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
What is important to know about propranolol (Inderal)?
- non selective beta antagonist
- lipophilic
- extensive hepatic first pass metabolism
- local anesthetic properties
- blockade is activity dependent → be careful with patients that have asthma
What are the pharmacological effects of propranolol?
- decreased cardiac output and heart rate
- reduced renin release
- increase VLDL, decrease HDL
- inhibit lipolysis
- inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia
- increase bronchial airway resistance → be careful because of beta2 activity
What are the therapeutic uses for beta-adrenergic receptor antagonists?
hypertension, angina, cardia arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
What are important things to know about nadolol (Corgard)?
- less lipophilic than propranolol because of the OH groups on cyclohexane ring so liver metabolism is reduced which creates longer half life
- long half life of 20 hours
- mostly excreted unchanged in urine
- administered orally
- uses → hypertension, angina, migraine
- non-selective beta antagonist
What are important things to know about timolol (Timoptic, Blocadren)?
- thiadiazole nucleus with morpholine ring
- non-selective beta antagonist
- administered orally and ophthalmically
- uses → glaucoma, hypertension, angina, migraine
Why can timolol be used for glaucoma?
beta activity is responsible for reducing aqueous humor secretion
How do beta blockers affect pupil size?
has no effect on pupil size
What is the action, clinical use, and problems associated with propranolol and timolol?
- action → non-selective antagonist at beta1 and beta2 receptors
- clinical use for propranolol → hypertension (no effect on BP in normotensive individuals), angina, cardiac arrhythmias, ischemic heart disease, prophylaxis for migraines
- clinical use of timolol → open angle glaucoma (decreases production of aqueous humor)
- problems → minor but use cautiously in asthmatics due to blockade of beta2 receptors, rebound hypertension if discontinued rapidly (have to taper dose)
If someone has a kidney impairment, should they use propranolol or nadolol?
use propranolol but if they don’t have kidney impairment, use nadolol
If the beta blocker has a bulky group, how does it affect its route of administration?
bulky group means less MAO available so it can be administered orally
What are important things to know about pindolol (Visken)?
- non-selective beta antagonist
- possesses intrinsic sympathomimetic activity (ISA) → partial agonist
- less likely to cause bradycardia and lipid abnormalities
- good for patients who have severe bradycardia or little cardiac reserve
- administered orally
- uses → hypertension, angina, migraine
What do dose response curves look like with antagonists?
shifts to the right and needs the agonist present since antagonists inhibit agonist activity
What does the dose response curve look like with norepinephrine and pindolol compared to norepinephrine and propranolol?
pindolol is a partial agonist so it has some agonist activity and can be shown by itself for beta1 adrenergic activation (has some activation) → the NE + propranolol curve is more broad (longer and dips all the way down) compared to the NE + pindolol where it is higher up and smaller flatter curve
What is important to know about carteolol (Cartrol, Ocupress)?
- non-selective beta adrenergic antagonist
- possesses intrinsic sympathomimetic activity (ISA) → partial agonist
- less likely to cause bradycardia and lipid abnormalities
- administered orally and ophthalmically
- uses → hypertension and glaucoma
What are examples of selective beta1 blockers?
metoprolol, bisoprolol, atenolol, esmolol, nebivolol
What are important things to know about metoprolol and bisoprolol?
- selective beta1 antagonist
- cardioselective
- para substituted phenyl derivatives
- less bronchoconstriction
- moderate lipophilicity → short half life
- half life of 3-4 hours
- significant first pass metabolism
- administered orally and parenterally
- uses → hypertension, angina, antiarrhythmic, congestive heart failure
What is the main difference with beta1 selective antagonists?
their aromatic moiety only contains a single aromatic ring with a para substitute! compared to non-selective beta antagonists that have two rings
What is important to know about atenolol?
- selective beta1 antagonist
- cardioselective
- less bronchocontriction
- low lipophilicity (aka water soluble metoprolol because of the amide group on the para substitute on the aromatic moiety)
- half life is 6-9 hours → metabolism is reduced
- administered orally and parenterally
- uses → hypertension, angina
What is important to know about esmolol?
- very short acting
- half life of 9 minutes
- selective beta1 antagonist
- rapid hydrolysis by esterases found in red blood cells → esters in vivo can be hydrolyzed by esterases so it is very short acting with little side effects
- administered parenterally (is incompatible with sodium bicarbonate)
- uses → supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension
What are third generation beta1 antagonists?
derivative of the agonist phenlethylamine
What is an example of a third generation beta1 selective antagonist?
nebivolol → beta1 selective with low lipid solubility (low lipophilicity), causes vasodilation due to nitric oxide production and is used for hypertension
What are some mechanisms underlying vasodilating actions of beta blockers?
- agonist → beta2 receptor → cAMP → vasodilation
2. NO (nitric oxide) → sGC → cGMP → vasodilation
What is the role of nitric oxide in beta blockers?
nitric oxide is a strong vasodilator and can lead to platelet/leukocyte aggregation and adhesion, LDL oxidation, and smooth muscle cell proliferation → but can also lead to reactive oxygen species (ROS) leading to LDL oxidation, lipid peroxidation, endothelial dysfunction, and apoptosis
What are common side effects of beta blockers?
bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome
What is the effect of the chronic beta receptor blockade?
with long term usage, can modify and cause more adrenergic receptors to be made → causing more motility and mobility
What are some contraindications when using beta blockers?
asthma, COPD, congestive heart failure (type IV)
What are examples of mixed adrenergic receptor antagonists?
labetalol and carvedilol
What are important things to know about labetalol?
- phenylethylamine with bulky group
- non selective beta receptor antagonist and alpha1 receptor antagonist
- two asymmetric carbons (1 and 1’)
- (1R, 1’R)- isomer possesses beta blocking activity
- (1S, 1’R) isomer possesses greatest alpha1 receptor blocking activity
- beta blocking activity prevents reflex tachycardia normally associated with alpha1 receptor antagonists
- administered orally and parenterally
- uses → hypertension, hypertensive crisis (can reduce BP but not induce much tachycardia)
What are important things to know about carvedilol?
- non selective beta receptor antagonist and alpha1 receptor antagonist
- both enantiomers antagonize alpha1 receptors
- only S enantiomer possesses beta-blocking activity
- beta blocking activity prevents reflex tachycardia normally associated with alpha1 receptor antagonists
- administered orally
- uses → hypertension, congestive heart failure
What is the action, clinical use, and problems associated with carvedilol and labetalol?
- action → nonselective adrenergic antagonist: blocks beta1, beta2, and alpha1 receptors (1:10 alpha:beta antagonism for carvedilol)
- clinical use:
→carvedilol: heart failure, hypertension
→labetalol: hypertension, particularly hypertensive emergencies (mainly for emergency use) - problems → minor but rebound hypertension if discontinued abruptly (have to taper dose)
What are the three pharmacologic manipulations of the adrenergic system (indirect)?
- metyrosine → inhibit dopamine synthesis
- reserpine → inhibits VMAT activity
- bretylium → inhibit final release
How does metyrosine inhibit norepinephrine synthesis?
it blocks tyrosine hydroxylase from converting tyrosine to DOPA which means DOPA can’t be converted to dopamine and dopamine can’t be converted to norepinephrine and norepinephrine can’t be converted to epinephrine → metyrosine is potent!! →→ BASICALLY INHIBITS THE FIRST STEP OF MAKING NEUROTRANSMITTERS
What is the action, clinical use, and problems associated with inhibiting the catecholamine synthetic path with metyrosine?
- action → inhibits tyrosine hydroxylase and depletes catecholamines everywhere
- clinical use → perioperative management of pheochromocytoma (tumor or adrenal medulla that results in excessive epinephrine and norepinephrine synthesis and release)
- problems → depletes catecholamines everywhere (and not just the adrenal medulla where it is excessive)
What drug reduces storage or release of norepinephrine?
bretylium tosylate (Bretylol)
What are important things to know about bretylium tosylate?
- aromatic quaternary ammonium
- precise mechanism unknown
- displace and release NE and prevent further release (depletion)
- local anesthetic
- administered parenterally
- uses → antiarrhythmic (ventricular fibrillation)
What is another drug that can reduce storage or release of norepinephrine?
guanethidine which is an indirect sympathomimetic → short term use is that it inhibits release of NE transmitter but long term use can cause a depletion of all transmitters
Is bretylium tosylate commonly used?
no → it is not commonly used unless you have a very severe disease
What is an example of a catecholamine depleter?
reserpine (Serpasil)
What is important to know about reserpine?
- indole alkaloid obtained from the root of Rauwolfia serpentina → natural product
- block vesicular monoamine transporters
- deplete vesicular pool of norepinephrine
- slow onset of action
- sustained effect (weeks)
- used in the treatment of hypertension (rarely because of adverse effects)
- may precipitate depression → in addition to other side effects
What is the main mechanism behind reserpine?
inhibits VMAT activity so in the end, it will deplete all transmitters in the vesicle → catecholamines will be depleted
What are the represented adrenergic drugs of ANS?
- endogenous ligands → epinephrine, norepinephrine, dopamine
- NET inhibitors → cocaine, methylphenidate, atomoxetine
- indirect sympathomimetics → amphetamine and methamphetamine, ephedrine/pseudoephedrine, tyramine
- modulators of synthesis → metyrosine
- alpha1 agonists → phenylephrine
- alpha2 agonists → clonidine, brimonidine, methyldopa
- beta agonists (nonselective) → isoproterenol
- beta1 agonists → dobutamine
- beta2 agonists → albuterol, terbutaline
- beta3 agonists → mirabegron
- alpha antagonists (nonselective) → phenoxybenzamine, phentolamine
- alpha1 antagonists → prazosin, tamsulosin
- beta antagonists (nonselective) → propranolol, timolol
- beta1 antagonists → metaprolol
- mixed alpha/beta blockers → carvedilol, labetalol
- VMAT inhibitor → reserpine
