Neuro & Psych Drugs

Neuro & psych Drugs 1. Sedatives & hypnotics 2. Anesthetics & analgesics 3. Antidepr Antidepressants essants & anxiolytic anxiolyticss 4. Mood st stabilizers; abilizers; ant antiepileptics iepileptics 5. Antipsychotics, Parkinson’s disease 1.1 – “L’eggo my Benzo!” Be Benzodiazepine nzodiazepine nzodiazepines, s, flumazenil Physiology • GABA, along with glycine, is one of the major CNS inhibitory neurotransmitters (“Take it easy” sign on cab). • GABA receptors are divided into A, B, & C subtypes. GABA-A is a chloride ion channel formed of 5 subunits (“Chlo-rider” sign on cab). GABA-A is the main site of action for many sedative/hypnotics including benzodiazepines, alcohol, and barbiturates (Ben’s diner, drinking guy, and barbershop respectively) • Mediates Mood changes, neuronal excitability, sleep, anxiety. Alcohol • Allosterically binds GABA-A receptor (separate site from benzos) (Cab-A outside, with guy drinking on the trunk). Functions to enhance inhibitory action of GABA. • Chronic ingestion induces downregulation of GABA A receptor complex & decreased GABA sensitivity & tolerance (“All are welcome” banner). So have to increase alcohol intake to have same effects. • Withdrawal: Abrupt cessation in intake will cause a decrease in GABA mediated inhibitory tone → CNS excitation. 3 stages (demonstrated by patrons at the bar with lots of bottles): o Start within 8-12 hours. Insomnia, tremor, ANS hyperactivity (diaphoresis, variable BP, tachycardia) (closest patron with brown shirt) o 12-48 hour: seizures (middle patron) o 48-96: delirium tremens. Includes fever, disorientation, severe agitation. (farthest, angry patron) Benzodiazep Benzodiazepines ines (Ben’s Diner) • Many of the names end in -pam (diazepam, oxazepam, diazepam) (“Best PAM-cakes” sign) or -olam suffix for the short acting benzos (triazolam, alprazolam, midazolam) (“All A.M.”). • MOA: allosterically bind GABA-A receptor (separate site from alcohol) (Cab-A outside). Potentiate GABA A transmission throughout the CNS (special delivery of pam-cakes increasing cab driver effects). o Major inhibitory CNS neurotransmitter (along with glycine) (CNS & “take it easy” signs on cab). o Activated GABA-A receptor is a chloride channel (Chlo-rider cap). ↑chloride conductance inhibits synaptic transmission → CNS depression (CNS light on cab). Increased permeability hyperpolarizes & stabilizes membrane potential, making less excitable. o Chloride channel conductance is d/t an increase in frequency of opening rather than increased duration (“Now Open More Frequently”) • All are metabolized by the liver (liver on ox). o Short acting: Rapidly metabolized & inactivated o Long acting: form active metabolites that have very long half-lives and exert effects of their own. o Note that effects can be cumulative with repeat dosing, which is important when considering the half-lives of the different formulations. o Active metabolites tend to accumulate with liver disfunction, leading to increased sedation • Short-acting: o Alprazolam, Triazolam, Oxazepam, Midazolam (ATOM) o Short serum half-life, fast acting (Better Act fast!). Makes more addictive & likely to lead to dependence (“Addictive Flavor”) • Duration of action of common benzos (per UWorld) Short (half-life <6h) Triazolam, midazolam Intermediate (half-life 6-50h) Oxazepam, alprazolam, lorazepam, clonazepam Long (half-life > 50h) Diazepam, chlordiazepoxide, flurazepam • Clinical indications o Benzos are first line treatment for alcohol withdrawal. ▪ Long acting preferred d/t self-tapering effects which → smoother course of withdrawal. (long tapering flag). ▪ In patients with severe liver disease, may use short acting agents to prevent accumulation of active metabolites in liver disease. ▪ treatment of seizures is one of the major concerns with alcohol withdrawal; hence IV administration is indicated in EtOH withdrawal. o IV administration used for seizures, including epilepsy, alcohol withdrawal. This is especially useful with continuous seizure activity (i.e. status epilepticus). (Construction worker with jackhammer next to ivy-bound pole; workmate pulling the plug.) o Anesthesia: ▪ Causes muscle relaxation & amnesia. Can be used for general anesthesia, e.g. rapid sequence intubation (sleeping guy with straw) ▪ Can be used for a state of conscious sedation for minor procedures & surgeries (guy drinking a Lite) o Commonly used for short term treatment of insomnia (sleeping guy). Not first line d/t physical dependence. o Can be helpful in childhood parasomnias (crying kid with pajamas) o Central muscle relaxants. Diazepam especially can help with spasticity d/t UMN disorders including MS, stroke, spinal cord trauma, even tetanus. However, will produce sedation at the dosing needed to relax muscle tone (very relaxed guy reclining in booth, sleeping) o Used for management of acute anxiety states ▪ GAD (anxious date). SSRIs & SNRIs are first line for long-term management. ▪ Can be useful in the management of somatic symptoms of acute anxiety (e.g. headache, insomnia, other) (sweating, shaking date clutching head). ▪ Panic disorder (Edvard Munch’s Scream). SSRIs & SNRIs are first line for long-term management. • Side effects/toxicities o Dose related CNS depression. Should not be coadministered with any other CNS depressants, including alcohol, barbiturates, neuroleptics, first gen antihistamines (bee swatter). o Significant dose related anterograde amnesia (useful clinically during sedation) (question mark on sleeping man’s hat) o Elderly patients are more sensitive to adverse effects. Most common reversible cause of confused states in the elderly is the overuse of sedative hypnotics; may present with somnolence, confusion, disorientation (confused elderly man) o Can cause central ataxia. ▪ ↑ fall risk in the elderly. Included in BEERS criteria. (Falling stack of pancakes in front of older man) o High dependence & withdrawal potential ▪ Chronic use induces downregulation of GABA-A receptor complex & decreased GABA sensitivity & tolerance (“All are welcome” banner). ▪ Withdrawal may look like alcohol withdrawal, d/t similar CNS effects. Can include tremors, anxiety, perceptual disturbances, dysphoria, seizures, psychosis. • Flumazenil (fluffy muzzled dog) o Competitive antagonist at the BZD receptor (dog is antagonizing man with pancakes). o Used for reversal of BZD induced sedation. o Use in OD is controversial. May precipitate seizures d/t withdrawal symptoms in patients who’ve developed tolerance. 1.2 – “Catchi “Catching ng some Zs”: N Non on-be -benzo nzo hypnotics, melatonin, rame ramelteon lteon • Pharmacotherapy for insomnia should be limited to short term management Nonbenzodiazepine hypnotics • Include zolpidem, zaleplon, eszopiclone (“ZZZ mattresses) • MOA: allosterically bind GABA-A receptor at the same site as benzos (lady & Ben’s Diner customary grabbing Cab-A door at once). more targeted action than BZDs. Potentiate GABA A transmission throughout the CNS (special delivery of pam-cakes increasing cab driver effects). o Major inhibitory CNS neurotransmitter (along with glycine) (CNS & “take it easy” signs on cab). o Activated GABA-A receptor is a chloride channel (Chlo-rider cap). ↑chloride conductance inhibits synaptic transmission → CNS depression (CNS light on cab). Increased permeability hyperpolarizes & stabilizes membrane potential, making less excitable. o Chloride channel conductance is d/t an increase in frequency of opening rather than increased duration (“Now Open More Frequently”) o Different site altogether from alcohol & barbiturates (drinking man & barber shop around cab outside) • As a consequence of more specific activity, have decreased anxiolytic and anti-seizure activity compared to benzos • Rapid onset & short duration of action (“Fall asleep FAST”; sheep jump and fall) • Rapidly metabolized by the liver. Serum half-life is 1-2 hours, so residual effects (e.g. next morning drowsiness) rare. o Zaleplon & zolpidem treat sleep onset insomnia (“Fall asleep”) o Eszopiclone has the longest half-life & is effective for both sleep onset & sleep maintenance insomnia. • Adverse effects: o Similar to those associated with benzos with lower frequency and severity. o Less likely to cause tolerance than benzos (“Returns not tolerated”). Ergo less addiction, dependence, reliance. o Elderly are more sensitive to effects including excessive sedation, delirium, night wandering, cognitive impairment, aggravation. o Can cause central ataxia. ▪ ↑ fall risk in the elderly. Included in BEERS criteria. (Falling stack of pillows in front of older man) o Do not combine with other CNS depressants (“Do not combine with coupons” sale sign; bee swatter) Ramelteon & tasimelteon • Melatonin receptor agonists. o MT1 & MT2 receptors located above the suprachiasmatic nucleus of the hypothalamus (fan nucleus above the X-shaped blades; X for optic chiasm, ergo suprachiasmatic nucleus) • Involved in circadian rhythms involved in maintaining sleep/wake cycle (lights on and off) • Few adverse effects. No rebound insomnia or significant withdrawal symptoms • Demonstrated safety profile in geriatric patients; one of the few with no dose adjustment needed in geriatrics. (Old man falling asleep) Flumazenil (fluffy muzzled dog) • Competitive antagonist at the BZD receptor (dog is antagonizing man on sidewalk). • Used for reversal of non-benzo induced sedation. 1.3 – “Barber Shop”: Barbiturate Barbituratess • Barbiturates are some of the oldest anti-seizure drugs. Nowadays, limited clinical use d/t CV, pulmonary, CNS sedation, & addiction risk. • Uses: critically ill sedation, occasionally antiseizure. • MOA: allosterically bind GABA-A receptor at the different site from benzos (Cab-A cap). Potentiate GABA A transmission throughout the CNS. o Major inhibitory CNS neurotransmitter (along with glycine) (CNS & “take it easy” signs on cab). o Activated GABA-A receptor is a chloride channel (Chlo-rider cab). ↑chloride conductance inhibits synaptic transmission → CNS depression (CNS light on cab). Increased permeability hyperpolarizes & stabilizes membrane potential, making less excitable. o Chloride channel conductance is d/t an increase in duration of opening rather than increased frequency (“Longer hours!”) o Different site altogether from alcohol & barbiturates (drinking man & Ben’s Diner outside) • Generally have longer half-lives than BZD and may have residual hangover effects d/t extended serum half-life (tapered white flag). Exception is thiopental. • Adverse effects: o Clinical utility limited by significant depressive effects. o Half-life is 75 to more than 100 hours, with cumulative effects. Can → profound cardiac & respiratory depression (sweater with brain & heart) & hypotension (fainting) o Can cause severe CNS depression, even progressing to coma. Should always be avoided in the elderly (elderly woman fainting) o Long term use can lead to tolerance (tolerance banner), physical dependence (“addicted to curls” sign) o Potent inducer of CYP450 (kiddie car license plate) • Thiopental (“The Ol’ Quick Shave”). o Used IV for induction of anesthesia, especially in rapid sequence intubation (scrubs with sedated patient with a straw). o Rapid onset (30 seconds) & rapid clearance. Highly lipid soluble → rapid entrance into CNS with equilibration within 1 minute’s loss of consciousness. Duration of action is only 5-10 minutes d/t drug redistribution rather than metabolism (accumulates rapidly in adipose tissue & SKM) (hair “redistributed” onto arms & belly). Outlined at Right: ▪ Decay line (solid black line): rapid decay of plasma thiopental levels d/t redistribution. ▪ Brief peak (dashed line): rapid accumulation of thiopental in brain tissue & rapid redistribution ▪ Growth line (purple line): rapid accumulation of thiopental in muscle & adipose tissue. • Phenobarbital o Used IV for suppression of seizures (unplugging jackhammer; ivy) o One of the oldest antiseizure drugs still in use. For both generalized & focal. Stops any seizure at sufficient doses. ▪ Used as a first line treatment in neonates. ▪ Causes prolonged sedation, so 2nd or 3rd line in adults. • Primidone (perm is done) o Used to treat partial or tonic clonic seizures o Treats essential tremor in low doses; 1st line along with propranolol (stylist with shaking hands). 2.1 – “You’re getting sleepy… sleepy…”” IV anesthetic anestheticss (Propofol, eto etomidate, midate, ketamine) • IV anesthetics are used for rapid induction of anesthesia (lots of ivy in the picture). Preferred over inhaled for induction in most settings. Propofol (Prospero the hypnotist) • Most frequently used anesthetic for induction of anesthesia (“Introducing”). Lipophilic; preferentially enters CNS, accounting for rapid onset. Allows for continuous infusion, so used for maintenance as well (“Maintain your sanity!”). Can be used standalone or in combination with sedatives, opioids, inhaled anesthetics. • MOA presumed to be by potentiating chloride current through the GABA-A complex (Cab-A in the background) • Profound venous & arterial vasodilation →hypotension (dilated sleeves and pants of hypnotist) Etomidate (The Intimidator) • Can be used for induction of anesthesia (“Introducing”). Lipophilic & preferentially enters CNS, accounting for rapid onset. • MOA presumed to be by potentiating chloride current ought the GABA-A complex (Cab-A in the background) • Maintains CV stability, with minimum change to CO, HR, BP (person being lifted is stabilized) Ketamine (snaKE TAMING) • Used for induction (“introducing”) • MOA complex. Major effects probably d/t inhibition of NMDA receptor complex (nomadic camel tied up). Results in dissociative anesthesia. Eyes remain open with slow nystagmus (entranced men with wide eyes) • Common emergence reactions involve vivid colorful dreams, hallucinations, out of body experiences, visual/tactile sensitivity (vividly colored smoke). May induce fear and anxiety or euphoria (used recreationally) • Stimulates CV →↑BP, HR, CO (heart shaped cobra) • Other unique properties include analgesia, minimal respiratory depression, bronchodilation, convenient route of administration. Useful in mentally challenged & Peds patients Benzos (Ben’s Diner) • Midazolam may be used IV perioperatively. • Used for conscious sedation for minor procedures (e.g. colonoscopy) (colonic pump) Barbiturates • Occasionally used for induction (Introducing the Barber). Have been largely replaced as induction agents by propofol • Thiopental used for induction (Sweeney Pentol) • Highly lipid soluble, acts rapidly & finishes quickly (“the Ol’ Quick Shave”) 2.2 – “Laughin “Laughing g gas”: inhaled anesthetics, dantr dantrolene olene Properties • Inhaled anesthetics are taken up by gas exchange through the alveoli of the lungs, with consequences for pharmacokinetics, uptake, and distribution and partitioning. • Solubility of gas in the blood is also referred to as the blood:gas partition coefficient (partition in the ball pit); the higher the coefficient, the higher the solubility. Solubility determines speed at which blood becomes saturated, and ergo uptake and duration in the CNS. o Less soluble → more rapid saturation → more rapid onset & offset of CNS effects (e.g. N2O) (Kid sleeping in vascular ball pit; immediately getting pulled to safety). Takes less anesthetic to saturate the blood (only one kid in the ball pit rather than 2). o More soluble inhaled anesthetics have a slower onset and longer duration (e.g. halothane) (kid moving freely in the ball pit; KO’d by the end; long tapering flag)) • Arterial tension curves correlate to solubility (side of ball pit) o steeper arterial tension curve = lower blood:gas partition coefficient o Less steep arterial tension curve = higher blood:gas partition coefficient • MAC (minimum alveolar concentration) (mac & cheese) is the percentage of anesthetic needed in inspired gas mixture that renders 50% patients unresponsive (1 kid awake, 1 kid asleep). Corresponds to ED50 on dose-effect curve. o The lower the MAC, the more potent the drug (i.e. potency of the inhaled gas is inversely proportional to MAC) (inverted bowl of mac’n’cheese). The potency for inhaled anesthetics is the minimal concentration that reaches the brain that results in sufficient anesthesia. Inversely proportional to MAC. • Solubility of anesthetic in peripheral tissues is a major factor in onset/offset as well as it affects how much of the anesthetic will make it to the brain. Can be measured by the arteriovenous concentration gradient; if tissue solubility is high, a large amount of anesthetic is taken up from arterial blood, resulting in low venous concentration and larger AV concentration gradient. • Gaseous anesthetics may be used to deepen anesthesia after induction with IV agents. Precise MOA not known; may involve glycine, GABA, or antagonism of NMDA receptors. • All can cause myocardial depression → ↓CO & ↑arterial & ventricular pressures (clown with heart balloon). May cause hypotension (kid passing out) • Can cause respiratory depression, leading to decreased minute ventilation & hypercapnia (deflating lung balloons). Also decrease mucociliary clearance which may contribute to pos-op atelectasis. Agents • Gaseous: Nitrous oxide = laughing gas (N2O) o Lowing boiling point, gaseous at room temperature (gas canister). o Physically impossible to overdose. o Fairly benign. • Volatile anesthetics o Include enflurane, isoflurane, halothane. All are fluorinated. End in -thane or -flurane (kid in pool holding flower) o High boiling point, liquid at room temperature (Air tank getting wet in pool) o Can decrease cerebral vascular resistance → increased cerebral blood flow →↑ICP (crown with red brain wig) o Halothane rarely used d/t hepatotoxicity with massive hepatic necrosis (liver with cracked piñata). Presents within 2d – 4w. Will have widespread centrilobular necrosis and up to 80% mortality. o Enflurane: nephrotoxicity (guy getting hit in the kidney with bat). Convulsions (shaking) o Malignant hyperthermia (Magnificent birthday) ▪ Life threatening. Presents with fever and muscle rigidity soon after surgery with inhaled anesthesia (flame hat) ▪ Muscular hypersensitivity to volatile anesthetics or succinylcholine (SUCKS poster). Results in excess Ca2+ release from defect in ryanodine receptors (RyR) in the sarcoplasmic reticulum (Ryan sign falling). Causes excessive ATP-dependent reuptake by the sarcoplasmic reticulum, resulting in heat production (flame theme) and consequent muscular damage (bitten drumstick) ▪ May see potassium, CK, myoglobin released into circulation on labs (chicken legs) ▪ Treatment: Dantrolene (mm relaxant) (trampoline). Blocks RyR and prevents further release of calcium into muscle fibers (adult blocking Ryan from getting on trampoline). 2.3 – “Utop “Utopia ia resort”: Opiates, naloxone, naltre naltrexone xone Physiology • An opioid is any compound that that acts on at an opioid receptor (utopia resort). 3 endogenous receptors, all expressed throughout the central & enteric nervous systems (colon shaped table): o μ (mu-ssage parlor): major analgesic receptor (pain relieving massage); also responsible most adverse effects including sedation, constipation, respiratory depression, miosis, physical dependence??. Exist in high density in the GI tract & modulate enteric NS. Stomach, SI, LI decrease motility & increase tone → delayed passage of stool & increased H2O absorption oκ oΔ • At the molecular level, activated opiate receptors interact with G i proteins and open ion channel. In nn, open K+ channels → hyperpolarization of the membrane (open banana barrels). Also close VG Ca channels on presynaptic nn terminals (calci-YUM ice cream; unplugging presynaptic wire) →↓transmitter release (glutamate, ACh, Ne, serotonin, substance P). These effects combines to stop transmission of pain signals to brain Opioid withdr withdrawal awal • Tolerance is accompanied by physical dependence. Stopping abruptly can cause withdrawal (“withdraw to the spa” sign). Referred to as abstinence syndrome when occurs abruptly d/t stoppage of analgesics or illegal substances; also in neonates with opioid withdrawal. • Presentation: “anxious, hot, & moist” – anxiety, hyperventilation, hyperthermia, muscle aches, rhinorrhea, lacrimation, yawning, nausea/vomiting, diarrhea, mydriasis. • With Morphine or heroin: withdrawal SSx start within 6-10 h of last dose, peak 36-48 h, slowly decrease over a few days. • Detox involves curbing withdrawal SSx and minimizing symptoms using a long-acting opioid agonist (white tapering flag) o Methadone is a long-acting opioid full agonist used to attenuate withdrawal symptoms (done timer). Once tapered off, effects slowly subside with much less intense withdrawal. Patient can be slowly weaned off all opiates. o Buprenorphine is another long acting mu-opioid partial agonist (blueprint). Safer than methadone. Effects slowly subside as tapered. • Neonatal abstinence syndrome (irritable, moist, tachypneic baby in pool). Occurs when a newborn undergoes withdrawal from transplacental transmitted opiates. o Treatment: full mu-agonist, usually morphine or methadone. Pure μ agonists • Morphine & derivatives (hydromorphone) (“More fun, less pain”) o Prototypic drugs o μ receptor agonist o Used in management of chronic pain • Fentanyl (“make your pain a fantasy”) o μ receptor agonist o Used for post-operative & chronic pain • Tramadol (tram) o Weak μ receptor agonist (in the background). Used for management of chronic pain. o Centrally acts on blockade of 5-HT & norepinephrine reuptake (N/S compass), making effective for neuropathic pain specifically. • Loperamide (lop-eared rabbits), diphenoxylate (dolphins) o Don’t cross BBB; work on enteric system. o Increase colonic phasic segmental activity (i.e. tract squeezes down on stool rather than moving it along) (dolphins back & forth between haustra) o Antidiarrheals (muddy footprints) • Codeine (barcode), dextromethorphan (coughing orphan on package) o Opioid antitussives (coughing patron). MOA is poorly understood as the physiology of coughing is complicated. o dextromethorphan also antagonizes NMDA receptors (Nomadic camel on package) • Shared adverse effects o Direct extensions of pharmacologic action and may be utilized clinically in certain situations: ▪ Because principal effects are in CNS, can cause significant sedation & respiratory depression (lady with towel on head). Drowsiness & clouding of mentation are common adverse effects especially in the elderly, or in combo with other sedatives ▪ ↓brainstem respiratory mechanisms. Dose dependent. May initially be seen as ↑PCO2. Can be fatal with underlying respiratory disease (deflating lung vest). ▪ Constipation. Major problem with chronic use or ↑↑dosing, as in the case of managing cancer pain (plunger for clogged bathroom). ▪ Miosis (constricted hoodie) ▪ Biliary colic d/t contraction of biliary smooth muscle (biliary tree with seagull) o Side effects that are always undesirable ▪ Tolerance (“All are welcome” sign). Repeated doses have decreasing analgesic effect. After only a few days of exposure, high tolerance for euphoric, sedating, and respiratory effects. • No tolerance develops to miosis and constipation (“Out of order” bathroom). Anyone on prolonged opiates should be on prophylactic bowel regimen. ▪ LT use (chronic) activation of opioid receptor on nociceptive nn can cause ↑ pain sensitivity; this is referred to as opiate induced hyperalgesia (masseuse hurting client). Not known how this phenomenon occurs. May be due in part to downregulation of opiate receptors and/or upregulation of glutamatergic pathways. Partial agon agonists ists (partial foo foott massage) • Include buprenorphine, nalbuphine, butorphanol (-buphin = bluefin) • Used as analgesic. o Exception is in patients who have developed tolerance to full agonists and still have full agonists onboard. Giving such patients a partial agonist has the same effect as giving a direct antagonist & may precipitate withdrawal (waiter tripping into withdrawal spa) Pure antagoni antagonists sts • Naloxone (“No Lax Zone” trainer) o Used to reverse acute opioid toxicity. Completely & dramatically reverses OD effects within 3-5 minutes. Will virtually instantaneously precipitate withdrawal. o IF you suspect someone of OD’ing on opiates, IMMEDIATELY administer Naloxone!!! ▪ No ill effects of administering naloxone when someone has OD’d on something else. • Naltrexone (“No Tricks” trainer) o helps maintain abstinence in addicts. Blocks virtually all the effects of heroin, so useful in rehab. o May also reduce craving for alcohol & nicotine (trainer with XXX beer). o When combined with bupropion, can provide synergistic approach for weight loss (guy working out). 3.1 – “Ser “Serotonin otonin sitcom”: S SSRIs, SRIs, SNRIs, cyprohe cyproheptadine ptadine • Major depressive disorder (MDD) has 17% lifetime prevalence in US & is one of the major causes of disability in the developed world. While mechanisms are not clear, is thought to be related to a deficiency of CNS serotonin, NE, dopamine. There is a clear role for increasing available serotonin to address disease ( serotonin smiley faces; 5H-TV). SSRIs, SNRIs are some of the most prescribed meds in the US. • Clinical indications: o MDD (comedy/tragedy masks): Acute episodes may last 6-14 months if untreated. About ⅓ of patients will achieve remission on treatment with a new med. Treatment is continued for at least 6 mos., and may be used for maintenance therapy. SIGECAPS for diagnosis criteria. o long-term treatment of anxiety disorders are the second most common indication, Benzos provide much more rapid anxiolytic effects, but SSRI/SNRIs at least as effective for maintenance therapy, without many of the Adverse effects. Include many of the major anxiety disorders, including ▪ GAD (anxious coworker). ▪ Panic disorder (same deal with the benzos) (Scream-saver) ▪ PTSD (dog tags). Usually require therapy as well ▪ OCD (obsessively organized desk) o Note that neither are for the management of acute symptoms of anything (depression, anxiety, pain). On average, 2 mos. before onset of efficacy (2-month calendar). SSRIs (selective serotonin reuptake inhibitors) (Express Trips) • Include fluoxetine (Fly out poster), paroxetine (parrot air poster), sertraline (desert airline poster), citalopram (Celexa®) (The City poster) • Inhibit presynaptic serotonin reuptake transporter (SERT) →↑ concentration at the synapse (Smiley face pad not kept in drawer) • Increased availability of monoamines at the synapse responsible for many of the beneficial and detrimental effects. • Clinical indications where SSRIs are preferred: o Bulimia (binge snack drawer with lady bending over). Not useful for anorexia. o Social anxiety disorder (shy guy) • adverse effects o Rare: SIADH → hyponatremia (guy sweating and spilling water while replacing bottle) o Diminished sexual function & interest in up to 50% of patients (girl rejecting guy’s advances) o Weight gain (rotund dude) o Drowsiness (sleeping on the job) o Rapid cessation can cause discontinuation syndrome, particularly with drugs with a short half-life (e.g. paroxetine or sertraline) ▪ Presents with flu-like symptoms (dizziness, fatigue, headache, nausea) 1-2 days after stopping meds (“Out with the Flu” note) ▪ Avoid by tapering o Serotonin syndrome (excessive smiley-face post-it notes in corner office). Potentially fatal. ▪ Presentation: Hyperthermia, hypertension, hyperreflexia & clonus (flushed angry boss tapping foot) ▪ Can look like the neuroleptic malignant syndrome precipitated by dopamine blocking agents (e.g. antipsychotics). Differentiation: Hyperreflexia & & clonus (NMS characterized by hyporeflexia & rigidity) ▪ Can occur with OD of a single drug or combos with other serotonergic drugs (e.g. TCAs, MAO-Is) (mousetraps & trike in corner office) ▪ Management: discontinuation of all serotonergic agents, stabilization of vital signs, ± serotonin antagonist (e.g. cyproheptadine, a 5HT-2 blocker) (“Silly Pranks Prohibited” for cyproheptadine) SNRIs (serotonin-norepinephrine reuptake inhibitors) (Compass rose on wall map) • Include Venlafaxine (fax), duloxetine (dual copier, scanner), sibutramine, milnacipran, levomilnacipran, and other derivatives • Inhibit presynaptic reuptake of norepinephrine & 5-HT, increasing availability of monoamines at the synapse. • Clinical indications where SNRIs are preferred: o Drugs that have 5-HT & norepinephrine reuptake blocking are helpful in pain management, particularly of neuropathic pain (frayed wire). Examples include diabetic neuropathy (venlafaxine, duloxetine) (hand stuck in Diasweeties vending machine). o Duloxetine has been found effective in many other pain conditions including lower back pain (guy bent in really uncomfortable position), osteoarthritis, & fibromyalgia (fiber bars) • Adverse effects o ↑noradrenergic transmission →HTN, ↑HR, CNS activation (insomnia, agitation) (angry coworker) o Discontinuation syndrome o Serotonin syndrome 3.2 – “I want to ride my tricycle tricycle”: ”: Tricyclic anti antidepressants depressants • Depression is thought to be related to a deficiency of CNS serotonin, NE, dopamine. There is a clear role for enhancing availability of synaptic monoamines to address disease. TCAs are 2nd or 3rd line in treatment of depression because of adverse effects, and are generally reserved for patients with treatment resistant depression (student struggling with resistant door to drama room, marked by comedy/tragedy masks) Tricyclic antidepressants (TCAs) (tricycle) • Include imipramine & derivatives desipramine, clomipramine (imprint of ball on girl’s face); amitriptyline, nortriptyline (girl tripping over trike) • Inhibit presynaptic norepinephrine & 5HT reuptake by blocking NET & SERT (blocked uptake of compass & smiley-face balls) • Off label uses: o Pain disorders, neuropathic & otherwise; notably diabetic neuropathy (kid stuck in Diasweeties machine) & chronic pain (frayed wire) o Migraine prophylaxis, especially Amitriptyline (school bell). o Clomipramine may be used to treat OCD, although SSRIs first line (child very neatly arranging marbles). o Central blockade of H1 histamine receptors, so may be used with allergies (bee ball) • Adverse effects o Many effects are a direct result of anticholinergic activity d/t inhibition of muscarinic acetylcholine receptors (child playing Mad Hatter’s tea party). ▪ Amitriptyline has most potent anticholinergic effect ▪ Less prevalent with secondary amines (e.g. nortriptyline & desipramine) (kid hiding under Secondary School sign) o Sexual dysfunction (rejected advances) o Relatively contraindicated in elderly patients d/t severe anticholinergic & antihistamine effects (just like dodgeball) (older man holding head) ▪ Urinary retention can be a clue to anticholinergic toxicity in delirium (bladder shaped tea kettle) o Central block of H1 histamine receptors can cause ↑appetite & weight gain (bee ball; heavy kid eating) o Can block α-1 receptors (extinguished α-1 candle). Can cause peripheral vasodilation & orthostatic hypotension, especially in the elderly (fainted girl) o CV toxicity ▪ Fatal cardiac arrhythmias are the most common cause of death in OD d/t blockage of fast Na channels (broken heartshaped peanut cookies; peanut butter jar). Causes ↓cardiac conduction → QRS & QT prolongation & arrhythmias (QRS shaped crack in bake sale sign; torsades streamers). ▪ Contractility depression can cause fatal hypotension. ▪ When a patient on TCAs presents with widened QRS or ventricular arrhythmia, treat with sodium bicarb (girl throwing baking soda). Alkalinizes serum, favoring non-ionized form of the drug which decreases affinity for Na channels. Also increases extracellular Na, allowing outcompetition of TCAs. o Seizures, probably d/t antagonist effect of TCAs on GABA-A receptor (kid in convulsions) o Serotonin syndrome (stack of smiley faced balls) o Can cause coma (kid sleeping it off) o *3 C’s: Cardiac, coma, convulsions 3.3 – “Of Mice & MAOIs” Physiology • Monoamine oxidases (MAO) breaks down monoamines (serotonin, NE, dopamine) (MAO = mouse). Two forms: o MAO-A deaminates dopamine, serotonin, and norepinephrine (albino mouse nibbling from smiley-faced & compass cheeses as well as dopamine rope). Usually breaks down tyramine in the GI tract (albino mouse eating meat) o MAO-B preferentially metabolizes deaminates dopamine (black mouse eating rope) • MAO-inhibitors (MAOIs) (mousetraps) o Include tranylcypromine (“Try a sip of wine!”), phenelzine (funnel in bottle), isocarboxazid (boxed wine) o Selegeline is a selective MAO-B inhibitor(sledgehammer hitting black mouse) ▪ inhibits breakdown of dopamine, increasing CNS levels. Useful in management of motor SSx of Parkinson’s as adjunct therapy to levodopa (cogwheeled clock). Especially useful with fluctuating or decreasing response to levodopa. o Block monoamine oxidase, decreasing breakdown of monoamines and thereby increasing their availability & increasing serotonin, NE, & dopamine transmission in CNS & periphery, enhancing activity of all of these. Irreversible (dead rat). o Historically used for depression & anxiety, but out of favor d/t adverse effects (comedy/tragedy masks) ▪ Not first line. Like TCAs, have potential lethal OD, require careful titration, many drug interactions & many adverse effects. Reserved for treatment resistant depression (bottle resistant to opening). ▪ May be useful in treating atypical depression with traits like hyperphagia, hypersomnia, leaden paralysis. o Adverse effects ▪ Most common are orthostatic hypotension, weight gain, & decreased sexual function; • Most severe sexual dysfunction effects of any antidepressant. ▪ Should be avoided with tyramine containing food (aged meats, wine, cheese). Without MAO-A activity, tyramine enterers circulation & acts as a sympathomimetic (Falling norepinephrine cheeses). May lead to tyramine toxicity, which can precipitate a hypertensive crisis. ▪ Chronic use of tyramine + MAOIs may cause malignant HTN ▪ Associated with serotonin syndrome (pile of smiley-face cheeses). Most serotonergic antidepressants should be discontinued at least 2 weeks before beginning an MAOI. 3.4 – “March Sadness”: Atypical antidepressants (Bupropion, mirtazapine, trazadone) • Atypical antidepressants are used in treatment of depression non-responsive to treatment • Bupropion o Blocks NET & DAT, leaving more NE, DA available in the synapse (“Net Dat Ball pro!”). Has no effect on serotonin. o Chemical structure similar to amphetamines. CNS activating affects, helps with hypersomnolence (kid cheering on the sidelines) o Can treat nicotine dependence; MOA unknown (“Pros don’t Smoke”) o Fewer sexual adverse effects than other antidepressants (lovebirds under net) o Less likely to cause weight gain (“Stay Fit” poster) o Adverse effects ▪ Lowers seizure threshold (player holding net). contraindicated in any patient with h/o seizures. ▪ Contraindicated with h/o bulimia (play with popcorn) ▪ Contraindicated with h/o anorexia (cachectic player) • Mirtazapine (mirth & misery cam) o Alpha-2 blocker (extinguished double-α candle) causing increased catecholamine release. o Also blocks 5HT-2 & 5HT-3 receptors (retired jerseys) o Potent H1 histamine antagonist (bee swatter). ▪ Can cause sedation (sleeping dude). ▪ May be therapeutic in patients with major depression & insomnia. May also be used to balance out effects of more activating agents. o Can cause weight gain (heavy eater drifting off while watching the game). May be preferable in elderly or with concurrent anorexia o Does not cause sexual adverse effects (kiss cam) • Trazadone (trombone) o Serotonin modulator. Antagonizes postsynaptic 5HT-2 R with some prevention of reuptake (smiley face drummer marching to the beat of his own drum with 52 jersey) o Antagonizes α-1 receptors (extinguished α lighter) ▪ May rarely cause priapism d/t α one effects (trombone; “trazabone”) • should be used with caution in conditions that predispose to priapism ▪ orthostatic hypotension (fainting dude) o H1 receptor antagonist, with major hypnotic effects (yellow team is out) ▪ Main therapeutic benefit is for patients with comorbid depression & insomnia. ▪ Should be avoided in the elderly (older man is sleep) ▪ Should not be used with other CNS depressants o Can cause sexual dysfunction (kid not getting kissed) o Serotonin syndrome (tipped over rack of balls) 4.1 – “Ski Man Mania”: ia”: Lithium • Bipolar consists of manic phases and depressive phases (two ski poles stabilize; peaks and valleys of mountains) • Lithium (lift) o Can be used to treat acute mania, or prophylactically for mania and depression. o Inhibits signal transduction pathways, including inositol triphosphate and other signaling. o Narrow therapeutic index (narrow window to get off the lift) o Urinary excreted. Anything that affects GFR will affect levels (e.g. diuretics such as thiazide may ↓ by as much as 25%; NSAIDS decrease) (kid on high dive; “low clearance” sign). o Adverse effects: ▪ Acute toxicity with GI SSx (skier on lift looks ill) ▪ Chronic → development of neuro SSx (e.g. tremor, confusion, ataxia) (trembling ski pole). ▪ Reversible thyroid inhibition in most patients (penguin with untied bow tie). Generally not symptomatic; may occasionally present with hypothyroid (e.g. weight gain) (snowboarder) ▪ Can induce diabetes insipidus (frozen fountain). Antagonizes action of ADH in collecting tubules. Polydipsia & polyuria usually resolve with cessation, but may be permanent with chronic use. ▪ Teratogenic (tarantula hats). Causes Epstein’s abnormality: arterialization of the R ventricle, ASD, malformation tricuspid (shapes of snowmen heads). Kids will present in later life with fatigue, tricuspid regurgitation. ▪ If patient on lithium presents with new onset neuro or psych SSx while on lithium, take a break from treatment. • Valproate therapy (“Festival” on violet banner) o Antiepileptic that can be used first line for acute mania or maintenance therapy. Can be combined with lithium for treatment refractory to either agent alone. • Carbamazepine (classic carved car) o Antiepileptic that can be used first line for acute mania or maintenance therapy • Lamotrigine (llama outfit) o Antiepileptic that can be used first line for maintenance therapy; can prevent depressive cycles. • Both first- & second-generation antipsychotics can treat acute mania (paintings on the peak) o Include haloperidol (halo in starry sky) 4.2 – “Seize the land”: Broad spectru spectrum m anti-ep -epileptics ileptics (valproate (valproate,, topiramate, lamotrigine, levetiracetam) Physiology • Epilepsy is a chronic disorder characterized by seizures (cerebral dysfunction caused by abnormal discharge of cerebral nn) (seizures = seizure, in this case of land). Can be from a variety of causes, but have characteristic patterns. • Focal: attack begins in a specific locus & typically involves only 1 part of the body (person dodging cannonball with one arm shaking). Multiple types, although treatments generally the same. o Simple: no LOC + clonic jerking of extremity or other sensory, psych, or motor symptom. o Complex: loss of consciousness; often associated with automatisms (e.g. lip smacking, swallowing) • Generalized involve both hemispheres at onset (trembling person falling off wall). Most common type is generalized tonic-clonic (historically grand mal)characterized with diffuse muscle contraction, rhythmic jerking, often have post-ictal state. • Partial seizures may also become generalized and turn into tonic-clonic • Juvenile myoclonic epilepsy is a type of generalized seizure disorder (kid making chicken wings) • Absence seizure • Others Manageme Management nt • Valproate (Festival) o Effective for all seizure types discussed above. One of the go-to agents o Binds VG Na channels, preventing sustained high-frequency firing and sustaining inactivation phase of neurons (open basket of sodium peanuts, with open lid “gates”) o Also affects other channels, ions, and neurotransmitters, notably elevating levels of inhibitory neurotransmitter GABA (taxicab colored palanquin elevated in the air) o Metabolized by CYP450 (ship with CYP 450 nameplate). o Adverse effects: ▪ GI adverse effects (ill emperor Atahualpa) ▪ Increased appetite & wight gain (Emperor’s girth) ▪ Tremor (trembling weapon) ▪ Rare but potentially fatal hepatotoxicity (cow with liver spot) ▪ Pancreatitis (pancreas sponge) ▪ Teratogen: causes neural tube defects and increases risk of spina bifida (tarantula shields; mother playing on pipe flute) • Topiramate (toupee) o Effective in many of the seizure types discussed above; not as effective as valproate or lamotrigine o Binds VG Na channels, preventing sustained high-frequency firing and sustaining inactivation phase of neurons (open basket of sodium peanuts, with open lid “gates”) o Allosterically binds to the GABA-A receptor (directly binding hands) o Metabolized by CYP450 (ship with CYP 450 nameplate). o Adverse effects ▪ Dose related somnolence & fatigue (tired soldiers) ▪ Confusion & cognitive slowing (soldier scratching head) ▪ Wight loss (cachectic soldier) ▪ Urolithiasis (kidney shaped wheel and cannonballs) ▪ Acute myopia & angle-closure glaucoma (closing angle on high-pressure tea-kettle). Must stop medication immediately. • Lamotrigine (llama) o Effective against many seizure types, including absence. o Binds VG Na channels, preventing sustained high-frequency firing and sustaining inactivation phase of neurons (open basket of sodium peanuts, with open lid “gates”) o Metabolized by CYP450 (ship with CYP 450 nameplate). o Adverse events ▪ Skin rash in up to 10%. ▪ 1%, especially children, may have SJS/TEN (red mask) ▪ Diplopia (cross-eyed llama) • Levetiracetam (Keflex) (elevator) o Effective against many seizure types; not used much against absence o Metabolized by CYP450 (ship with CYP 450 nameplate). o Adverse effects: ▪ Somnolence (sleeping person on elevator) 4.3 – “Seize the night”: Narro Narrow w spectrum anti anti-ep -ep -epileptics ileptics (Carbamazepine, phenyt phenytoin, oin, gabapent gabapentin, in, tiagabine, vigabat vigabatrin) rin) • Generally used to treat focal seizures (waitress with shaking arm). Note that narrow spectrum prescriptions may be used to treat generalized tonic-clonic seizures, but should be avoided in other generalized disorders, including JME, as may cause exacerbation. • Carbamazepine (classic car) o Ineffective against absence seizures and should be avoided in other generalized disorders o Binds VG dependent Na channels, probably after closure of inactivation gate (closed bags of chips). preventing sustained high-frequency firing and sustaining inactivation phase of neurons. o First line for treatment of trigeminal neuralgia (three gems on seize the night sign). Reduces pain in 80% of patients o Adverse effects ▪ Dose related diplopia (cross car headlights). Often occurs first ▪ Dose related ataxia (toppling stack of burgers) ▪ Rare: SIADH (inappropriately wet head). Due in part to increased responsiveness of collecting tubules to ADH causing dose related hyponatremia that develops over the first few months of therapy. ▪ Idiosyncratic blood dyscrasias • Leukopenia (12% children, 7% adults). May be transient or persistent. Doesn’t usually require immediate discontinuation • Fatal aplastic anemia, Fatal agranulocytosis (hourglass; falling level of granulocytes in anemia). Usually within 3-4 months of initiating therapy. WBC < 3000 or neutrophil < 1000 are indications for lowering dose or cessation. ▪ CYP450 inducer; drug interactions (license plate) ▪ Rare, potentially life-threatening DRESS syndrome (=drug reaction with eosinophilia & systemic symptoms). Can occur 2-8 weeks after exposure; px with fever, generalized lymphadenopathy, diffuse morbilliform rash, facial edema (waitress wearing spotted dress) ▪ Teratogenic (greaser’s spider jacket) Neural tube defects, esp. spinal bifida. May be implicated in fetal malformation of nails, distal phalanges, hypertelorism, characteristic facial features. ▪ Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) (mask). Much more common with HLA-B15 allele, which occurs almost exclusively in people of Asian ancestry; screening for this allele prior to initiating treatment recommended. ▪ Drug induced lupus (lupus wolf) • Phenytoin (classic tow truck) o Ineffective against absence seizures and should be avoided in other generalized disorders o Binds VG dependent Na channels, probably after closure of inactivation gate (closed bags of chips). preventing sustained high-frequency firing and sustaining inactivation phase of neurons. o Treat status epilepticus with benzos or phenytoin (Order Status at Ben’s Diner). Maintenance therapy is usually with IV phenytoin or fosphenytoin (tow truck under Order Status sign) ▪ If patient doesn’t respond, start IV phenobarbital (barbershop) o Adverse effects ▪ Dose related ataxia (toppling stack of burgers) ▪ Diplopia, nystagmus ▪ Low folate & megaloblastic anemia have been reported; clinical significance unknown (spilled salad) ▪ Gingival hyperplasia (bubble gum) ▪ Hirsutism & coarsening of facial features (especially rugged man) ▪ Drug induced lupus (lupus wolf) ▪ Rare, potentially life-threatening DRESS syndrome (=drug reaction with eosinophilia & systemic symptoms). Can occur 2-8 weeks after exposure; px with fever, generalized lymphadenopathy, diffuse morbilliform rash, facial edema (waitress wearing spotted dress) ▪ Rash. Patients who have rash to phenytoin are more likely to have with carbamazepine too ▪ SJS/TEN (mask). Much more common with HLA-B15 allele, which occurs almost exclusively in people of Asian ancestry; screening for this allele prior to initiating treatment recommended. ▪ Teratogenic (greaser’s spider jacket) Orofacial clefts, genitourinary defects, cardiac malformations (cleft trucker hat). ▪ CYP450 inducer; drug interactions (license plate) ▪ Altered bone and mineral metabolism & decreased bone density (osteoporotic axel). Related to increased induction of CYP450 combined with decreased Vitamin D catabolism. Suggest supplementation • Gabapentin, pregabalin (grab a pint) o Sometimes used as addon therapy for refractory focal seizures o Binds avidly to VG calcium channels; may inhibit inward calcium currents and attenuate NT release (calci-yum ice cream door blocked). No binding to GABA o Used more often to treat neuropathic pain (Frayed wire), including post herpetic neuralgia (Zeus’s Ice Cream), fibromyalgia (fiber bars), & painful diabetic neuropathy (diasweeties candy). o Adverse effects ▪ Dose dependent dizziness, sedation, ataxia (tall falling ice cream cone) • Vigabatrin o Irreversible inhibitor of GABA transaminase (transmission), which is normally responsible to GABA degradation. Results in sustained elevation of GABA levels in the CNS (elevated Cab-A), resulting in tonic inhibition of the CNS o Used as adjunctive treatment for partial seizures • Tiagabine o Inhibits GABA uptake, prolonging inhibitory action of GABA in the synaptic cleft (cab driver stuck outside of cab) o Used as adjunctive treatment for partial seizures 4.4 – “Seize the daydream”: Ethosuximide • Used to treat absence seizures (absences clipboard). Generalized seizures that occur most often in children, characterized by sudden momentary lapse in awareness accompanied by staring, blinking, or clonic jerks (kid gazing out window). Behavior returns to normal and patients will not typically remember anything. Usually last ~10s. Will typically present with 3 Hz spike wave complexes on EEG (kid in EEG/dunce cap sitting under “3 spikes” sign) • Ethosuximide (ethos) o Blocks t-type calcium channels in thalamic neurons, preventing sustained rhymical burst discharges occurring in that region (closed bottle of calci-yum chocolate milk; T- thermos for thalamic T-type neurons o Adverse effects ▪ Dose related GI distress (kid getting beat up) ▪ Lethargy, fatigue (sleeping student) ▪ Ethosuximide can cause fatigue, GI distress, headache, itching, SJS (“EFGHIJ” – per First Aid) • Valproate (Festival) o Highly effective in management of absence seizures. Used especially if there is also a h/o tonic-clonic seizures. • Lamotrigine (llamas) o Not quite as effective as valproate, but generally effective. 5.1 – “The Typical Impre Impressionist”: ssionist”: First generati generation on antip antipsychotics sychotics (hal (haloperidol, operidol, trifluoperazine, ffluphenazine, luphenazine, ch chlorproma lorproma lorpromazine, zine, thioridazine) Historical aside: Vincent van Gogh was a Dutch post-impressionist painter whose work is characterized by bold colors, expressive brushwork, and a variety of subjects, including landscapes, still life, portraits, and self-portraits. While highly influential on 20th century modern art, van Gogh was considered a madman and a failure during his lifetime, and only achieved fame & recognition after his death by suicide in 1890 at 37 yo. He suffered from psychotic episodes, depression, and delusions, and spent a period of his life in a psychiatric hospital in Saint-Rémy in southern France. In 1880s Paris, van Gogh ran in avant-garde art circles, where he apparently befriended Paul Gauguin; their friendship fell apart when van Gogh, angry at Gauguin following a fight, cut off his own ear. Van Gogh apparently had no recollection of this event afterward, suggesting an acute psychotic episode. Now on to the medical stuff. Physiology • Several NTs are involved in psychosis, including dopamine and serotonin. o FGAs target dopamine transmission, specifically bock D2 receptors in the mesolimbic & striatofrontal system (snapping double rope with D-rings) o 5HT-2A receptors are key in modulating release of both excitatory and inhibitory NTs, and are a main target of 2 nd generation antipsychotics. • Antipsychotics are highly lipophilic, highly protein & tissue bound, and consequently have a large Vd, leading to long half-lives (long tapering flag). Typically have half-lives of 20-40 hours, and many have active metabolites as well. Indications • Antipsychotics are used in many condition with characteristics of psychosis. While schizophrenia is the primary indication, may also be used in psychotic mania in bipolar, MDD with psychotic features, delirium, psychosis associated with Alzheimer’s or Parkinson’s, and drug induced psychosis • Schizophrenia is the primary indication for antipsychotic drugs. o FGA are generally effective at treating positive symptoms (hallucination, delusions, disorganized thoughts, or behavior) (positive angel sitting on van Gogh’s shoulder next to his dead ear – i.e. angel is “blocked”) o Not so effective at treating negative symptoms (apathy, flat affect, lack of energy) (negative devil on opposite shoulder is still audible) • Acute psychotic episodes, regardless of etiology, are generally managed with antipsychotics (patient running up angled roof). • Can be used to treat acute aggression or anxiety. In particular, psychosis is often associated with increased motor activity, heightened emotional arousal, anxiety (angry patient not wanting to share roof). • Manage motor tics of Tourette’s (marionette), although has fallen out of favor for other dopamine depleting agents Rx • Can be classified as high- or low-potency drugs. • Note the -azine ending of many names (starry gazing) • High potency include trifluoperazine, fluphenazine (person on roof trying to fly), haloperidol (halo around moon in painting) o High clinical potency = greater dopamine receptor binding. o Associated with less sedation, weight gain and anticholinergic activity o Higher risk of extrapyramidal adverse effects • Low potency include thioridazine (color theory wheel) & chlorpromazine (Color-pro paints) o higher histaminic & muscarinic activity with corresponding sedation & antimuscarinic effects o Lower incidence of extrapyramidal effects • Adverse effects (for all antipsychotics) result from effects on multiple receptors and NTs. Most of these effects are more prominent with FGAs than SGAs, or in high- or low-potency drugs; however, any adverse effects may be seen in any antipsychotics o QT prolongation, increasing risk for torsades des pointes (twisted streamers) o Can lower seizure threshold (shaking escapee). Should be used with caution in patients on other seizure exacerbating meds. More prominent with high potency rx (characters high up on roof): o Extrapyramidal symptoms are the major limiting factor in FGA use, and the incidence of such symptoms is the defining difference between FGA & SGA (patient trying to fly is wearing pyramid shaped newspaper hat with “Extra”) . Occur d/t D2 dopamine blockade in the nigrostriatal tract, which is normally involved in the control of muscle movement. Will most often present with initiation of treatment or changes in dosing; may include: ▪ Acute dystonia (i.e. sudden onset sustained muscle contractions); may occur within hours of treatment (observer with cocked head & rigid back). More common in young men on high-potency FGAs. Depending on muscle group may involve • Spasmodic torticollis • Oculogyric crisis with forced sustained elevation of the eyes • Arching of back and neck ▪ Akathisia (subjective restlessness with inability to is still) (critic knocking over chair); may occur within days. ▪ Drug induced parkinsonism with cogwheel rigidity, bradykinesia, masked facies, tremor (cogged wheels). Usually occur within weeks. Cannot be managed with levodopa, which may precipitate psychosis; instead, ▪ Tardive dyskinesia; abnormal choreoathetoid movements following months to years of use (escapee in carriage with newspaper hat sticking out tongue). Advanced cases may be irreversible, so want to catch early and decrease dose or change to SGA. ▪ Tuberoinfundibular blockade → hyperprolactinemia (person laughing milk out nose). More common with high-potency. Downstream effects include inhibition of GnRH release, resulting in central hypogonadism (galactorrhea, amenorrhea, impotence, ↓libido) ▪ Neuroleptic malignant syndrome (“Now More Spicy” chicken bucket). Occurs in patients extra sensitive to dopaminergic effects (patient is sensitive to friend’s antics & is laughing). • Treatment: Dantrolene (mm relaxant) (trampoline). Blocks RyR and prevents further release of calcium into muscle fibers (adult blocking Ryan from getting on trampoline). ▪ More common with high-potency FGAs, but can be seen with any antipsychotic meds. • Lead pipe rigidity (person holding onto pipe) • Altered mental status, fever, autonomic instability (crazy, sweating, and tachycardic) • Rhabdomyolysis (eating chicken). Watch for elevated CK. ▪ Note D2 dopamine blockade in the nigrostriatal tract is often accompanied by excess cholinergic activity. So may coadminister with rx with M1 antagonism effects (e.g. benztropine, diphenhydramine) to reestablish dopaminergic/cholinergic balance. More prominent with low potency rx o Systemic effects are most prominent with low-potency rx (painting with Color-Pro paints) o Antimuscarinic action (tea party in Café Terrace at Night): dry mouth & constipation common; blurred vision, urinary retention less common. Results from inhibition of central and peripheral muscarinic blockade. Symptoms significantly less or entirely absent with higher potency drugs. o Orthostatic hypotension d/t blockade of α-1 receptors (Siesta painting; extinguished α candle). Often accompanied by tachycardia, especially in the first days of treatment or with increased dosing. o Block H1 activity (bees around Sunflowers); can be highly sedating (may be utilized clinically with aggressive or agitated patients) (Bedroom in Arles painting) o Chlorpromazine: gray deposits in cornea and lens (corn yellow paint) o Thioridazine: retinal deposits (deposits on retinal palette). May cause browning of vision; advanced cases may look like retinitis pigmentosa. 5.2 – “The Atypical surrealist”: Second generati generation on ant antipsychotics ipsychotics (o (olanzapine, lanzapine, quetiapine, ari aripiprazole, piprazole, ziprasid ziprasidone, one, risperidone, cl clozapine) ozapine) Historical note: surrealism was a cultural movement developed in the aftermath of World War I, best known for juxtaposing uncommon imagery to create scenes to unnerving or illogical effect. These works drew on dreams and the unconscious as means of expressing a surrealist philosophy. Salvador Dalí was a Spanish Surrealist renowned for technical skill, precision, and striking and bizarre imagery in a variety of visual art forms. Themes prevalent in his work include dreams, the subconscious, sexuality, religion, science, and his personal relationships. Now on to the medical stuff. Atypical anti antipsychotics psychotics • Clozapine is the prototype (closet). Quetiapine, olanzapine, risperidone, aripiprazole, ziprasidone (“Quiet please, only whispering appropriate”; zippered dress). • MOA o SGAs block 5HT-2A receptors, which are key in modulating release of both excitatory and inhibitory NTs including dopamine, glutamate, GABA, NE, ACh release in the CNS (block cut out of serotonin cake). Serotonin signaling is also often involved in psychoactive substance use, e.g. LSD – a serotonin agonist (these paintings are pretty trippy) o Like FGA, block postsynaptic D2 receptors in the mesolimbic & striatofrontal system, although effect is less than in the FGAs (snapping double rope with D-rings). MOA is not completely understood; the degree of blockade of D2 receptors does not necessarily correlate to effects at other receptors throughout the body. • Indications o As with FGAs, primary indication is schizophrenia. SGAs are more effective in treating negative symptoms (devil and angel can both be heard; and that mustache – no flat affect here). o Adjunctive treatment for treatment resistant depression (difficulty opening wine bottle with masks) o risperidone can be combined with SSRIs for refractory OCD (person fixing crooked panel of Millet’s The Angelus; Dali was obsessed with this painting) o Motor tics of Tourette’s (funky marionette). • Adverse effects o Cause fewer of the “typical” extrapyramidal effects seen with FGAs, hence “atypicals” (newspaper hat patron). Of the SGAs, risperidone highest risk (person whispering, asking disruptive patron to leave) ▪ Elevated prolactin d/t Tuberoinfundibular D2 blockade (laughing milk out nose). Much more of a problem than with FGAs. Downstream effects include inhibition of GnRH release, resulting in central hypogonadism (galactorrhea, amenorrhea, impotence, ↓libido) ▪ Neuroleptic malignant syndrome (“Now More Spicy” chicken). More common FGAs but can be seen with any antipsychotic meds. • Lead pipe rigidity • Altered mental status, fever, autonomic instability (patron being intrusive, may have altered mental state) • Rhabdomyolysis (eating chicken). Watched for elevated CK. • Treatment: Dantrolene (mm relaxant). Blocks RyR and prevents further release of calcium into muscle fibers o H1 antagonists → sedation (bee swatter); especially clozapine & quetiapine o Orthostatic hypotension d/t α 1 antagonism (extinguished α candle); accompanied by tachycardia, especially in the first days of treatment or with increased doses. May be severe enough to warrant changing medication. o Antimuscarinic action (tea party painting): dry mouth, constipation common; blurred vision, urinary retention less common. Result from inhibition of central and peripheral muscarinic receptors. Clozapine has highest affinity (painting behind closet). Less antimuscarinic affinity than FGAs (partly obscured painting) o Unlike FGAs, can have significant metabolic syndrome: ▪ Weight gain (fat face). Mechanism not totally clear; evidence for ↑appetite & altered metabolism ▪ Dyslipidemia (elevated melting butter) ▪ Hyperglycemia (candy filled landscape) ▪ All SGAs cause to varying degrees (clozapine & olanzapine most, ziprasidone) (gal in zippered dress looking pretty slim) o QT prolongation, increasing risk for torsades des pointes (twisted streamers). Hypothesized to be d/t direct inhibition of cardiac potassium channels. o Clozapine specifically is infamous for the following, although others may cause as well (The Persistence of Memory inspired painting on closet) ▪ Agranulocytosis (hourglass). Absolute neutrophil counts must be routinely monitored. If ANC < 1500, change agents (has been reported in other SGAs as well) ▪ Fatal myocarditis or cardiomyopathy (surrealist heart) ▪ Lowered seizure threshold (shaking alarm clock). Also seen to lesser degree with other SGAs. 5.3 – “Money for Old Rope”: Par Parkinson kinson management (L (Levodopa, evodopa, carbidopa, entacap entacapone, one, tolcapone, sele selegiline, giline, ropinirole, pra pramipexole, mipexole, amanta amantadine) dine) • Parkinsonism (Park & Sons bank) characterized by “pill-rolling” tremor, bradykinesia, cogwheel rigidity (cogwheel safe door), and postural instability. Most common causes is Parkinson’s disease d/t degenerative loss of dopaminergic nn in the nigrostriatal pathway. Parkinson’s disease also has non-motor abnormalities, but most medical management is focused on motor symptoms. • Note that dopamine therapies are generally contraindicated in psychotic patients, d/t central dopamine control with these conditions (crossed out painting of Van Gogh) • Levodopa (coiled rope) o Most effective treatment for treatment of Parkinson’s motor symptoms. o Dopamine doesn’t cross the BBB (bank vault threshold). Levodopa (L-DOPA) is the immediate metabolic precursor to dopamine, and does cross the BBB (rope coiled, waiting to be used, on spool with L-shaped handle; can enter the vault). Decarboxylated to form dopamine by DOPA decarboxylase. Normally, 97% of L-DOPA converted to dopamine peripherally by intestinal DOPA decarboxylase. o Dopamine is also peripherally methylated to 3-O-methyldopa by catechol-O-methyltransferase (COMT). Central COMT metabolizes L-DOPA to 3-methoxy-tyrosine. o Adverse effects: ▪ Some consequences of peripheral conversion (hostages held in lobby = peripheral effects) • Cause GI distress (bound & nauseated hostage). Results in emetic effect d/t stimulation of the chemoreceptor trigger zone; tolerance usually develops after initiating therapy. • Peripheral conversion can also cause arrhythmias – tachycardia, ventricular extrasystole, postural hypotension, a-fib (unconscious bound woman) ▪ High doses can cause behavioral changes – anxiety, agitation, insomnia, confusion, hallucinations (central effects) (confused hostage). Reducing dose can be helpful in alleviating these effects. May also co-administer with atypical antipsychotic to block central dopaminergic effects. ▪ Long-term administration characterized by • Fluctuations in clinical response occur with increasing frequency with disease progression; this “wearing off” effect may result in parkinsonian symptoms nearing the end of a dosing period (e.g. akinesia, dyskinesia) (worn out end of rope inside vault) • Fluctuations may be unrelated to dosing; can cause on-off phenomenon: periods of akinesia alternating with periods of improved mobility, with timing unrelate to dosing (light flashing on and off; robber pointing to watch for chronic use) • With disease progression, therapeutic window narrows, causing motor fluctuations with even small changes in dose. Fluctuations become unpredictable (narrowing window to make escape). • Fluctuations will often be marked by significant dyskinesias in up to 80% of patients who are on levodopa for 10+ years. May include choreoathetosis of the face & distal extremities is the most common presentation (robber twisting to sneeze) • Carbidopa o Peripheral DOPA decarboxylase inhibitor (police car on periphery). Increases central bioavailability of levodopa (L-DOPA crooks with cranks escaping from lobby into vault). ▪ Does nothing to inhibit COMT, so only about 10% of L-Dopa crosses BBB (guard on intercom shooting L-crank). o Significantly decreases peripheral Adverse effects of levodopa (freeing hostages), but exacerbates neuropsychiatric effects (not releasing delirious hostage) • Entacapone, tolcapone (entrance guy & tall guy are Al Capone bandits) o COMT inhibitors (inhibiting clerk from using intercom) o Increases plasma half-life of levodopa. Used especially as patients begin to experience motor fluctuations with levodopa/carbidopa. ▪ Entacapone only active peripherally (Al Capone gangster at entrance to vault) ▪ Tolcapone active peripherally and centrally (tall Al Capone gangster entering vault and impeding guard with intercom). o Only effective combined with levodopa; ineffective as monotherapy. o Adverse effects ▪ Tolcapone: hepatotoxicity (liver-shaped clip on gun) • Selegiline (sledgehammer) o MAO-B inhibitor. Recall MAO-B selectively metabolizes dopamine (black mouse eating dope rope in vault). Selegiline enhances levodopa availability centrally; used in conjunction with levodopa – has little effect on parkinsonism alone. • Direct dopaminergic receptor agonists o Ropinirole (double ropes in a roll) is a D2 receptor agonist; pramipexole (Robber with big pecs) Preferentially agonizes D3 receptors. Ergot alkaloids (e.g. bromocriptine) are the originals, but are rarely used nowadays d/t Adverse effects o Important role as first line monotherapy for Parkinson’s. Associated with fewer long-term response fluctuations and dyskinesias from levodopa. ▪ May also be added with a dopaminergic agonist to delay inevitable end-of-dose akathisia o Also used to treat restless leg syndrome (escapee climbing ladder and shaking legs) o May have more severe psychiatric Adverse effects than; particularly impulse control disorders (e.g. gambling, compulsive shopping, hypersexuality) (“rock and roll” tattoo) o Contraindicated with h/o psychotic illness • Amantadine (manatee) o Enhances effect of endogenous dopamine by increasing synthesis and release & inhibiting reuptake (extra dope rope crate broken open) • Benztropine & trihexyphenidyl (tri-hexagon logo on Benz outside) o Centrally acting antimuscarinics. Help restore balance of dopaminergic & cholinergic effects on basal ganglia. Can help improve tremor & rigidity of Parkinson’s, with no effect on bradykinesia (car is trembling).