Adrenergic Receptor Antagonists

Question 1

Blockade of Adrenoceptors:

Answer 1

• 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)

Question 2

Alpha Antagonist Pharmacology, Mechanism:

Answer 2

• reversible antagonist
  
  • e.g. phentolamine (Oraverse); prazosin (Minipress); labetalol (Normodyne)
  • duration of action depends upon drug t1/2 and dissociation rate from the receptor

Question 3

Alpha Antagonist Pharmacology, irreversible antagonist:

Answer 3

• e.g. phenoxybenzamine (Dibenzyline)

* duration of action depends upon synthesis of new receptors (several days after administration

Question 4

Pharmacological Effects of α-adrenergic Antagonists, Cardiovascular:

Answer 4

• 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

Question 5

Other Actions of α-adrenergic Antagonists:

Answer 5

• Eye – miosis
• Nasal membranes – stuffiness
• Genitourinary tract – decreased resistance to urine flow
• useful for treatment of urinary retention related to prostate hyperplasia

Question 6

phenoxybenzamine; Dibenzyline:

Answer 6

• 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)

Question 7

phentolamine

Answer 7

• 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

Question 8

α1-selective antagonists:

Answer 8

Modification of the furan alters rate of metabolism for longer duration of action

Question 9

prazosin; Minipress:

Answer 9

• α1&raquo_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

Question 10

terazosin; Hytrin:

Answer 10

• 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

Question 11

doxazosin; Cardura:

Answer 11

• 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)

Question 12

tamsulosin; Flomax:

Answer 12

• 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

Question 13

Other Alpha Antagonists:

Answer 13

• 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)

Question 14

Pharmacology of β-adrenergic antagonists:

Answer 14

• 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

Question 15

Pharmacology of β-adrenergic antagonists, ADME:

Answer 15

• 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

Question 16

Pharmacology of β-adrenergic antagonists, ADME, cont:

Answer 16

• 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

Question 17

Pharmacology of β-adrenergic Antagonists Pharmacodynamic Effects - Cardiovascular:

Answer 17

• 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

Question 18

β-adrenergic Antagonist Pharmacodynamic Effects – Respiratory System:

Answer 18

• β2 antagonists may lead to bronchoconstriction and airway resistance in asthmatics
• β1 antagonists (metoprolol; atenolol) may avoid problems of β2 blockade

Question 19

Pharmacology of β-adrenergic Antagonists Pharmacodynamic Effects – Metabolic:

Answer 19

• 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)

Question 20

Propranolol:

Answer 20

• 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

Question 21

metoprolol; atenolol:

Answer 21

• 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)

Question 22

nebivolol (Bystolic):

Answer 22

• most highly β1-selective
• hypertension; mitral prolapse
• can cause vasodilation (possibly stimulating the nitric oxide pathway in the endothelium)

Question 23

nadolol:

Answer 23

very long duration of action

Question 24

pindolol; acebutolol; carteolol; penbutolol:

Answer 24

• 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?)

Question 25

labetalol:

Answer 25

• two pairs of chiral isomers

* S,R – α1-blocker (affinity

Question 26

carvedilol (Coreg):

Answer 26

• 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

Question 27

esmolol (Brevibloc):

Answer 27

• 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

Question 28

Toxicity of β-receptor Antagonists:

Answer 28

• 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