Adrenergic Receptor Antagonists Flashcards
Blockade of Adrenoceptors:
- Dopamine receptor blockade
- peripheral receptor blockade is of little clinical importance
- receptor blockade in CNS is important and will be covered in future course topics
- α-adrenergic receptor blockade
- nonselective antagonists used to treat pheochromocytoma
- α1 antagonists predominantly used for hypertension, benign prostatic hyperplasia (BPH)
- β-adrenergic receptor blockade
- much broader clinical use (e.g., hypertension, ischemic heart disease, arrhythmias, endocrine and neurological disease)
Alpha Antagonist Pharmacology, Mechanism:
- reversible antagonist
- e.g. phentolamine (Oraverse); prazosin (Minipress); labetalol (Normodyne)
- duration of action depends upon drug t1/2 and dissociation rate from the receptor
Alpha Antagonist Pharmacology, irreversible antagonist:
- e.g. phenoxybenzamine (Dibenzyline)
* duration of action depends upon synthesis of new receptors (several days after administration
Pharmacological Effects of α-adrenergic Antagonists, Cardiovascular:
- decrease PVR & blood pressure
- α-receptor antagonist can convert the response of dosed agonists with α & β2-mediated effects from pressor to depressor activity – “ephinephrine reversal”
- alpha receptor blockade can lead to orthostatic hypotension with reflex tachycardia
- α2 receptor blockade on presynaptic sympathetic fibers in heart can stimulate more marked tachycardia – removal of feedback inhibition of NE release
Other Actions of α-adrenergic Antagonists:
- Eye – miosis
- Nasal membranes – stuffiness
- Genitourinary tract – decreased resistance to urine flow
- useful for treatment of urinary retention related to prostate hyperplasia
phenoxybenzamine; Dibenzyline:
- irreversible antagonist covalently binds to α-receptors
- selectivity – α1 > α2
- inhibits reuptake of NE by presynaptic adrenergic nerve terminals
- also blocks H1, acetylcholine, and 5HT receptors
- pharmacological actions & adverse affects occur primarily via α-receptor blockade
- ADME
- absorbed orally with low bioavailability
- given orally at low doses until pharmacological effects are achieved
- Primary Indication – Pheochromocytoma
- Adverse effects (and most alpha antagonists)
- orthostatic hypotension (primary)
phentolamine
• selectivity α1 = α2
• decrease peripheral vascular resistance via blockade of α1 and
possibly α2 on vascular smooth muscle
• cardiac stimulant – antagonist of α2 on presynaptic fibers increasing NE release; also contributing to the baroreceptor sympathetic reflex
• antagonist of 5-HT receptors & agonist at H1 & H2 receptors
• Indication – pheochromocytoma
• adverse reactions
• severe tachycardia; arrhythmia; myocardial ischemia
α1-selective antagonists:
Modification of the furan alters rate of metabolism for longer duration of action
prazosin; Minipress:
• α1»_space;» α2 (1000 x less potent at α2)
• α1 blockade relaxes arterial and venous vascular
smooth muscle, and prostatic smooth muscle
• ADME
• extensively metabolized in humans with only 50% oral bioavailability
• t1/2 approx 3 hours
terazosin; Hytrin:
- reversible α1 antagonist
- Indications
- hypertension
- benign prostatic hyperplasia (BHP)
- ADME
- high bioavailability
- extensively metabolized in liver with very little excretion of parent drug
- t1/2 approx 9-12 hours
doxazosin; Cardura:
- reversible α1 antagonist
- Indications
- hypertension
- benign prostatic hyperplasia (BHP)
- ADME
- moderately bioavailable
- extensively metabolized in liver with very little excretion of parent drug
- t1/2 approx 22 hours (primary feature vs prazosin or terazosin)
tamsulosin; Flomax:
- chemistry differs from most other α1 antagonists
- affinity higher for α1A (found in prostate) & α1D vs α1B
- greater potency for relaxation of prostate vs vascular smooth
- Indications
- benign prostatic hyperplasia (BHP)
- overactive bladder
- less effect on standing BP than other alpha receptor blockers
- ADME
- highly bioavailable
- extensively metabolized in liver with very little excretion of parent drug
- t1/2 approx 9-15 hours
Other Alpha Antagonists:
- alfuzosin (Uroxetral) – BPH; 60% BA; extensively metabolized; t1/2 approx 5 hours
- labetalol (Normadyne) – α1 and β
- chlorpromazine & haloperidol (DA receptor antagonists) – adverse reactions related to activity as alpha antagonists (e.g., hypotension)
- trazadone (antidepressant); ergotamine/dihydroergotamine (ergot alkaloids)
Pharmacology of β-adrenergic antagonists:
- competitively bind to β-receptors and block interaction of endogenous catecholamines and other β-agonists
- most are pure β-agonists
- some partial β-agonists
- beta antagonists differ in relative affinity for β1 vs β2
- none of available beta-antagonists are absolutely specific for β1 which tends to be dose related(specificity decreases at higher concentrations)
- primary differences in beta blockers
- PK/ADME; local anesthetic/membrane stablizing effects
- no obvious clinical application for β2-specific antagonists
Pharmacology of β-adrenergic antagonists, ADME:
• most well absorbed orally, peak concentrations in 1-3
hours
• propranolol (Inderal) is subject to extensive first-pass metabolism with relatively low BA
• variability of first-pass metabolism results in wide variability in plasma concentrations between individuals after an oral dose
• betaxolol (Kerlone), penbutolol (Levatol), pindolol (Visken) and sotalol (Betapace) are exceptions to first-pass related variability in BA
Pharmacology of β-adrenergic antagonists, ADME, cont:
• rapidly distributed with large volumes of distribution (Vd)
• propranolol ; penbutolol are highly lipophilic & cross the bbb
• t1/2 approx 3-10 hour range across the beta blockers
• esmolol t1/2 of 10 minutes (rapidly hydrolyzed)
• propranolol (Inderal) & metoprolol (Lopressor) extensively metabolized by the liver with little parent drug in the urine (metoprolol by CYP2D6)
• atenolol (Tenormin), celiprolol, pindolol (Visken) less metabolized
• nadolol (Corgard) excreted unchanged in urine and longest t1/2
(24hrs) of any available beta antagonist
• elimination of propranolol and similar drugs significantly impaired in liver disease, decreased hepatic blood flow, or CYP enzyme inhibition
Pharmacology of β-adrenergic Antagonists Pharmacodynamic Effects - Cardiovascular:
• reduce BP in patients with hypertension
• reduction in renin release and CNS effects
• acutely may rise PVR, but chronically decrease PVR
• prominent effects on heart
• important for Rx of angina; chronic heart failure; mycardial
infarction
• (-) inotropic and chronotropic effects; slowed atrioventricular conduction
• β-receptor blockade blocks vasodilation mediated by β2
β-adrenergic Antagonist Pharmacodynamic Effects – Respiratory System:
- β2 antagonists may lead to bronchoconstriction and airway resistance in asthmatics
- β1 antagonists (metoprolol; atenolol) may avoid problems of β2 blockade
Pharmacology of β-adrenergic Antagonists Pharmacodynamic Effects – Metabolic:
- β antagonists inhibit sympathetic stimulation of lipolysis
- β2 antagonists inhibit gycogenolysis
- β antagonists should be used with caution in insulin- dependent diabetics
- β1 antagonists not as likely to inhibit recovery from hypoglycemia
- Increase VLDL/ decrease HDL; decrease HDL/LDL may increase risk of CAD (mechanism not understood)
Propranolol:
• β-receptor prototype
• safe and effective for multiple indications
• angina, aortic stenosis, arrhythmia, benign essential tremor, myocardial infarction, hemangioma, hypertension, migraine prophylaxis, mitral valve prolapse, panic disorder, performance anxiety, pheochromocytoma, tardive dyskinesia, thyrotoxicosis
• low, variable bioavailability
• negligible α or muscarinic activity; may block central 5-HT
receptors
• no partial agonist activity
metoprolol; atenolol:
- β1-selective
- safer in patients exhibiting propranolol- induced bronchconstriction (should not be used in asthmatics)
- benefits for e.g., mycardial infarction may exceed the risks in COPD patients
- preferable beta blocker in diabetics or for peripheral vascular disease (beta 2 involved in liver metabolism & vascular tone)
nebivolol (Bystolic):
- most highly β1-selective
- hypertension; mitral prolapse
- can cause vasodilation (possibly stimulating the nitric oxide pathway in the endothelium)
nadolol:
very long duration of action
pindolol; acebutolol; carteolol; penbutolol:
- partial agonists (but clinical significance is not known)
- effective for hypertension and angina
- bradycardia, alterations in plasma lipids less likely
- pindolol may potentiate traditional antidepressants (actions on serotonin transmission?)
labetalol:
- two pairs of chiral isomers
* S,R – α1-blocker (affinity
carvedilol (Coreg):
• angina, atrial fibrillation, heart failure, hypertension, left ventricular
dysfunction
• nonselective beta antagonist (more potent antagonism of β receptors vs α1)
• moderate lipid solubility
• t1/2 approx 6-8 hours
• extensively metabolized in the liver with stereoselective metabolism (R-carvedilol by CYP2D6 affected by polymorphism and by CYP2D6 inhibitors – e.g., quinidine, fluoxetine) – subject to DDI
• moderates O2 free radical induce lipid peroxidation & inhibits vascular smooth muscle mitogenesis – could be beneficial in heart failure
esmolol (Brevibloc):
- ultra-short-acting β1-selective antagonist
- ester linkage makes it a substrate for RBC esterase enzymes = t1/2 approx 10 minutes
- steady state reach quickly with iv infusion & actions terminated quickly upon cessation of infusion
- safer than longer-acting antagonists in critically ill patients requiring β antagonists
- supraventricular arrhythmias, thyrotoxicosis – mediated arrhythmias, myocardial ischemia
Toxicity of β-receptor Antagonists:
- bradycardia most common adverse effect
- coolness of extremities
- CNS depression, sedation, sleepiness, fatigue
- β2-receptor blockade (nonspecific agents) may worsen preexisting asthma
- depression of myocardial contractility and excitability
