ANS drugs

Question 1

Norepinephrine

Answer 1

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

Question 2

Epinephrine

Answer 2

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

Question 3

Isoproterenol

Answer 3

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

Question 4

Dopamine

Answer 4

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

Question 5

phenylepherine

Answer 5

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

Question 6

clonidine

Answer 6

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

Question 7

Dobutamine

Answer 7

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

Question 8

Albuterol

Answer 8

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

Question 9

Mirabegron

Answer 9

Newly FDA approved B3-agonist for treatment of overactive bladder; relaxes the detrusor muscle. Can cause tachycardia, HTN

Question 10

Ephedrine

Answer 10

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

Question 11

Amphetamine

Answer 11

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

Question 12

Tyramine

Answer 12

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

Question 13

Cocaine

Answer 13

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

Question 14

a1-AR

Answer 14

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

Question 15

a2-AR

Answer 15

Inhibits NE release

constricts smooth muscles of blood vessels

relaxes smooth muscles of GI tract

causes platelet aggregation

Question 16

b1-AR

Answer 16

Increases heart rate and contractility

relaxes smooth muscles of GI tract

increases heart rate, force, av node conduction velocity

Promotes lipolysis, and amylase

Question 17

b2-AR

Answer 17

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

Question 18

a-AR blockers

Answer 18

Vasodilation, decrease BP

Non-selective: Phentolamine (reversible, not used) and Phenoxybenzamine (irreversible, used for peripheral vasospasm)

adverse reactions include hypotension and tachycardia

Question 19

Prazosin

Answer 19

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

Question 20

B1-AR blockade

Answer 20

Reduces HR, delays AV node, decreases depolarization, decreases force, decreases O2 consumption, decrease BP, inhibit renin

Question 21

B2-AR blockade

Answer 21

Vasoconstriction in arterioles, increased airways resistance, decreased glycogenolysis + gluconeogenesis, inhibit insulin release

Question 22

Beta blockers

Answer 22

1. Use for HTN, arrhythmias, IHD, also useful for hyperthyroidism, glaucoma, migraine, anxiety
2. well absorbed after oral administration, peak concentration 1-3 hours
3. extensive first-pass metabolism, half-lives around 3-10 hours
4. gradually taper doses when d/c; do not stop cold turkey due to receptor up regulation
5. dangerous drug interactions, ie verapamil
6. caution w/ airway disease, diabetes, heart failure
7. tend to be big, clunky molecular structures

Question 23

Propanolol

Answer 23

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

Question 24

Timolol

Answer 24

B-AR non selective blocker

• no intrinsic sympathomimetic activity
• no membrane stabilizing
• low lipophilicity
• treats open-angle glaucoma (eye drops)
• can cause bronchoconstriction

Question 25

Pindolol

Answer 25

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

Question 26

Sotalol

Answer 26

b-AR non selective blocker * prolongs cardiac action potential * blocks K+ channels * used for atrial and ventricular tacharrythmias

Question 27

Metoprolol

Answer 27

Selective b1-AR * no intrinsic sympathetimimetic * hepatic biotransformation * useful for HTN, IHD * causes bronchoconstriction, bradycardia

Question 28

Atenolol

Answer 28

Selective b1-AR * used for HTN, IHD * excreted renally (careful with patients with compromised renal fan) * can cause bronchoconstriction, bradycardia

Question 29

Labetolol

Answer 29

Non-selective b-AR non-selective blocker & a1-AR blocker * b1 = b2 > a1 > a2 * useful for htn, pheochromocytoma * hypotension, tachycardia

Question 30

Carvedilol

Answer 30

Non-selective b-AR and a1-AR blocker * b1 = b2 > a1 > a2 * antioxidant effects * improves survival with heart failure

Question 31

Acetylcholine

Answer 31

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

Question 32

cholinergic syndrome

Answer 32

overactivation of muscarinic receptors only (not nicotinic) Dumbelss = diarrhea, urination, miosis, bronchorrhea + bronchoconstriction, bradycardia, emesis, lacrimation, salivation, sweating

Question 33

Methacholine

Answer 33

used to diagnose asthma via aerosol challenge. poorly absorbed (low bioavailability) methylated ACh

Question 34

metoclopramide

Answer 34

replaced bethanechol stimulates presynaptic D2 (dopaminergic) receptors to trigger ACh release

Question 35

nicotine

Answer 35

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

Question 36

nicotine poisoning

Answer 36

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)

Question 37

Varenicline (Chantix)

Answer 37

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

Question 38

Acetylcholinesterase inhibitors

Answer 38

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)

Question 39

Edrophonium

Answer 39

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)

Question 40

Carbamates

Answer 40

Intermediate acting acetylcholinesterase inhibitors bind anionic and esteric sites, forms ester bond to slowly hydrolyze ACh lasts much longer than edrophonium

Question 41

physostigmine

Answer 41

carbamate uncharged and lipid soluble > penetrates BBB not useful in treating myasthenia gravis (peripheral dz)

Question 42

Neostigmine

Answer 42

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

Question 43

Organophosphates

Answer 43

long acting AChE inhibitors Echotiophate once used to treat narrow angle glaucoma Insecticides like Malathion/parathion weaponized nerve gases like sarin, soman

Question 44

Pralidoxime (2-PAM)

Answer 44

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

Question 45

Muscarinic receptors

Answer 45

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)

Question 46

Nicotinic receptors

Answer 46

Ligand-gated Na+/K+ channels 2 major subtypes: Nm in skeletal muscle; Nn in autonomic ganglia + CNS

Question 47

Atropine

Answer 47

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

Question 48

Atropine toxicity

Answer 48

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

Question 49

Scopolamine

Answer 49

Muscarinic blocker #1 therapy for motion sickness; reduces vertigo/nausea induces amnesia

Question 50

GI muscarinic blockers

Answer 50

dicyclomine: IBS and diarrhea (M3 selective antagonist) Methscopolamine, pirenzepine, propantheline: peptic ulcer Rx, inhibits acid secretion

Question 51

GU urgency/bladder spasms

Answer 51

oxybutynin + glycopyrrolate

Question 52

Ipratropium

Answer 52

nonselective muscarinic blocker, aerosol delivery, low CNS penetration used in persistent COPD by inhibiting bronchoconstriction packaged with albuterol (b2-AR agonist)

Question 53

Trimethaphan

Answer 53

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

Question 54

Succinylcholine

Answer 54

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

Question 55

d-Tubocurarine

Answer 55

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

Question 56

Nondepolarizing nicotinic blockers

Answer 56

Aminosteroids: pancuronium (renal clearance), vecuronium (hepatic clearance), rocuronium (hepatic clearance) Benzylisoquinolines: cisatracurium (inactivated by plasma AChE)

Question 57

Botox

Answer 57

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