Exam 1 Sympatholytics Flashcards
What is the difference between receptor agonists and receptor antagonists?
receptor agonists activate signal transduction pathways while receptor antagonists block agonist binding to the receptor
What effect would an antagonist alone have on receptor activation?
NONE → antagonists don’t have activity by themselves without the neurotransmitter, they need the agonist in order to block its binding
What is the receptor it binds to, route of administration and clinical uses of phenoxybenzamine?
- receptor → alpha1, alpha2
- route of administration → oral
- clinical uses → pheochromocytoma, hypertensive crisis
What is the receptor it binds to, route of administration and clinical uses of phentolamine?
- receptor → alpha1, alpha2
- route of administration → parenteral
- clinical uses → pheochromocytoma, hypertensive crisis, male impotence
What is the receptor it binds to, route of administration and clinical uses of prazosin?
- receptor → alpha1
- route of administration → oral
- clinical uses → hypertension, benign prostatic hypertrophy
What is the receptor it binds to, route of administration and clinical uses of terazosin?
- receptor → alpha1
- route of administration → oral
- clinical uses → hypertension, benign prostatic hypertrophy
What is the receptor it binds to, route of administration and clinical uses of doxazosin?
- receptor → alpha1
- route of administration → oral
- clinical uses → hypertension, benign prostatic hypertrophy
Why can’t phenoxybenzamine and phentolamine be used to treat hypertension?
they are non selective alpha receptors which means they can’t be used to treat hypertension → have to be alpha1 selective
What are some side effects of alpha1 receptor antagonists?
orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
What are the overall structure of beta-haloalkylamines?
have an amine group (with different R groups attached to it), carbon chain, and a halogen → carbon chain in the middle with the halogen and amine group on its either side
What are some important things to know about phenoxybenzamine (Dibenzyline)?
- beta-haloalkylamine
- non-selective alpha receptor antagonist
- also blocks acetylcholine, histamine, and serotonin receptors
- irreversible antagonist resulting from covalent modification of receptor
What is the mechanism of receptor inactivation for beta-haloalkylamines?
the lone pair on the nitrogen attacks the carbon connected to the halogen which kicks out the halogen → created the aziridinium ion → nucleophile on receptor can attack carbon on the aziridinium ion → creates an alkylated receptor via a covalent bond
What’s important to know about phentolamine?
- imidazoline
- non-selective alpha receptor antagonist
- competitive (reversible) blocker
- potent vasodilator but induces pronounced reflex tachycardia → can’t be used to treat hypertension
- block of presynaptic alpha2 receptors may promote release of NE
- also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist
- also used for lab testing
What is the difference in dose response curves with a reversible and irreversible receptor?
- reversible → curve shifts to the right which means you need a higher concentration of the drug to get the same effect (example is phentolamine)
- irreversible → curve shifts down like it’s dying (potency decreases) because the available receptors are reduced so the maximum effect is reduced (concept of spare receptors) (example is phenoxybenzamine)
What is the action, clinical use, and problems associated with the nonselective alpha antagonists (phentolamine and phenoxybenzamine)?
- action:
→phenoxybenzamine is a noncompetitive (irreversible) antagonist at alpha1 and alpha2 receptors → new receptors have to be synthesized in order to restore receptor function leading to a long drug effect
→phentolamine is a competitive (reversible) antagonist at alpha1 and alpha2 receptors - clinical use → perioperative management of patients with pheochromocytoma (tumor of adrenal medulla that results in excessive epinephrine and norepinephrine synthesis and release)
- problems → not useful in treating hypertension due to alpha2 effects
What is another perioperative pheochromocytoma treatment?
metyrosine
Why can’t alpha2 receptor antagonists be used to treat hypertension?
alpha2 receptors have the effect of prejunctional inhibition of NE release (hypertension won’t be controlled) → by blocking alpha2 receptors, we get a greater release of NE at the heart which increases heart rate
What are examples of quinazolines?
prazosin, terazosin, and doxazosin
What are the structural features of a quinazoline?
quinazoline ring (determines alpha receptor binding), piperazine ring, and acyl moiety with an R group that differs for each drug
What are important things to know about prazosin, terazosin, and doxazosin?
- quinazolines
- vary in half life → prazosin is 3 hours, terazosin is 12 hours, and doxazosin is 20 hours
- undergo extensive metabolism, excreted mainly in the bile
- vasodilators → for hypertension
- relaxation of smooth muscle in enlarged prostate and in bladder base
- first dose effect → sudden and severe fall in blood pressure when going from a lying to standing position the first time an alpha blocker is used
How do alpha1 antagonists treat benign prostatic hyperplasia (BPH)?
stimulation of alpha1A receptors in the trigone muscle of the bladder and urethra contract which contributed to the resistance to outflow of urine → BPH is a problem with voiding which may lead to overactive bladder →→alpha1 blockers antagonize this effect! (example is Tamsulosin (Flomax) which is very selective to prostate urethra and is less prone to induce fall in BP as compared to classic alpha1 blockers like prazosin)
What is the action, clinical use, and problems associated with prazosin and tamsulosin?
- action → selective competitive alpha1 antagonists that decrease total peripheral resistance and promotes vasodilation
- clinical use → hypertension, Reynaud’s disease (numbness due to cold or stress producing vasoconstriction in hands/feet), benign prostatic hyperplasia
- problems → minor
Tamsulosin is a derivative of what molecule?
phenylethylamine
What is important to know about yohimbine (Yocon)?
- indole alkaloid
- found in Rubaceae and related trees in addition to Rauwolfia Serpentina
- blockade of alpha2 receptors increases sympathetic drainage
- folklore suggests use in the treatment of male impotence → natural product for male impotence with many side effects
What are the cardiovascular indications for beta blockers (mainly beta1)?
- angina → reduction in myocardial oxygen demand due to decreased heart rate and contractility
- cardiac arrhythmia → slow AV nodal conduction
- post-myocardial infarction → reduction in myocardial oxygen demand, slow AV nodal conduction
- hypertension → decrease cardiac output, inhibition of renin secretion
- congestive heart failure → decreases chronic overstimulation/toxicity of compensatory catecholamines
What is the typical structure of a beta antagonist?
aryloxypropanolamine →contains a non carbon atom in the side chain (such as oxygen) which has an aromatic ring structure attached to it and the right half of the structure resembles an agonist with an amine group that is attached to a bulky alkyl group (isopropyl or tert-butyl) → antagonists are normally larger than agonists! have bulky groups!
What is the general structure of an aryloxypropanolamine?
- chiral carbon attached to the OH group (middle of the structure) → divided into left and right sides
- resemble beta adrenergic agonists in the right half of the structure
- must be secondary amine for optimal activity
- S configuration of the aliphatic OH group is more active, has same spatial arrangement as R configuration in beta agonists → most are used as racemic mixtures except timolol and penbutolol
- left half of the structure contains an aromatic moiety which is more lipophilic and more complex
- aromatic moiety is the primary determinant of beta antagonist activity → determinant in the beta1 selectivity