One Epic Summer Band Camp Direct Sympathomimetics

2.1 – “One Epic Summer Band Ca Camp”: mp”: Direc Directt Sympath Sympathomimetics omimetics (norepinep (norepinephrine, hrine, phenylephrine, epinephrine, dobutam dobutamine, ine, isoprotere isoproterenol) nol) • Direct sympathomimetics work predominately on sympathetic nervous system (SNS) (all the nervous energy of adolescent summer camp!). Adrenergic receptors respond to norepinephrine (NE) or epinephrine (E); norepinephrine acts as a neurotransmitter on postsynaptic adrenergic receptors, while epinephrine is produced in adrenal medulla & acts as a circulating hormone on targets. Particularly key in regulating BP. • Sympathomimetic drugs stimulate some aspect of this system (mimetic mime fleeing bear in “fight or flight” mode) Adrenergic rece receptors ptors • Four main adrenergic receptors: α1, α2, β1, β2. All are GPCRs – Gq, Gi, Gs, Gs respectively (misspelled “KISS”). Each represented by a cabin. • Alpha receptors (α camp) o α1 (single candle): Gq → IP3-DAG cascade → ↑intracellular calcium in smooth muscle cells (3-dog teams, carrying a bone) ▪ ↑peripheral resistance via vasoconstriction at small arteries, arterioles, precapillary sphincters. Dose dependent (α1 scout with dogs on artery-like red leashes. More dogs would pull leads tighter.) ▪ ↑ mean arterial pressure (MAP) (Map) ▪ Venoconstriction →↑ venous return & ↓ venous capacitance (Scout with dogs on blue leashes) ▪ Pupillary dilatory muscles → mydriasis (wide-eyed binoculars) ▪ Urethral sphincter & prostatic smooth muscle contraction → urinary retention (scouts tight belt & full canteen) o α2 (two candles): sympatholytic; Gi →↓cAMP (falling tent) ▪ act centrally to decrease SNS tone (“No Sympathy” sign). Activity in presynaptic neuron → localized negative feedback (α2 scout rolling in presynaptic cord). ▪ Activity at pancreatic islet cells →↓insulin release (rolled up “welcome inside” mat) ▪ ↓lipolysis & fatty acid release (dousing fat roasting pig) ▪ α2 activation at ciliary body →↓aqueous humor production (emptying water from eyeball hat) • Brimonidine is an α2-agonist used to treat chronic open angle glaucoma (water draining over brim of hat) ▪ Decreased cAMP → ↑platelet aggregation (plates aggregated on steps of α2 cabin) • β receptors → ↑cAMP (band camp sign) o β1 (bugle) ▪ Found in heart tissue (I <3 band camp shirt) • Cardiomyocytes β1 activity → ↑cAMP →↑intracellular calcium→↑ contractility (counselor’s flexed ) arm • SA node →↑HR (elevated heart clock) • AV node → ↑ conduction • Overall effect: ↑ CO (heart hydrant) ▪ Juxtaglomerular cells →↑ renin release (raining = umbrella = renin) o β2 (tuba) ▪ Lungs: ↑cAMP → PKA activation → smooth muscle relaxation → bronchodilation (tuba-player taking a big breath) ▪ Cardiac & skeletal muscle vasodilation → ↓SVR→↓diastolic BP (bell-bottom sleeves for vasodilation; diamond earring for ↓diastolic BP) ▪ ↑lipolysis & fatty acid release (roasting pig) ▪ Promotes hepatic gluconeogenesis (pulling marshmallows from liver shaped bag) ▪ Pancreatic islet cell stimulation → ↑insulin (“welcome inside” mat) ▪ Hypokalemia d/t insulin-stimulated ↑K uptake into cells (banana peels – aka deficient bananas) ▪ Ciliary body activity →↑aqueous humor production→↑IOP (eyeball shaped balloons at increased pressure) Specific symp sympathomimetic athomimetic agen agents ts • α agonists • Phenylephrine (Flannel friends) o α1 agonist (Single burning candle). All about smooth muscle activation o treats nasal congestion via vasoconstriction (flannel dude with nasal spray) o Causes mydriasis via α1 activation at pupillary dilator muscle (wide-eyed binoculars) o Cardiovascular action ▪ Pressor action →↑SVR. • In cases of hypovolemic or distributive shock, pressures can be lifesaving (septic tank with shock bolts) ▪ Pressure tracing: (the ↑MAP map looks like diastolic/systolic pressure tracing.) • α1 Arteriolar constriction →↑SBP • • • • • • • • • • • α1 ↑SVR → ↑MAP • α1 venous constriction →↑DBP. ▪ Reflex bradycardia (↑MAP → ↓HR from baroreceptors). Note that ↓ANS function (e.g. diabetic neuropathy) cannot elicit baroreceptor reflex, resulting in wildly labile BP in response to pressor & other BP agents (flannel dude with low dangling heart watch) β agonists Dobutamine (do-β-one) o Primarily a β1 agonist, with some β2 activity (“Just Do Bugling” shirt) o Cardiovascular effects ▪ β1 activity → CV effects all up: ↑HR, ↑contractility, ↑CO (winding up heart flashlight). Used in HF ▪ Pressure tracing: • β1 →↑CO →↑SBP • β1 →↑contractility →↑pulse pressure • β2 arteriolar dilation →↓DBP ▪ β2 vasodilation → ↓SVR (tuba-player with dilated sleeves) ▪ Used to treat cardiogenic shock d/t ↑CO, ↑contractility (batteries fallen out of heart flashlight) ▪ Used in pharmacologic cardiac stress test (↑CO→↑O2 demand) Isoproterenol (“iso-pro-tunnel”) o β1 & β2 activity (tent tunnel between two camps) o Cardiovascular effects ▪ β1 → ↑HR & contractility (β1 camper with , elevated heart watch) ▪ β2 → vasodilation →↓SVR (β2 camper with dilated sleeves) ▪ Pressure tracing (↓MAP so no map!) • β1 ↑contractility → ↑pulse pressure • β2 ↓SVR → ↓MAP • β2 arteriolar dilation →↓DBP (dangling diamond earring) β2 agonists Ritodrine (“I dream of band camp” shirt) o β2 relaxation of uterine smooth muscle o Used for short term suppression of premature labor (very pregnant counselor) Terbutaline (“Do not disturb” sign) o β2 relaxation of uterine smooth muscle o Used for short term suppression of premature labor (very pregnant counselor) Bronchodilators o Include albuterol, formoterol, salmeterol (roll call, for -rol suffix) Mixed α & β effects Norepinephrine (compass pointing North) o Primarily α activity (α1 & α2) (α scout on α side of river). Has some β1 activity (blowing a β bugle) o Cardiovascular action: ▪ HR & contractility: • α effects →vasoconstriction & resultant reflex bradycardia (low hanging heart shaped watch) • β1 activity → ↑ cardiac contractility & tachycardia • β1 tachycardia is eventually superseded by α1 mediated reflex bradycardia; β1 contractility still remains in effect → ↑SV & CO. ▪ Pressor action →↑SVR. • In cases of hypovolemic or distributive shock, pressures can be lifesaving (septic tank with shock bolts) ▪ Pressure tracing (note difference from phenylephrine, d/t β1 effects) • α1 Arteriolar constriction →↑SBP • α1 ↑SVR → ↑MAP • α1 venous constriction →↑DBP. Epinephrine (young lovebirds leaning in for an epic kiss) o β > α agonist with dose dependent effects ▪ At LOW dose, β effects dominant (β side of raft is lower, probably because of the tuba) • β2 → bronchodilation (nervous girl on inhaler) • β2 → Vasodilation → ↓SVR → ↓DBP (diamond falling off raft) • β1 → ↑HR (heart watch) • β1 → ↑contractility ) ( ▪ At HIGH doses, α effects dominate • Pressure tracing. Note increased pulse pressure o α1 arteriolar constriction → ↑SBP o α1 ↑SVR → ↑MAP o β2 arteriolar dilation →↓DBP. This is partly outweighed by α1 activity o Used in anaphylaxis: α1 counteracts vasodilation, β1 improves tissue blood flow, β2 opens airways. (Anna + Phil with bolt. “Love can feel a lot like anaphylaxis”) o Inotropic & chronotropic effects make useful in resuscitation attempts