ANS drugs Flashcards
Norepinephrine
Pharmacologic class: direct-acting 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 placenta but not 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 propanolol
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
Epinephrine
Pharmacologic class: direct acting 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 (5-15m), and via inhalation (1-5m onset), opthalmic topical; metabolized by COMT and then excreted by urine
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
Monitor: BP, HR, rhythm, infusion site, evidence of extravasation
Isoproterenol
Pharmacologic class: non-selective beta-AR agonist
Therapeutic class: lowers TPR, increases CO, prevents bronchoconstriction
Pharmacodynamics: Non-selective direct agonist of beta-adrenoceptors, low affinity for alpha-receptors. Positive chronotropic and ionotropic effects, bronchodilates via beta2-receptors. No BP rise due to vasodilation.
Pharmacokinetics: readily absorbed via injection/aerosol. Metabolized by liver.
Toxicity: Sympathomimetics-parenteral; Can cause vasoconstriction causing ischemia/hypoxia; HTN; tachycardia; gangrene secondary to extravasation.
Interactions: Contraindicated for angina pectoris, digitalis-induced tachycardia, tachyarrhythmias. Use caution with convulsive disorders, coronary insufficiency, DM, HTN, hyperthyroidism
Special considerations:
Indications and dose/route: IV only for bronchospasm (anesthesia), asthma, cardiac arrest, cardiogenic shock, CHF, decreased vascular flow, heart block, shock, Stokes-Adams
Monitor: BP, HR, ECG; electrolyte panel; CVP
Dopamine
Pharmacologic class: Direct acting and adrenergic agonist; indirect adrenergic agonist
Therapeutic class: vasopressor, vasoconstrictor, cardiac stimulant
Pharmacodynamics: low doses stimulate DA to cause renal and mesenteric vasodilation; medium doses stimulate Beta-1 receptors by increasing release of NE from sympathetic nerves, increasing HR and contractility; High doses stimulates alpha-adrenoceptors to vasoconstrict
Pharmacokinetics: Widely distributed; metabolism via hepatic, renal, plasma (MAO + COMT), metabolized to NE; excreted via urine, mostly as metabolites.
Toxicity: similar to all sympathomimetics (risk of tachycardia, HTN, ischemia/hypoxia due to vasoconstriction)
Interactions: MAOI, cardiac stimulants
Special considerations: Caution/contraindicated for angina pectoris, extravasation, hypovolemia, occlusive vascular dz, MAOIs, sulfite sensitivity, ventricular arrhythmias, pheochromocytoma,
Indications and dose/route: Shock (cardiogenic, septic, MI, trauma, surgical, etc); CHF, decreased CO, renal failure; Non-FDA: bradyarrhythmia, cardiac arrest, cardiac catheterization, hypotension, organ transplant
Monitor: ECG, BP, HR, urine output/renal fxn, CVP, CO, extravasation
phenylepherine
Pharmacologic class: selective direct acting alpha-receptor agonist
Therapeutic class: vasoconstrictor, mydriatic fxn,
Pharmacodynamics: direct agonism of post-synaptic alpha1-receptors, with little/no effect on beta-receptors. Causes increase in HR and reduction in CO. Potent vasoconstrictor.
Pharmacokinetics: F = 38%; Hepatic metabolism via MAO, but not COMT. Half-life 2 - 3.5 hours.
Toxicity: similar to sympathomimetics (tachycardia, nausea, vomiting, HTN, etc)
Interactions: MAOI contraindicated.
Special considerations: caution with cardiovascular disease, htn, hyperthyroid, narrow opthalmic angle, ventricular tachycardia
Indications and dose/route: Glaucoma (eye drops 2.5% solution), hypotension (.1-.5mg IV; 2-5mg subq; 100-180mcg/min continuous IV)), mydriasis induction (eye drops 2.5%), nasal congestion (0.25-0.5% nasal spray; 10-20mg orally), paroxysmal supraventricular tachycardia (up to 0.5mg IV), shock (100-180mcg/min continuous IV), spinal anesthesia (2-5mg to anesthetic solution), regional anesthesia (1mg per 20mL anesthetic), priapism (injection into corpus cavernosum)
Monitor: hypotension during anesthesia, mydriasis, congestion improvement, blood pressure
clonidine
Pharmacologic class: selective direct acting alpha-receptor agonist
Therapeutic class: reduced sympathetic outflow from CNS, decreased TPR, decreased renal vascular resistance, decreased HR, decreased BP, analgesia
Pharmacodynamics: selective alpha 2-adrenergic receptor agonist. Decreases release of NE and stimulates imidazoline receptor, both of which decrease CNS sympathetic outflow
Pharmacokinetics: F(oral) = 75-100% F(rectal) = 95%; Hepatic 50% metabolism; Excretion 22% fecal, 40-60% unchanged renal; elimination half-life 12.5-16 hours (oral)
Toxicity: confusion, hallucinations, dry mouth, hypotension, nausea/vomiting, constipation, contact dermatitis, sedation
Interactions: avoid beta-blockers, tetracycline antidepressants, tricyclic antidepressants, calcium channel blockers
Special considerations: avoid use with anticoagulant therapy, caution with bleeding diathesis; stop therapy slowly (taper down) to avoid withdrawal
Indications and dose/route: ADHD, Cancer pain, HTN, menopausal flushing, migraine
Monitor: HTN, pain, HR, BP
Dobutamine
Pharmacologic class: selective direct acting B1-agonist; synthetic catecholamine, related to dopamine
Therapeutic class: inotropic agent
Pharmacodynamics: Stimulates B1 receptors only; causes hypertension, mild chronotropic effects, inotropic effects, mild vasodilation, arrhythmogenic effects
Pharmacokinetics: methylation and conjugation; excreted as metabolites;
Toxicity: vasoconstriction leading to ischemia and hypoxia in end organs, toxic effects from htn/hypotension, cardiac strain. Can cause arrhythmias.
Interactions: Linezolid (antibiotic) and Isocarboxazid (MAOI)
Special considerations: Can cause arrhythmias; increases conduction via AV node, so avoid use with patients with a fib; Contraindicated in patients with hypersensitivity to corn; avoid in patients with subaortic stenosis; can cause hypokalemia
Indications and dose/route: Indicated for decreased CO (initial 0.5 to 1mcg/kg/min IV, maintain at 2 to 40 mcg/kg/min IV; titrate dose), CHF (same as CO, unless post-cardiac arrest, then 5-10 mcg/kg/min IV)
Monitor: ECG, BP, HR, wedge pressure, CO, potassium
Albuterol
Pharmacologic class: direct acting B2-agonist
Therapeutic class: bronchodilator, short acting; anti-hyperkalemia agent
Pharmacodynamics: increases smooth muscle cyclic AMP via B2 receptors, causing relaxation; also stabilizes mast cells (limits hypersensitivity mediator release)
Pharmacokinetics: F for MDI is below quantitation, less than 20% for nebulizer; preferentially metabolized in GI tract to 4-O-sulfate ester; primarily renal excretion
Toxicity: over stim of beta-adrenergic receptors causes loss of selectivity; can cause tremors, tachycardia, etc; tolerance develops over time.
Interactions: avoid with beta-blockers, MAOI,
Special considerations: caution with: cardiovascular dz, especially coronary dz; diabetes + ketoacidosis; convulsive disorders; hyperthyroidism; hypokalemia;
Indications and dose/route: Asthma, hyperkalemia, COPD
Monitor: proper inhalation technique, PFTs
Mirabegron
Newly FDA approved B3-agonist for treatment of overactive bladder; relaxes the detrusor muscle. Can cause tachycardia, HTN
Ephedrine
Indirect acting adrenergic agonist
Increases NE release (binds to end of boutons, receptors and causes Ca+ influx), direct agonism of adrenoceptors
prolonged action, potent CNS stimulant
used in nasal decongestion; treatment of hypotension
causes HTN, insomnia, tachyphylaxis
Amphetamine
Indirect acting adrenergic agonist
Releases biogenic amines from storage to cause, but no direct stimulation
potent CNS stimulation
prolonged action duration
Treats obesity, narcolepsy, ADD
Causes restlessness, tremor, irritability, insomnia, dependency, tolerance
Tyramine
Indirect acting adrenergic agonist
Release biogenic amines from storage, no direct stimulation
byproduct of tyrosine metabolism, and can be found in high concentration in fermented foods (cheese and wine)
metabolized by MAO ***Contraindicated with MAOI, can cause severe HTN
Cocaine
Indirect acting adrenergic agonist
Inhibits NE and DA reuptake
local anesthetic + potent CNS stimulant
shorter lasting that amphetamine, more intense
causes HTN, AMI, arythmie, seizure
a1-AR
constricts smooth muscles of the blood vessels, bronchi, GI sphincter, uterus, urinary sphincter, seminal tract, iris (radial)
causes liver glycogenolysis, K+ release
salivary gland K+ release
a2-AR
Inhibits NE release
constricts smooth muscles of blood vessels
relaxes smooth muscles of GI tract
causes platelet aggregation
b1-AR
Increases heart rate and contractility
relaxes smooth muscles of GI tract
increases heart rate, force, av node conduction velocity
Promotes lipolysis, and amylase
b2-AR
Relaxes smooth muscles of airway/uterus
Relaxes smooth muscles of blood vessels, bronchi, GI sphincter, Uterus, detrusor, seminal tract, ciliary muscle (pupillary dilation)
causes liver glycogenolysis, inhibits histamine release in mast cells
a-AR blockers
Vasodilation, decrease BP
Non-selective: Phentolamine (reversible, not used) and Phenoxybenzamine (irreversible, used for peripheral vasospasm)
adverse reactions include hypotension and tachycardia
Prazosin
a1-AR selective blocker
antihypertensive
can cause first-dose postural hypotension
a1-AR selective blockers generally vasodilator and reduce BP; do not cause reflex tachycardia; useful for HTN and BPH; no decrease in cardiac fxn
B1-AR blockade
Reduces HR, delays AV node, decreases depolarization, decreases force, decreases O2 consumption, decrease BP, inhibit renin
B2-AR blockade
Vasoconstriction in arterioles, increased airways resistance, decreased glycogenolysis + gluconeogenesis, inhibit insulin release
Beta blockers
- Use for HTN, arrhythmias, IHD, also useful for hyperthyroidism, glaucoma, migraine, anxiety
- well absorbed after oral administration, peak concentration 1-3 hours
- extensive first-pass metabolism, half-lives around 3-10 hours
- gradually taper doses when d/c; do not stop cold turkey due to receptor up regulation
- dangerous drug interactions, ie verapamil
- caution w/ airway disease, diabetes, heart failure
- tend to be big, clunky molecular structures
Propanolol
B-AR non selective blocker
- degree of antagonism is dependent on prevailing sympathetic tone
- propranolol exhibits equal affinity for B1 & B2-AR
- highly lipophilic, readily enters CNS
- membrane stabilizing effect observed at higher concentrations
- used for treatment of HTN and IHD
- IV for life threatening arrhythmias
- IV and oral formulations
- serious reactions include bradycardia, congestive cardiac failure, bronchoconstriction, hypoglycemia, aggravated PVD
Timolol
B-AR non selective blocker
- no intrinsic sympathomimetic activity
- no membrane stabilizing
- low lipophilicity
- treats open-angle glaucoma (eye drops)
- can cause bronchoconstriction
Pindolol
B-AR non selective blocker
- has intrinsic sympathomimetic activity (partial agonist activity) – maintains some degree of B1-AR activation while blunting cardiac response to SANS; smaller reductions in resting HR; useful in patients dependent on sympathetic drive b/c of poor cardiac reserve; preferred in patients w/ bradycardia
- low degree of membrane stabilization
- can cause bronchoconstriction and bradycardia
Sotalol
b-AR non selective blocker
- prolongs cardiac action potential
- blocks K+ channels
- used for atrial and ventricular tacharrythmias
Metoprolol
Selective b1-AR
- no intrinsic sympathetimimetic
- hepatic biotransformation
- useful for HTN, IHD
- causes bronchoconstriction, bradycardia
Atenolol
Selective b1-AR
- used for HTN, IHD
- excreted renally (careful with patients with compromised renal fan)
- can cause bronchoconstriction, bradycardia
Labetolol
Non-selective b-AR non-selective blocker & a1-AR blocker
- b1 = b2 > a1 > a2
- useful for htn, pheochromocytoma
- hypotension, tachycardia
Carvedilol
Non-selective b-AR and a1-AR blocker
- b1 = b2 > a1 > a2
- antioxidant effects
- improves survival with heart failure
Acetylcholine
Not useful therapeutically b/c rapid degradation. Does not usually circulate in blood.
Actual effects based on access of ACh to effector sites: endothelial cells (M), para and symp effector tissues (M), NMJ, ganglia, CNS
Rapidly cleared from blood by plasma pseudocholinersterase (prevents access to less perfused sites)
theoretical effects: poor CNS penetration (doesn’t cross the BBB), skeletal muscles at MNJ, parasympathetic excitation at parasympathetic ganglia + postganglionic termini (end organs), sympathetic excitation at sympathetic ganglia + adrenal gland (nicotinic receptors) + postganglionic sympathetic-cholinergic fibers, vascular endothelial cells
cholinergic syndrome
overactivation of muscarinic receptors only (not nicotinic)
Dumbelss = diarrhea, urination, miosis, bronchorrhea + bronchoconstriction, bradycardia, emesis, lacrimation, salivation, sweating
Methacholine
used to diagnose asthma via aerosol challenge. poorly absorbed (low bioavailability) methylated ACh
metoclopramide
replaced bethanechol
stimulates presynaptic D2 (dopaminergic) receptors to trigger ACh release
nicotine
Nicotinic receptor agonist (promotes Na+ influx, K+ efflux, membrane depolarization)
Nicotine receptors in nucleus accumbens and prefrontal cortex deliver dopamine to mesolimbic system = addiction
Toxicity: after initial activation receptors become desensitized (depolarization-desensitization blockade via phosphorylation). results in flaccid paralysis which cannot be reversed until agonist is cleared
nicotine poisoning
rapid onset, rapid absorption
stimulates parasympathetic/sympathetic ganglia + adrenals, then become depolarization-desensitized resulting in flaccid paralysis
sympathetic symptoms predominate: tachycardia, HTN, n/v/diarrhea/salivation, urinary incontinence, cold sweat, syncopy, flaccid paralysis (can result in death from respiratory paralysis)
Varenicline (Chantix)
very selective partial agonist of a2-b4 nicotinic receptors
promotes CNS mesolimbic dopamine but partial stimulation prevents low dopamine/cravings by avoiding dopamine surges
well absorbed; peak 4h, t1/2 = 24h, excreted renal without metabolization
considerations = suicidal thoughts, aggressive/erratic behavior; contraindicated in pregnancy/lactation
1mg PO bid, 0.5mg po bid for renal impairment CrCl < 50ml/min
monitor neuropsychiatric symptoms
Acetylcholinesterase inhibitors
Generally: intensify all cholinergic effects; inhibits all cholinesterases (plasma pseudo, true, and RBC); anionic site binds 4˚ ammonium cation, esteric site catalyzes ACh ester bond to liberate choline and acetate
Poisoning: paralysis of intercostal muscles/diaphragm (nicotinic depol-desens blockade), increased bronchorrhea + bronchoconstriction, central respiratory arrest, respiratory support is essential
short acting: edrophonium (diagnose myasthenia gravis)
intermediate acting: neostigmine, physostigmine (treat myasthenia gravis)
long acting: echotiophate, parathion, malathion, sarin, soman (poisons/weapons/insecticides)
Edrophonium
Short acting acetylcholinesterase inhibitor (competitive)
highly charged, so no BBB penetration
IV or IM
Short lived (5-10 min IV or 30 min IM)
Dx myasthenia gravis (90-95% accuracy)
Carbamates
Intermediate acting acetylcholinesterase inhibitors
bind anionic and esteric sites, forms ester bond to slowly hydrolyze ACh
lasts much longer than edrophonium
physostigmine
carbamate
uncharged and lipid soluble > penetrates BBB
not useful in treating myasthenia gravis (peripheral dz)
Neostigmine
carbamate
charged, so no BBB penetration; useful in treating myasthenia gravis
too little drug is inadequate, resulting in myasthenic crisis (flaccid paralysis)
too much drug results in depol-desen blockade, resulting in cholinergic crisis (flaccid paralysis)
IV edrophonium can distinguish between the two
Organophosphates
long acting AChE inhibitors
Echotiophate once used to treat narrow angle glaucoma
Insecticides like Malathion/parathion
weaponized nerve gases like sarin, soman
Pralidoxime (2-PAM)
antidote to organophosphate poisoning; reactivates phosphorylated enzymes as long as “aging” has not occurred.
Contraindicated in carbamate poisoning, b/c competitive inhibition of AChE makes symptoms worse
Muscarinic receptors
G-protein coupled receptors
M1 - gastric parietal cells
M2 - heart
M3 - most tissues
M4 & M5 - CNS
M1, M3, M5 - Gq (odd ones use Gq to stim Phospholipase C, increases intracellular Ca+)
M2, M4 - uses Gi (inhibits adenylyl cyclase, to activate K+ channels)
Nicotinic receptors
Ligand-gated Na+/K+ channels
2 major subtypes: Nm in skeletal muscle; Nn in autonomic ganglia + CNS
Atropine
muscarinic subclass non-specific blocker, anti-Dumbbelss
predominately blocks parasympathetic transmission at end organs, sweat glands, CNS
Mechanism: reversible blockade Inverse agonist (decreases constitutive activity of M receptors)
sensitivity highest in salivary, bronchial, sweat glands; potency highest in heart, bronchial, GI muscle
Atropine toxicity
Mad as a hatter (delirium, hallucinations, CNS effects like schizophrenia), blind as a bat (mydriasis, cycloplegia, exacerbates closed angle glaucoma), dry as a bone (no salivation, no sweat, no lacrimation, no bronchial secretions), hot as a hare (elevated body temp, anhydrous, life threatening in pediatrics), red as a beet, blocks detrusor muscle (causes urinary retention)
Additional effects = bronchodilation, constipation, tachycardia, HTN
Scopolamine
1 therapy for motion sickness; reduces vertigo/nausea
Muscarinic blocker
induces amnesia
GI muscarinic blockers
dicyclomine: IBS and diarrhea (M3 selective antagonist)
Methscopolamine, pirenzepine, propantheline: peptic ulcer Rx, inhibits acid secretion
GU urgency/bladder spasms
oxybutynin + glycopyrrolate
Ipratropium
nonselective muscarinic blocker, aerosol delivery, low CNS penetration
used in persistent COPD by inhibiting bronchoconstriction
packaged with albuterol (b2-AR agonist)
Trimethaphan
Nn Ganglionic blocker: causes NMJ and/or CNS blockade (but minimal CNS effects)
Blocks all ganglia, useful for blocking sympathetics
potent BP effects; causes orthostatic hypotension, urinary retention, constipation, impaired accommodation; only used in emergencies, ie HTN crises or dissecting aortic aneurysm
Succinylcholine
Only useful depolarizing nicotinic blocker, used for short surgical procedures/intubations; initially effects large muscles
causes depol-desens blockade resulting in paradoxical flaccid paralysis
can cause hyperkalemia (net efflux of K+ from cells), histamine release, malignant hyperthermia
d-Tubocurarine
Nondepolarizing nicotinic blocker
reversible competitive inhibition, minimal CNS
causes complete paralysis, but doesn’t cause CNS effects
Small muscles affected before large
Reversed by neostygmine
Nondepolarizing nicotinic blockers
Aminosteroids: pancuronium (renal clearance), vecuronium (hepatic clearance), rocuronium (hepatic clearance)
Benzylisoquinolines: cisatracurium (inactivated by plasma AChE)
Botox
indirect anticholinergic
Toxin A acts by cleaving SNARE proteins which are required for vesicle docking
causes flaccid paralysis at NMJ and atropinic effects at muscarinic junctions; prevents axillary hyperhydrosis; treats strabismus, blepharospasm, torticollis, anal achalasia
