (Cardura)
Uses: Hypertension, benign prostatic hypertrophy
Tamsulosin
Competitive alpha blocker; binds alpha1A with little alpha1B binding
Very limited vascular effects, but highly efficacious in benign prostatic hyperplasia (BPH).
Conclusion is that vascular effects of alpha blockers is likely an alpha1B receptor, whereas prostate alpha receptors are a1A subtype
Yohimbine
a2 and 5-HT blocker
aphrodisiac, improves erectile function
Viagra has replaced its usefulness
Ergot Alkaloids
Ergotamine, Ergonovine
originally found in spoiled rye (fungus), caused abortions, gangrene, convulsions
used to treat migraine (also 5-HT agonists)
Nonselective Beta Blockers (Beta receptor antagonists)
Nonselective = both beta 1 and beta 2
Propranolol (prototype) Timolol Pindolol - partial agonist ISA =intrinsic sympathomimetic activity Nadolol
cardioselective beta blockers
Cardioselective = beta 1-selective
Atenolol (prototype)
Others
– Acebutolol : partial agonist, ISA
Metoprolol***
-Betaxolol
short-acting beta blocker
and non-selective alpha and beta blockers
Very short acting - Esmolol
Alpha and Beta Blockers:
- Labetolol
- Carvedilol
Propranolol
(Inderal) is the prototype beta blocker
Mechanism: Non-selective competitive antagonist at b-1 and b-2 receptors (& b-3).
High therapeutic doses may also have a non-receptor related quinidine-like or membrane-stabilizing effects.
Relatively high lipid solubility allows distribution to the CNS (some drowsiness)
Propranolol: Pharmacological Effects on heart and blood vessels
The effect of antagonists is due to blocking existing tone. Effects are greater if sympathetic tone is high.
- Heart: decreases HR, cardiac output, and pacemaker activity.
- Blood vessels: Slow developing decrease in peripheral resistance. Possibly due to: central reduction in sympathetic tone and reduction in renin release (beta-1 effect)
Decreases exercise tolerance, rate of depolarization of ectopic pacemakers, decreases O2 demand, decreases AV nodal conduction (can produce AV block), decreases infarct size and re-infarction- prevent sudden death
Propanolol: effects on bronchial smooth muscle and metabolic
- Bronchial Smooth Muscle
Block sympathomimetic bronchodilation
*** precaution or contraindication in asthma & COPD - Metabolic
Blocks beta receptor effects on lipolysis and glycogenolysis.
*** May mask signs of hypoglycemia, e.g., tachycardia, BP changes. May potentiate insulin-induced hypoglycemia. - Quinidine-like effect
“Membrane stabilizing activity”, decreased cardiac excitability
Propanolol metabolism
Well absorbed following oral administration.
Up to 75% may be inactivated by first pass metabolism. There is large inter-individual variation. Variation is relatively constant for a given patient. Must titrate the dose upward for each patient.
Beta blockers: clinical uses
- Angina pectoris. Reduces cardiac work and O2 consumption.
- Hypertension. Decreases CO and produces slow decrease in peripheral resistance due to blockade of renin release. May see Na+ and water retention with prolonged use because of reduced CO.
- Migraine headache (Prophylactic treatment)
- Arrhythmias: sinus tachycardia and supraventricular ectopic beat
- Recurrent VT, VF - especially when due to ischemia
- Pheochromocytoma
- Thyrotoxicosis:
hyperthyroid patients have increased receptor sensitivity - Adjunctive treatment for anxiety (panic) attacks (reduces peripheral sympathetic signs and symptoms, e.g., palpitations)
- MI & Post-MI prophylaxis
protects against arrhythmias & limits infarct size
Acute MI: assess LV function
5-12 days after MI, reduces O2 demand & spread of infarct zone
Congestive Heart Failure
Dramatic results in recent clinical trials
Beta blockers prevent HF in more than 50%, strokes reduced by more than 38%, occurrence of CAD and other CV events significantly decreased
Mortality rate reduced 65% by carvedilol, 34% by metoprolol, 33% by bisoprolol
Beta blockers increase LVEF, cause beneficial remodeling of heart
Use only in stable CHF (class II & III), gradually titrate dose
Patients also treated with diuretic, ACE inhibitors, & digoxin
Propranolol: Side Effects
Common:
dizziness, fatigue, diarrhea, constipation, nausea, depression, bizarre dreams
Severe:
purpura, rash, fever
Interferes with SGOT and BUN tests
`
Chronic use (hypertension) increases VLDL & HDL
Beta blocker side effects
Use with caution in diabetics
- inhibits compensatory response to hypoglycemia (glycogenolysis with glucose release)
- masks signs of hypoglycemia (tachycardia) that are important “clues” to diabetic patient
Contraindicated in most asthmatics and COPD
- because block b2 bronchodilation
beta blockers sudden withdrawal and other contraindications
Sudden Withdrawal: rebound hypertension, anginal attack & possibly MI if drug suddenly withdrawn after chronic therapy. Beta receptor synthesis is increased by beta blocker use. Example of receptor up-regulation.
Other Contraindications: Acute treatment of decompensated heart failure; 2nd and 3rd degree heart block, and cardiogenic shock.
beta blocker drug interactions
Other hypotensive medications
–reserpine, guanethidine, methyldopa
Other anti-arrhythmic agents
- -calcium channels blockers
- -lidocaine
Insulin and oral hypoglycemic drugs
– prolongs hypoglycemia and masks signs
Masks symptoms of hyperthyroidism
Other nonselective beta blockers
Nadolol (Corgard) - longer acting; once-per-day dosing
Timolol (Blocadren) - more potent than propranolol
Timolol (Timoptic) -
- lowers IOP in glaucoma
- reduces aqueous humor production
Pindolol (Visken) - partial agonist; partial blockade
- less incidence of rebound hypertension
- less bradycardia
Carteolol - like pindolol
Beta-1 selective blockers
- All are more potent at beta 1 than beta 2 receptors
- at higher doses, block beta 2 as well
- lessen risk of bronchospasm -still contraindicated in asthmatic
- do not usually prolong hypoglycemia
- Atenolol (Tenormin)
Acebutolol (Sectral) - partial agonist, hypertension, dysrhythmias
- Metoprolol (Lopressor, Topral XL) – hypertension, CHF
Betaxolol (Betoptic) – glaucoma
Bisoprolol (Zebeta) - CHF
The AThENs METROPOLis BETA (beat) the spartans… they ONE (won)!
ATENolol, METROpolol Beta One
Esmolol
** Very rapid onset & short duration of action
beta 1-selective
Used as IV infusion for peri-operative tachycardia and hypertension, arrhythmias
Used in electroconvulsive therapy
Beta-Blockers with Partial Agonist Activity
Pindolol
Acebutolol
No demonstrated therapeutic advantage over pure antagonists. Lessened bradycardia, better lipid profile ?
ISA (Intrinsic sympathomimetic activity)
Labetolol
Selective alpha 1 blocker
Nonselective beta 1 & beta 2 blocker
Clinical Uses:
hypertension
pheochromocytoma
Carvedilol
Nonselective b-blocker + a-blocker Very lipid soluble Also has antioxidant properties Very dramatic results in CHF clinical trials Decreased mortality by 65%
