2013-08-30 Adrenergic Drugs Flashcards
Objective 1: For catecholamines, describe their:
- -synthesis
- -storage
- -release
- -removal
- -interactions w/ drugs
Catecholamine
terminal NE stores replenished via:
a) reuptake
b) de novo synthesis
- -de novo synthesis:
1. tyrosine actively transported in
2. — tyr hydroxylase —> DOPA —> decarboxylase —> dopamine
–storage: the dopamine synth’d in cytosol is then stored in vesicles where it is…
–synth: …made into NE via dopamine β-hydroxylase in the vesicle
–storage: stored in vesicle until AP arrives
–release: AP —> Ca2+ influx —> triggers fusion of vesicle w/ PM = exocytosis of NE
–removal: diffusion, reuptake, metabolization (via MAO and COMT, catechol-o-amine methyl transferase which are both high in liver —> S and glucuronate conjugates —> urine)
–interactions w/ drugs
Pharm card: Epinephrine
SEE ALSO LANG CARD 2.03
Drug class: pharmacologic class—direct-acting, non-selective adrenergic agonist; therapeutic class—vasopressor, cardiac stimulant, bronchodilator, adjunct to local anesthetics, treatment for anaphylaxis
Pharmacodynamics: major action is to stimulate peripheral alpha-1 adrenoceptors, thereby leading to vasoconstriction (resistance arterioles, increase SVR) and venoconstriction (in capacitance vessels, increase preload); beta-1 receptors leading to tachycardia and increased contractility; and beta-2 receptors leading to bronchodilation; these actions are also helpful in severe allergic reactions (e.g. anaphylaxis) by stabilizing mast cells
Pharmacokinetics: can be given iv (immediate), IM (variable), SC 5-15 min), and via inhalation (1-5 min onset), ophthalmic topical; metabolized by COMT and then renally excreted;
Toxicity: excessive vasoconstriction, HTN, hemorrhagic stroke, angina, arrhythmias,
Interactions: risk of excessive hypertension in patients taking propranolol
Special considerations: utility with local anesthetics; drug of choice in severe anaphylactic reactions (along with others)
Indications and dose/route: for anaphylaxis, 0.1-0.5 mg SC or IM; for cardiac arrest, 1-5 mg IV push; for infusion, 1-4 mcg/min; also for allergy-induced asthma
Monitor: BP, HR, rhythm, infusion site, evidence of extravasation
Pharm card: Norepinephrine
NO LANG CARD
Drug class: pharmacologic class—direct-acting, non-selective adrenergic agonist; therapeutic class—vasopressor, vasoconstrictor
Pharmacodynamics: major action is to stimulate peripheral alpha-1 adrenoceptors, thereby leading to vasoconstriction (resistance arterioles, increase SVR) and venoconstriction (in capacitance vessels, increase preload). This increases CO, SVR, and MAP, but decreases blood flow to vulnerable tissues like skin, muscle, and kidney. Also, stimulates beta-1 receptors in the heart, increasing HR and contractility. Main effects are vasoconstriction and cardiac stimulation.
Pharmacokinetics: F ~100%. Given IV only. Metabolized by COMT and MAO, mostly in liver. Metabolites are excreted in urine. Half-life 1-2 minutes (e.g. can be titrated quickly IV). Can cross the placenta, but not the blood/brain barrier.
Toxicity: excessive vasoconstriction in mesenteric vessels, peripheral arterioles causing ischemia, infarction, gangrene; reflex bradycardia
Interactions: use cautiously in patients taking an MAO inhibitor such as phenelzine (use lower doses); risk of excessive hypertension in patients taking propranolol
Special considerations: correct volume depletion with IV fluids BEFORE giving NE infusion; select infusion site carefully—extravasation is a major problem; monitor patient and BP continuously in ICU setting; use cautiously in pediatric and geriatric patients
Indications and dose/route: for adults with acute hypotension and shock (related to low SVR) infuse 2-12 mcg/min
Monitor: BP, HR, infusion site, evidence of extravasation
Pharm card: dopamine
NO LANG CARD
endogenous, non-selective catecholamine
- -actiavtes β1-AR in heart
- -tx: shock, acute HF
Pharm card: isoproterenol
extremely potent β-AR (non-selective for β-ARs)
- -potent vasodilator
- -poz chronotropy
- -adverse: tachy, BP, arrythmias
Pharm card: phenylepherine (neosynephrine, Sudafed PE)
See LANG card
Pharm card: clonidine (Catapress)
NO LANG CARD
MOA: α2-AR agonist; epidurally prevents pain signal transmission to the brain, producing analgesia at spinal presynaptic and postjunctional α2-adrenergic receptors
indications: HTN, menopausal flushing, migraine (severe cancer-related pain, ADHD in kids, Tourettes syndrome in kids)
- -po: prolonged hypotensive response
- -i.v: acute hypertensive response followed by hypotension
- -dermal patch - ?
adverse effects: dry mouth, sedation, contact dermatitis
precautions: rebound HTN w/ abrupt d/c
Pharm card: dobutamine
see LANG card
Pharm card: albuterol
β2-AR agonist
bronchodilator: oral, inhalation or IV
adverse: tachy, tremor, tolerance
Pharm card: Ephedrine
No LANG Card (similar to amfetamine lang card)
- -indirect-acting agonist
- -alkaloid obtained from plant
- -increase NE release —> direct agonism
- -prolonged action duration, potent CNS stimulant
Uses: nasal decongestant (psuedoephedrine), tx of hypotension
Adverse: HTN, insomnia, tachyphylaxis (an acute (sudden) decrease in the response to a drug after its administration.)
Pharm card: Amphetamine
See LANG card
Pharm card: Tyramine
Not a drug. No Lang card.
Indirect acting adrenergic agonist
- -causes release of catecholamines from storage
- -high conc in fermented foods; made from fermentation of Tyrosine
- -metabolized by liver MAO
- -caution to pts on MAOIs—> severe HTN
Per wiki: “Foods containing considerable amounts of tyramine include meats that are potentially spoiled or pickled, aged, smoked, fermented, or marinated (some fish, poultry, and beef); most pork (except cured ham); chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream and Neufchâtel cheeses), sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, teriyaki sauce, tofu, tempeh, miso soup, sauerkraut, broad (fava) beans, green bean pods, Italian flat (Romano) beans, snow peas, avocados, bananas, pineapple, eggplants, figs, red plums, raspberries, peanuts, Brazil nuts, coconuts, processed meat, yeast, and an array of cacti.”
Pharm card: cocaine
See Lang card
Clicker Q: What are s/sx in EtOH/TCA interaction?
What is best pharm mgmt? A. timolol B. metoprolol C. prazosin D. phentolamine E. isoproterenol
D
Which drug is absolutely contraindicated in EtOH/TCA interaction? A. phenozybenzamine B. metoprolol C. prazosin D. phentolamine E. labetolol
B - metoprolol is contraindicated; it will lower HR, but all the epi that can’t bind β ARs will be freed up and bind to α ARs further increasing HTN
What are the different subclasses of sympathomimetics? Give an example drug for each.
Direct (e.g. epi, NE) Indirect: --affecting release (e.g. amphetamines) --affecting reuptake (e.g. cocaine) --affecting degradation (e.g. tranylcypromine)
NE vs. epi
epi has been demethylated (= more hydrophobic?)
Big picture activation of: α1-AR f(x) α2-AR f(x) β1-AR f(x) β2-AR f(x)
α1-AR = contaction and constriction (α2-AR = inhibits NE release) β1-AR = incr chronotropy and ionotropy β2-AR = relaxes airway and uterine SMM
References for this lecture:
Katzung Chapters 9 & 10
What are the three mechanisms of sympatholysis?
A. Decrease sympathetic outflow from brain
B. Supress nerve terminal NE
—-inhibit synth
—-deplete granules
—-supress release
C. Block postsynaptic receptors (“cleanest” way)
Compare/contrast reversible vs. irreversible adrenergic blockade. Give one example of each.
Irreversible (e.g. phenoxybenzamine)
- -doesn’t dissociate
- -antagonism outlasts presence of compound
- -block is insurmountable, can’t overcome it by giving more NE
Reversible (e.g. phentolamine or prazosin)
- -antagonist dissociates from receptor
- -produce equilibrium blockade
- -block disappears as the drug is metabolized
structure of adrenergic antagonists
unlike most of the adrenergic agonists, the antagonists often look nothing like the chemical compounds they inhibit (i.e. catecholamines)
Big Picture non-selective α-AR-blockers (both reversible and irreversible)
vasodilation, lower BP
Reversible - more rarely used (e.g. phentolamine)
Irreversible - use in peripheral vasospasm (e.g. dibenzyline)
Adverse: hypotension, tachy
Big Picture selective α2-blockers
not used clinically
Big Picture selective α1-blockers
vasodilate —> reduce art pressure
- -no reflex tachy
- -useful for HTN and BPH (relaxes bladder sphincter tone; inhibits hypertrophy of bladder and prostate)
no decr in cardiac function
(e.g. prazosin)
phenoxybenzamine
See LANG card
Beta blocker complications in diabetics? Why?
Beta2 blockade decreases glycogenolysis and gluconeogenesis; also suppresses the s/sx of hypoglycemia
Effect of β1 on RAAS?
Blockade of β1 on JGA inhibits renin release
β-AR blockers: big picture
“selectivity” is a relative term
–propranolol is non-selective
Tx: HTN, arrythmias, IHD (also hyperthyroid, glaucoma, migraine, anxiety)
Well-absorbed p.o. (Cmax at 1-3 hrs) but have extensive first-pass metab (t1/2 ~3-10hrs)
DO NOT d/c abruptly, taper down
drug interactions: e.g. verapamil
caution w/: airway dz, diabetes, HF
structures: huge and heterogeneous in shape
propranolol (inderal)
MOA
Txs
Adverse
Other
[See RANG 5.04]
MOA: non-selective β-AR blocker (equal affinity for β1 and β2)
Tx: HTN, IHD, life threatening arrythmias (IV)
Adverse: severe brady, CHF, bronchoconstriction, hypoglycemia, aggravated PVD
Other: membrane stabilizing effect observed at higher concentrations (anesthetic, blocks all APs per wiki)
- -degree of antagonism depends on pre-existing level of symp tone
- -highly lipophilic so readily enters CNS
Timolol
No LANG card
MOA: non-selective β-AR blocker
Tx: open-angle glaucoma (eye drops)
Adverse: bronchoconstriction (if inhaled??)
Other: no intrinsic sympathomimetic activity (ISA)
- -no membrane stabilization
- -low lipophilicity
Pindolol
MOA: non-selective β-AR blocker w/ ISA (doesn’t block it down to zero, useful in pts susceptible to brady)
–useful in pts dependent on symp drive b/c of poor cardiac reserve
Tx: angina, HTN
Adverse: bradycardia, bronchoconstriction
Big thing: has intrinsic sympathomimetic activity
- -also partial agonist activity (?!) what the fuck is the drug?
- -low degree of membrane stabilization
Sotalol
MOA: non-selective β-AR blocker; also K+ channel blocker
—Prolongs cardiac AP
Tx: atrial and ventricular tacharrhythmias
Metoprolol (Lopressor)
β1 selective AR blocker no ISA hepatic biotrans (okay in pts w/ kidney dz)
Tx. HTN and IHD
Adverse: bradycardia, bronchoconstriction
atenolol (tenormin)
[Rang 2.02]
β1 selective AR blocker
Tx: HTN and IHD
Adverse: renal clearance so watch out for kidney DZ!; bradycardia, bronchoconstriction
labetolol
MOA: β-AR non-selective blocker AND α1-blocker
—- β1 = β2 >/= α1 > α2
Tx: HTN, pheochromocytoma
Adverse: bradycardia, bronchoconstriction
Carvedilol (Coreg)
.MOA: β-AR non-selective blocker AND α1-blocker
—- β1 = β2 >/= α1 > α2
antioxidant effects
improves survival w/ HF
