Autonomic Pharmacology

Autonomic Pharmacology 1. Parasymp Parasympathetics athetics 2. Sympath Sympathetics etics 1.1 – “I’d Like tto o Buy the W World orld an Acetyl Acetyl--Cola”: Ch Cholinomimetics olinomimetics • acetylcholine (ACh) is the primary signal molecule of parasympathetic nervous system (PNS). Cholinomimetic agents mimic effects of ACh by acting as ACh-receptor agonists or directly modifying ACh (Acetyl-cola mime = ACh mimetic). None of the cholinomimetics are especially specific, so when using clinically, monitor for negative effects. • There are two types of ACh receptors: o Nicotinic receptors (nAChR) (smoker) are ion channels (smoker has his eye on tv channel in storefront). Found in ANS ganglia (electric transformers connected wire-to-wire, like ganglia), NMJ endplate (outlet plate), & adrenal glands (beanie hat) ▪ ANS nerve typically synapse onto a ganglion before reaching target organs. The adrenal glands are an exception t o this. o Muscarinic receptors (mAChR) (motorcycle parking spots) are found generally in autonomic effector tissues (heart, SM, some tissues, but not ANS ganglia). All are GPCRs (QIQ market for M1-M2-M3 inducers). In general, Muscarinic agents increase glandular secretion & smooth muscle activity. ▪ M1: Gq → IP3-DAG cascade (3 dogs) →↑intracellular Ca (dog has bone). Found in CNS & enteric nervous system (brain helmet) ▪ M2: Gi → ↓ intracellular cAMP (a rolled-up tent & packs with ↓↓arrows). Found in cardiac atria, SA & AV nodes (jacket with nodal jewels) →↓atrial contraction, ↓sinoatrial HR, ↓AV conduction velocity. Note that cardiac ventricles are controlled primarily by SNS, not PNS (cardiac jacket doesn’t show ventricles) ▪ M3: Gq → IP3-DAG cascade (3 dogs). Found in glands, including bladder & eye, & smooth muscles (SM) (glandular sponge & muscle-like paint job of 3rd biker). In healthy vasculature, IV M3 agonists stimulate NO release → ↑cGMP release →→ vasodilation; with atherosclerosis NO interacts directly with mAChR → vasoconstriction. Cholinomimet Cholinomimetic ic drugs • Bethanechol (Beth the construction worker). Primarily muscarinic. Indications: o Used in neurogenic ileus, non-obstructive GI dysmotility, & congenital megacolon (cement coming from colon spout), d/t stimulation of GI secretion & motor activity ▪ contraindicated in obstructive processes (“DO Not Obstruct” sign). o Used to treat urinary retention from non-obstructive urinary retention, e.g. post-operatively or spinal injury (bladdershaped hose) • Pilocarpine (pile of carp). Primarily muscarinic. Indications: o Used to treat dry mouth, e.g. from Sjogren’s, nerve damage, prescription adverse effects d/t ↑salivary excretion (seawater around carp looks like drool) o Glaucoma. Stimulation of mAChR reduces IOP by contraction of ciliary body → relaxation of zonula fibers → outflow of aqueous humor (SM crane with zonula-like net fibers). Ciliary contraction also results in lens accommodation (round glass floats on top of net) o Activations sphincter pupillary muscle → pupillary constriction → miosis (dock worker with hoodie cinched all the way up – looks like miotic eyeball). Used in acute closed angle glaucoma • Carbachol (person on upper story with drawn hoodie). Nicotinic & muscarinic activity (dude is standing above smoker & looking at cyclists) o Pupillary constriction, used in acute angle closure glaucoma • Methacholine o Contracts bronchiolar SM. Used in pharmacological asthma challenge (marathon challenge = methacholine challenge). Will exacerbate existing obstructive pulmonary processes, such as asthma & COPD (wheezing runner in back) • Varenicline. Nicotinic partial agonists. (1-800-VERY-CLEAN smoking cessation) o Used for smoking cessation • Common adverse effects o COPD, asthma exacerbation o Peptic ulcer exacerbation 1.2 – “Stigmata Gravis”: Cholinesterase inhibitors (ne (neostigmine, ostigmine, pyridostigmine, edrophonium, physostigmine, organophosphat organophosphates, es, galantamine, rivastigmine, donepez donepezil) il) • Acetylcholinesterase (AChE) hydrolyzes ACh in post synaptic cleft, decreasing its availability for signaling (dumpster full of acetyl-cola bottles; anti-establishment graffiti). • Indirect cholinomimetics reversibly or irreversibly bind AChE, blocking ACh degradation →↑ availability for signaling in synaptic cleft (“Acetyl-Cola” billboard visible indistinctly, or indirectly, in the distance; acetyl-cola bottles spill out of knocked over dumpster, suggesting ↑ACh availability in synaptic cleft). Most end in -stigma drug suffix (stigma graffiti). Effect is similar to that of cholinomimetics in eye, GI tract, respiratory tract, & urinary tract. Specifically: o Enhances effects of ACh at NMJ endplate by acting on nicotinic ACh receptors (brick wall looks like skeletal muscle, with electrical outlet). Results in increased contraction strength, used in treatment of myasthenia gravis (Gravis graffiti with a grave marker). ▪ Myasthenia gravis is an autoimmune disorder with production of antibodies against NMJ nicotinic receptors. Presents with progressive proximal weakness, ptosis, diplopia, difficulty swallowing. Cholinesterase inhibitors are used for symptomatic relief; immunosuppression is used for autoimmune disease. • Endogenous & exogenous tertiary amines can cross BBB. Synthetic quaternary amines class do not, because of charge. Drugs: Gene General ral • Pyridostigmine (volunteer with “Pride” jacket cleaning graffiti) o Used in long term treatment of myasthenia gravis o Quaternary amine (“Quarters only” sign on phone booth) • Neostigmine (neon sign) o Not used as commonly as pyridostigmine in treatment of MG. o Treats urinary retention d/t muscarinic activity (bladder hose) o Can be used to reverse nondepolarizing neuromuscular blockade o Quaternary amine (“Quarters only” sign on phone booth) • Edrophonium (phone both) o Very short action, ~5 minutes, allows use for tensilon test to determine whether exacerbation of MG symptoms is d/t overtreatment or undertreatment. MG overtreatment → ACh receptor overstimulation & refractory receptors = cholinergic crisis; looks similar to MG symptomatology. If signs & symptoms improve with edrophonium, suggest undertreatment (tense phone wire for ⊕ tensilon test) . (Phone booth in working order to remind of edrophonium reversing muscle weakness in undertreated. Busted up phone booth with slack wire suggests edrophonium fails to reverse muscle weakness = ⊖ test) o Quaternary amine (“Quarters only” sign on phone booth) • Physostigmine (phys-ed center) o Reverses atropine OD in the CNS by increasing ACh concentration at synapse to overcome competitive inhibition (Alice graffiti; phys ed teacher reprimanding atropine graffiti artist). Also used in cases of belladonna (deadly nightshade) or Jimson weed toxicity (flower in Alice’s hand, weeds in front of gym). o Crosses BBB, which can cause central cholinergic effects (“Your brain on drugs” poster). Toxicity remembered as “DUMBBELSS” (guy working out in gym, unable to lift weights) ▪ Diarrhea ▪ Urination ▪ Miosis/muscle weakness ▪ Bronchorrhea ▪ Bradycardia ▪ Emesis ▪ Lacrimation ▪ Salivation/sweating o Weak nAChR effects, such that toxicity includes flaccid paralysis (limp kid) Drugs: NMJ bblockade lockade • NMJ blockade used in, e.g., surgery. • Nondepolarizing agents o Curare compounds include tubocurarine, pancuronium, cisatracurium ▪ Inhibit nAChRs at NMJ endplate (CURARE brand crayons stuck in electrical outlet) • Depolarizing agents o Succinylcholine (“Sucks” graffiti) ▪ Overstimulate nAChRs at NMJ endplate, causing a prolong refractory period (Volunteer is getting a shock; he is overstimulated). ▪ Two phase block • Phase 1 of depolarizing blockade is irreversible (phase 1 clean-up crew getting shocked). Na channels surrounding motor end plate are inactivated & cannot reopen until the end plate is repolarized; results in flaccid paralysis. AChE inhibitors have no reversal effect in this phase. • Phase 2 With continued administration, nAChR become desensitized and gradual repolarization occurs. This is similar to a non-depolarizing blockade, & AChE inhibitors may help reverse. ▪ Hydrolyzed in the cytoplasm by pseudocholinesterase, such that typically only 10% of administered succinylcholine actually reaches NMJ. • In patients with a pseudocholinesterase deficiency, an autosomal recessive disorder caused by polymorphism in the BCHE gene, use of succinylcholine as an anesthetic can cause prolonged paralysis of respiratory musculature, and prolonged post-op apnea. Little risk of harm to patient if mechanical ventilation is maintained. Otherwise, this is a benign condition. ▪ Adverse effects: • Malignant hyperthermia in genetically susceptible patients, especially with halothane • Severe hyperkalemia in patients with burns, myopathies, crush injuries, & denervation. Occurs because the nAChR is a nonselective cation channel, and opening allows both Na influx & K efflux. Seen in these specific patient populations d/t upregulation of muscular nAChRs. • Bradycardia from PNS stimulation or tachycardia d/t SNS effects Alzheimer’s tre treatments atments • Galantamine (Alzheimer's gala), rivastigmine (release stigma), donepezil (done with puzzle) o All cross BBB o Benefits modest. Must be balanced against risk of major adverse effects d/t ↑ AChE activity. AChE inhibito inhibitorr OD • Seen with exposure to organophosphates, used commonly in insecticides, like parathion, malathion, echothiopate, as well as nerve agents & herbicides (dude spraying “THIOL” herbicide outside gym) Can cause thiosulfate toxicity, & major cause of acute cholinergic toxicity (green fumes causing weightlifter’s weakness). • Toxicity must be recognized immediately. Organophosphates bind covalently to AChE; left too long, aging of organophosphatecholinesterase complex leads to irreversible binding (older pest control man has irreversibly damaged AChE dumpster). o DUMBBELSS toxicity • Pralidoxime reverses peripheral toxicity (toxic dumpster with lid open) o increasing hydrolysis of covalent bond → regenerates AChE at peripheral muscarinic & nicotinic receptors, reversing cholinergic toxicity including flaccid paralysis (new AChE dumpsters). o Does not cross BBB, so will not reverse CNS muscarinic effects. • Atropine reverses muscarinic toxicity (Alice’s head on toxic waste dumpster) o Crosses CNS. Reverses muscarinic toxicity in both peripheral & central nervous systems. 2.1 – “Atropine in Wonderlan Wonderland”: d”: Muscarinic Antagoni Antagonists sts (atropine, ipratrop ipratropium, ium, tiotropium, oxybutynin, toltero tolterodine, dine, scopolam scopolamine, ine, benztropine, trihexyphenidy trihexyphenidyl) l) • Muscarinic antagonists reversibly inhibit muscarinic receptors (mouse’s car reversing into muscarinic parking place). Block effects of cholinomimetic agents, including toxicity (Tweedledum with dumbbells & Tweedledee with Acetyl-cola are blocked from parking) • Note that any of these will have desired effects in one system but undesirable effects in another. Elevated heart rate is a particularly common side effect. • Atropine (Alice) o Jimson weed & Belladonna flowers are naturally occurring alkaloids. May be of clinical relevance in gardeners and children (Alice’s flowers, Jim's tea) ▪ Side note: The name Belladonna derived from Italian for beautiful woman. During the Renaissance, large pupils were perceived as beautiful & so women used a tincture of Belladonna flowers to dilate their eyes o Non-selective antagonist of M1, M2, & M3 receptors, causing effects in many systems ▪ Mydriasis & cycloplegia (walrus with telescope & very large pupil) ▪ CV effects: • PNS activation of M2 receptors in SA & AV nodes →↓HR (queen of hearts with stars for SA & AV nodes on her staff) • Reverses depressed SA & AV node action in MI or shock →↑HR, ↑AV conduction. (rabbit rushing toward antimuscarinic table with elevated heart watch) • Used in heart block to ↑conduction through AV node (rabbit pushing over heart shield) ▪ Block M1 receptors in CNS • Scopolamine o M1 specificity o used to treat motion sickness (walrus in a sailor costume) • Ipratropium & tiotropium (Uncle Caterpillar) o inhaled M3 antagonists used as bronchodilators in management of COPD (caterpillar inhaling off hookah; is a blue bloater on a pink puffer) ▪ Inhibit vagal nerve stimulation of M3 receptor, which causes bronchial airway constriction. o ↓mucosal secretions. o Tiotropium dissociates more slowly from M3 receptor, so has longer-lasting bronchodilator action. (Tioooooo smoke) • Oxybutynin & tolterodine (Fox & turtle butlers) o M3 antagonists. Relax smooth muscle of bladder & ureters, o Relieve urinary incontinence d/t spasm (turning off bladder shape spigots) • Trihexyphenidyl & benztropine (mouse car with 3 hexagons, and Benz) o Central acting M1 antagonists (in parking space M1; parking center sign over space M1) o Used in Parkinson’s to reduce tremor and rigidity (tremor: shaking antennae; cogwheel rigidity: cogwheels on old car) ▪ Tremors may be d/t excess acetylcholine activity in absence of dopaminergic activity. o Used to treat extrapyramidal adverse effects of antipsychotic medications by re-establishing dopaminergic/cholinergic balance (extra parking pyramid cone) ▪ Side effects d/t increased transmission of dopamine at nigra striatal tract ▪ Include dystonia, akathisia, drug-induced parkinsonism Anticholinerg Anticholinergic ic Toxicity • “Hot as a hare, red as a beet, blind as a bat, dry as a bone, mad as a Hatter, full as a flask, fast as a fiddle” (many of these are represented by the guests at the table) o Hyperthermia results from antimuscarinic inhibition of sweat gland M3 receptors →↓ sweating. o Flushing results from ↓sweating & hyperthermia o Blurred vision d/t mydriasis & cycloplegia o Dry mouth & eyes d/t decreased salivation & lacrimation d/t M3 receptors o CNS effects: sedation, agitation, amnesia, up to hallucination & coma, especially in elderly patients. o ↓ smooth muscle contraction in the balder & intestine → urinary retention and constipation o Tachycardia d/t ↓vagal tone at the sinoatrial node o Acute closed angle glaucoma d/t mydriasis & consequent decreased outflow of aqueous humor (high-pressure tea kettle with a lid shaped like a dilated pupil). 2.1 – “One Epic Summer Band Camp”: Direc Directt Sympathom Sympathomimetics imetics (norep (norepinephrine, inephrine, 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 2.2 – “Catec “Catecholamine holamine Catch & Release”: Indirec Indirectt sy sympathomimetics mpathomimetics (coca (cocaine, ine, ephedrine, amp amphetamine, hetamine, met methylphenidate, hylphenidate, modafinil, ato atomoxetine) moxetine) • Indirect sympathomimetics enhance catecholamines by displacing them from nn ending or by inhibiting reuptake or metabolism (same scene, indirect perspective. Mime for mimetics. Catecholamine catfish). All act to ↑catecholamine concentration at adrenergic nerve terminals (dock = nerve terminals) • Adrenergic transmission at the synapse: o Tyrosine precursor to catecholamines is transported to nn terminals (tire being drawn to dock). o Once at terminal, tyrosine → L-dopa→ dopamine (tyrosine tire, L-shaped winch handle, dopamine dope rope). • In dopaminergic neurons, here ends the process. • In most sympathetic presynaptic nn, dopamine in vesicles is converted to E & norepinephrine (vessel) o Dopamine is converted to norepinephrine by dopamine β-hydroxylase (navigator with North oriented compass) o Dopamine is then release from the vesicle in response to intracellular ↑Ca o Synaptic transmission is discontinued by diffusion of dopamine or reuptake into the cell o NE Transporter (NET) transports catecholamines back into the presynaptic neuron; DAT is specific to dopamine (hauling in a net of catfish on presynaptic dock; “NET DAT Catfish!”) o Can be recycled into vesicles by vesicular monoamine transporter (VMAT) (catfish being hauled in on mat with Vs) Dopamine Rece Receptor ptor activat activation ion • D1 is a GsPCR, D2 is Gi (Dope Rope Swing – for D1 & D2 respectively) o D1 ▪ GsPCR→↑cAMP → PKA activation → smooth muscle relaxation • Renal vasculature stimulation → ↑ RBF, GFR, Na excretion. This is in contrast to norepinephrine & E α1-mediated constriction of renal afferents (Dope Rope 1 has a kidney on the end) ▪ DBA • Dopamine activates dopamine Receptors at low doses, β-adrenergic receptors ad higher doses, & α-adrenergic receptors at high doses. (bugler higher than kidney & scout with single candle highest up) o D2 (swing with 2 ropes) ▪ Important in CNS • Metyrosine (counselor claiming, “my tire!”) o a tyrosine analog o inhibits conversion of tyrosine to L-dopa • Cocaine o Inhibits NET & DAT → accumulation of NTs in synapse (scouts with hot cocoa not taking up net). Results in a variety of effects: ▪ Peripherally: HTN, tachycardia, mydriasis (flushed scout); coronary vasospasm, angina, a/o MI (crown on mug; angina anvil; clutching chest) ▪ Central DAT inhibition →↑dopamine in CNS → arousal, addiction, seizures o May see nasal mucosal atrophy or septal perforation d/t vasoconstriction (scout with bloody nose) o Management is supportive. NEVER give β-blockers; will → unopposed α1 action & HTN crisis (β1 bugle causing excessive head pressures) • Atomoxetine inhibits NET o Treats ADHD (kid distracted by AD channel in HD next to net) • Reserpine (serpent blocking catfish storage) o Inhibits VMAT o Not used clinically • Amphetamines (Friend of Mine shirt on ichthyophile) o CNS stimulated via norepinephrine > dopamine release. Mood elevating effect. Improved attention to repetitive tasks, & stimulating effects o Appetite suppression effects (untouched plate of dinner) o Methylphenidate for ADHD (distracted kid watching “Friend Date” on HDTV) o Modafinil used for narcolepsy (clock in sleep mode) ▪ Fewer adverse effects than straight amphetamines 2.3 – “The Phantom of the Alpha”: α-adre -adrenergic nergic dru drugs gs (α2 ag agonists: onists: clonid clonidine, ine, αmethyldopa ti tizanidine; zanidine; α antagonists: phentolamine, phe phenoxybenzamine, noxybenzamine, prazosin, mirtazapine) • Most of these bind to α1 & α2 receptors in periphery, preventing catecholamine & other agonists • α2 agonists • When given systemically reduce SNS outflow directly at the level of the brainstem → systemic BP (brain-shaped platform for CNS action) o Clonidine (Raoul with 2 claw weapons) ▪ Centrally acting α2 agonist – i.e. sympatholytic (2 lit candles; “sympathy” crossed out by claw marks) ▪ Indications • Used to treat HTN, including HTN crisis (High pressure pipes under stage, marked “urgent”) • Extended release effective in refractory ADHD (Raoul is distracted by HD mirror screen) • Tourette’s – α2 agonists preferred over neuroleptic agents d/t decreased risks of extrapyramidal adverse effects (Tourette’s marionette) o α-methyldopa (α-shaped noose) ▪ L-dopa analog (rope noose). Converted to α-methyldopamine & α-methyl-NE, which can act on central α2 receptors, similar to clonidine (2 lit α candles held near brain rug) ▪ Historically, used for HTN (high pressure pipes). Now, used mainly in gestational HTN (Christine is pregnant) ▪ Side effects: • Lupus-like syndrome (rare) (lupus wolf) • Autoimmune hemolytic anemia; may be d/t production of autoantibodies o Tizanidine (Letter to X-tine) ▪ Centrally acting α2 receptor. Muscle relaxant (recliner chair) • α antagonists (on stage, α-candles have been extinguished) o Phentolamine ▪ Reversible α1 & α2 receptor blocker (single & paired candles extinguished) ▪ Causes vasodilation (dilated sleeves). Can prevent pressor effects of sympathomimetics ▪ Can be used to treat cocaine induced HTN crisis, avoiding β-blocker effects (spilling mug of hot cocoa) ▪ Can be used intraoperatively in case of HTN crisis o Phenoxybenzamine (phoenix tattoo) ▪ Irreversible α1 & α2 receptor blocker (tattoos are permanent; single & paired candles extinguished) ▪ May take several days for new receptors to be synthesized. ▪ Normalize BP prior to pheochromocytoma removal (kidney-and-adrenal shaped ice cream) – causes intermittent headache, HTN, palpitation, sweating (scared looking manager holding head). o α agonists may be used to reverse widespread catecholamine-induced vasoconstriction, as in the case of cocaine toxicity (spilling mug of hot cocoa); tyramine-induced HTN crisis in patients on MAO-Is (tyramine found in aged wine & cheese) (wine & cheese table). o Side effects: ▪ Orthostatic HTN d/t ↓α1 effects (tilt table) accompanied by Reflex tachycardia (heart shaped reflex hammer). First dose is especially high risk • α1 selective antagonists o include prazosin, terazosin, doxazosin, tamsulosin (opera singer for -osin suffix holding 1 extinguished α candle) o Relax smooth muscle in urethra & prostrate (sitting on banner). Used for symptomatic control of BPH o Cause vasodilation (dilated sleeves) o Prazosin has CNS effects, including helping with sleep regulation. Used in PTSD (dog tags held by praying opera singer • Mirtazapine (misery & mirth masks) o Atypical antidepressant with antagonistic effects at α2 & other receptors (2 extinguished α candles) 2.4 – “Brahms’ “Brahms’ss LOL Lullaby”: β blocker blockerss • β-receptor antagonists (blocked β1 bugle & β2 tubas). Mostly end in -lol suffix (Brahms’ lullaby). o Decrease cardiac contractility d/t antagonism of β1 receptor (heart-shaped music stand weak arms) o β1: Inhibit SA node activity → bradycardia (low handing heart watch; SA & AV nodal notes) • • • • • o β1: Slowed AV conduction. Contraindicated in AV block (“Door to remain unblocked” on shield shaped sign – recurring symbol for AV) Indications o Used in management of chronic stable angina(xylophone on anvil). ↓Cardiac contractility & HR → ↓oxygen demand (oxygen cannula flying off) o β1 → ↓renin levels & JGA (blocked bugle in hand of rain jacket wearing player) o All have antihypertensive properties with mild to moderate HTN, but rarely used as initial monotherapy d/t risk for adverse CV outcomes (high pressure steam pipes on pipe organ). Especially helpful in CHF & MI. o Useful in management of hypertrophic obstructive cardiomyopathy, especially when acute hemodynamic collapse d/t obstruction (bagpiper with filled heart-shaped bags is blowing against an obstruction). o Metoprolol, propranolol, timolol can be used as episodic Migraine prophylaxis (pounding unilaterally on head-shaped bell). o Treatment of thyroid storm: catecholamine surge → agitation, delirium, fever, tachyarrhythmia, death (thyroid shaped bowtie with lightning bolts); treatment: propranolol, propylthiouracil, & prednisolone (3 Ps). β-blockers are used for symptomatic relief of thyroid overactivity as e.g. in Graves’ disease, thyroid toxicity o Essential tremor (conductor tremor while holding baton) o Type 1 antiarrhythmics. Effective in Ventricular and supraventricular arrhythmias (rhythmic record player in background) o Glaucoma. Topical administration of β blockers (timolol) inhibits β2 receptors at ciliary epithelium →↓aqueous humor production (Tim the tuba player with the eye-shaped block) Common adverse effects o Exacerbates asthma & COPD by non-selective β blockers (huffing blue bloated tuba player) o Impotence in men (floppy trombone) o Toxicity: glucagon administration (glucagon packets in conductor’s podium) β1 selective antagonists o include atenolol, betaxolol, esmolol, acebutolol, metoprolol (A-BEAM spotlight on β1 bugler). o Cardioselectivity (second A-BeaM spotlight). o Indications: ▪ β blocker reduces MI mortality if given within short order (MI = broken harp string; strings broken acutely for acute treatment). ▪ Used on CHF (sad heart balloon). Reduce structural remodeling and the effect of chronic exposure to catecholamines in CHF resulting in ↓mortality & morbidity (harpist in angle get-up, for ↓mortality; building is remodeling). May worsen acute HF, as catecholamines acutely help with cardiac contractility & maintaining sufficient function. o Carvedilol is nonselective β-antagonist with some α1 effects (carved candleholder with single snuffed α-candle). Used in conjunction with other β-blockers Laβlol o α1 & nonselective β activity (organ stops with snuffed α candle). o Vasodilation → ↓SVR (dilated sleeves). o Safe for pregnancy; may preserve utero-placental blood flow better than other blockers (pregnant organist). o Rapid onset makes useful in HTN crisis (“emergency stop” with ivy =IV). o Used in aortic dissection, where want to rapidly bring down BP (unlike other HTN crises where want to decrease, but more gradually) (dissecting pipe on organ) Partial agonists o Should not be used in HF & MI, as lack the protective effect of complete blockers (holes in failing heart balloon in audience) o Acebutolol – β1-selective with partial antagonist activity (plastic bugle). o Pindolol – Nonselective β blocker with partial agonist activity (agonizing sound of tiny bugle pin in audience).