GI and Endocrine Part 2

3.2 – “The Natural h/o Osteoporosis”: Bisphosphonate, raloxifene, calcitonin, denosumab • All of the rx here are useful in the treatment of osteoporosis by preventing or decreasing bone resorption. Will cause a moderate increase in bone mineral density & decreased fracture risk (TA is drawing out a fresh piece of chalk to replace the fractured boneshaped piece). • Mostly directed against osteoclasts (destructive kids in class) rather than osteoblasts (don’t disturb the builders) • PTH (PhD) stimulates osteoblasts to express RANKL (Receptor activator of nuclear factor κ-Β ligand) → osteoclast activation (RANKL = crank-drill; builder giving to kid, & kids drilling out bone). • Bisphosphonates o Alendronate, pamidronate, zoledronate, others (“Donate” box for -dronate) o Actions: ▪ Have a chemical strucutre similar to pyrophosphate (2 Ⓟ coins in the box). Attach to hydroxyapatite in bone (T-rex appetite). Osteoclasts that try to latch onto bone bind instead to the bisphosphonate & are unable to adhere to bone (kid is stuck in box so cannot destroy things). ▪ decrease development & recruitment of osteoclast precursors (lady with 2 Ⓟ coins blocking next class from entering. ▪ Induce osteoclast apoptosis (popping Apatosaurus balloon). ▪ Net result: decreased bone lost and stable or increased bone mineral density. o Indications: ▪ First line treatment for osteoporosis ▪ Alendronate, zoledronate used for hypercalcemia d/t ↓bone resorption (elevated ice cream). • Especially important in hypercalcemia of malignancy, a common cause of severe hypercalcemia requiring acute treatment (fossil with lots of crabs) ▪ Paget’s disease • uncontrolled osteoclast resorption with secondary disorganized bone formation (disorganized human skeleton • Helps prevent high bone turnover, preventing pain & progressive deformity o Adverse effects ▪ Upper GI effects (e.g. acid reflux, esophagitis, esophageal ulcers). Can be avoided by drinking lots of water & staying upright after taking (corrosion of dinosaur neck) • May administer IV (much less frequent administration) with severe intolerance. ▪ Rare: osteonecrosis of the jaw (crumbling jawbone). More likely with IV administration ▪ Can cause hypocalcemia d/t inability to resorb bone (fallen ice cream cup) • Selective Estrogen Receptor Modulators (SERMs) o Estrogen receptors are found throughout bone. Activation inhibits osteoclast differentiation. Estrogen therapy can prevent & treat postmenopausal osteoporosis (); however, not recommended d/t increased risk of breast cancer and other adverse effects. o Instead, use SERMs, such as Raloxifene (relax sign). o SERMs have estrogen agonist activity in bone (inhibiting osteoclast differentiation [slowing down the classmates] → net resorption is decreased, slowing postmenopausal osteoporosis), CV system, & blood lipoproteins. Estrogen antagonists activity in uterus & breast (↓risk of breast cancer) • Denosumab (dino-suit) o Monoclonal antibody against RANKL (antibody shaped spines) o As effective as bisphosphonates o Used in treatment of postmenopausal osteoporosis • Calcitonin – “tones down calcium” (curator) o Peptide hormone released by thyroid parafollicular cells → ↓serum calcium & phosphate by actions in bone & kidney (curator pointing down) Not as effective as bisphosphonates, so not first line. o Inhibits osteoclasts, and thereby decreases bone resorption (curator grabbing destructive kid). o Promotes Ca excretion by the kidney by inhibiting resorption (pouring ice cream down leg). o Used in hypercalcemia of malignancy (crabs on fossil) o Useful in Paget disease (misaligned skeleton) o Adverse effects: ▪ Hypocalcemia (fallen ice cream) 3.3 - "PthD in Paleontol Paleontology": ogy": Teriparatide, Vita Vitamin min D, Cinacalcet Cinacalcet,, Sevelamer • Treat osteoporosis by increasing bone formation & bone mineral density for the duration of treatment. • Parathyroid hormone (PTH) (PthD) o Regulates bone formation & resorption. Effects: ▪ Stimulates preosteoblast maturation to osteoblasts (osteo-builders = osteoblasts; PthD teaching builders). ▪ Stimulates osteoblasts to express RANKL (receptor activator of nuclear factor κ-Β ligand) (RANKL = crank-drill; builder giving drill to kids, and kids drilling away bones). RANKL binds to RANK on osteoclasts, increasing osteoclast proliferation & differentiation. Appropriately activated, osteoclasts increase bone resorption & turnover and release phosphate & calcium from bone, allowing bone development & systemic metabolic function (destructive class kids = osteoclasts; kids releasing both Ⓟ shaped shell fossils and calcified bones). Note that this activation is indirect. ▪ Net effect of endogenous PTH: ↑bone resorption o PTH increases kidney calcium resorption and phosphate excretion (PthD is gathering calcified bones and dropping P-shaped fossils at kidney-shaped pit). Net effect: ↑calcium levels & ↓phosphate levels o PTH increases activity of 1-α-hydroxylase in the kidney →↑production of 1,25-dihydroxy-vitamin D (calcitriol) (Calci-TRON robot = calcitriol; robot head with 1 antenna = 1-α-hydroxylase; PthD is activating robot) o High serum Ca feeds back to parathyroids, inhibiting PTH production and release via calcium-sensitive receptors (calcium backup on conveyer belt blocking the PthD from the field). • Vitamin D o Two forms: D2 (ergocalciferol) from plants (earth friendly battery under tree). D3 (cholecalciferol) is obtained from sun or dairy products (solar calciferol cart being pulled by dairy cow). Either form can be administered therapeutically. o Activated by: ▪ 1) Liver hydroxylates vitamin D to 25-hydroxy-vitamin D (robot body added to D battery in liver-barrow) ▪ 2) In kidney, 1-α-hydroxylase converts to 1,25-dihydroxy-vitamin D (calcitriol) (#1 on head to remind that’s the last step). o Activated vitamin D functionally acts as a steroid (lipophilic, intracellular receptor). Has a number of downstream effects: ▪ Calcitriol increases phosphate & calcium resorption in the kidney (robot picking up bones & phosphate shells at kidney pit) ▪ Potent stimulant of intestinal calcium & phosphate absorption (robot picking up bones & phosphate shells at colonic truck) ▪ Stimulates maturation of osteoblasts → ↑bone formation (robot teaching osteo-builders), and stimulates osteoblast production of RANKL → activation of osteoclasts. Potent stimulator of both; net effect is bone turnover (robot delivering crank drills to class). ▪ Inhibits PTH production (rolling over tent, trapping PTH) o Indications for exogenous administration ▪ Osteoporosis ▪ Topical treatment can be given for psoriasis (kidney worker with pads) ▪ Can be used for long-term management of hypocalcemia (robot stabilizing seizing scientist) • Hypocalcemia can cause seizures, paresthesias, muscle cramps, trismus, tetany (shaking structure, clenched fist) • Commonly caused by hypoparathyroidism (falling PhD badge; undone bowtie for thyroid surgery damage to PTH glands). Vitamin D will be less effective d/t decreased activation of kidneys o Note that inactivated vitamin D will be ineffective in kidney failure d/t inability to activate (cracked kidney tower). In this case, give as calcitriol (robot stabilizing kidney shaped water tower). o Deficiency ▪ Osteomalacia in adults, rickets in children (robot stabilizing rickety tower) ▪ May see in chronic renal failure, dietary deficiency, ↓sunlight exposure. o Adverse effects ▪ Teriparatide & Vitamin D therapy can both cause hypercalcemia (raised calci-yum ice cream) • Teriparatide (TA) o Recombinant PTH. Effects include: ▪ Net effect when given in low-intermittent doses increases bone formation (in contrast with the effects of endogenous PTH). • Stimulations maturation & increases anabolic function of osteoblasts (TA teaching osteo-builders). • Does not activate osteoclasts (TA not dealing with classmates) ▪ Increases kidney resorption of calcium, dumping phosphate (TA is gathering calcified bones and dropping P-shaped fossils at kidney-shaped pit). ▪ Increases calcitriol production (TA helping build robot o Used in treatment of osteoporosis (fresh piece of calcified chalk) o Adverse effects: ▪ Teriparatide & Vitamin D therapy can both cause hypercalcemia (raised calci-yum ice cream) • Cinacalcet (worker calculating calcium) o Calcimimetic; activates calcium sensing receptor in parathyroid gland → ↓PTH production. Useful to treat hypercalcemia d/t primary or secondary hyperparathyroidism (cinacalcet worker calculating the bone buildup going into the parathyroid tent). • Sevelamer (shoveler) o Non-absorbable phosphate binding polymer that binds Ⓟ in the GI tract, decreasing phosphate absorption (shoveler in truck) o Used to treat hyperphosphatemia d/t CKD 3.4 – “The C Court ourt of Sone He Henge”: nge”: Gluc Glucocorticoids ocorticoids • Cortisol (endogenous glucocorticoid), aldosterone (mineralocorticoid), & DHEA (androgen) all released from adrenal (head druid wearing adrenal cap). Here we focus on effects of glucocorticoids, either endogenous or exogenous (moon face). Exogenous formulations include dexamethasone, fludrocortisone, prednisone, budesonide (-sone suffix, hence sone henge) • Effects are mediated by widely distributed cytosolic glucocorticoid receptor (receptor scepter in outer scepter); enters the nucleus & acts as transcription factor at glucocorticoid receptor elements (GREs) (activated scepter in the inner circle, representing the nucleus; has many effects, pictured as blue squiggles). Effects include: o Upregulate inhibitor of PLA2 (inhibited A-frame catapult A2). ▪ PLA2 releases arachidonic from cell membranes → metabolism to several inflammatory compounds. By inhibiting this, GCs block COX (prostaglandin synthesis) (bat) & LOX (leukotriene synthesis) (lacrosse stick) o Inhibits NFκB (nuclear factor kappa-Β), inhibiting activation of lymphocytes by inhibiting proinflammatory cytokines (inhibited N-Flame Krossbow). ▪ End effect: ↓recruitment & activation of T & B cells (blocked T-cell knight and antibody archer). ▪ Decreased neutrophil recruitment by causing demargination & ↓synthesis adhesion molecules. Results in circulating neutrophilia (i.e. an acute rise in WBC count) (congregation of neutrophilic first responders). This will present as apparent elevation of white counts, but will increase risk of infection. o Rapidly reduce peripheral lymphocytes by ↓Ig synthesis, stimulation of apoptosis, & redistribution into spleen, lymph nodes, & bone marrow (T-cell knit, helper T-cell squire, & antibody archer, eosinophil slingshot dropping into chasm). ▪ Hence utility as immunosuppression (transplant rejection prevention, autoimmune disorders) (eclipsed inflammatory sun), ▪ inflammatory conditions (gout, RA, asthma, IBD) (cracked antibodies on standing stone). ▪ Eosinophil decrease; useful in atopic conditions (eosinophil slingshot dropping into chasm) o Metabolic effects ▪ Recall that glucocorticoids are essentially the body’s stress hormones. As such, will upregulate the systems needed to maintain metabolic & circulatory function in times of stress. ▪ Can cause hyperglycemia (elevated candy jar held by statue) • Peripheral antagonism of insulin, i.e. insulin resistance (locked welcome mat). • Stimulate gluconeogenesis via production of gluconeogenesis enzymes (liver shaped bag producing candy). • Increase glycogen synthesis → increased glycogen storage (candy filled liver-shaped candy jar) ▪ Will not see these homeostatic effects in adrenal insufficiency (fainted druid with cracked moon face on ground). Can see collapse of circulatory function, leading to shock and even death, with even minor noxious stimuli. • Exogenous glucocorticoids must be given to treat acute adrenal insufficiency (extra moon face being extended). May also prevent in cases of primary adrenal insufficiency (e.g. Addison’s disease). • Chronic exogenous glucocorticoid use causes adrenal cortical atrophy d/t negative feedback on the pituitary →↓ACTH production (secondary adrenal insufficiency) (shriveled adrenal hat on fallen man) o Note: oral budesonide often given in a delayed release preparation targeting the ilium; especially useful in Chron’s because it has high topical potency & fewer systemic adverse effects than other glucocorticoids d/t high first pass metabolism. o Adverse effects (altar and moon statue) ▪ ↓overall white counts → immunosuppression; ↑risk of infection • Reactivation of latent infections ▪ Promote peripheral catabolism, proteolysis in skeletal muscle, lipolysis. (falling ham & donuts). ▪ Cushing’s syndrome can occur with chronic glucocorticoid use (cushion; demonstrated in moon statue) • Results in adipose redistribution with central adiposis (fat stomach) • Myopathy, muscle wasting, proximal weakness (scrawny arms) • Inhibit fibroblast proliferation → weakened skin, capillary damage (fine cloth with purple striae) • Direct inhibition of osteoblasts → osteoporosis & fractures (osteoporotic altar). Chronic, can cause osteonecrosis, classically aseptic necrosis of the hip. o Chronic users should take supplementary calcium & vitamin D • Psychosis: hypomania, confusion, hallucinations (cracked and cross-eyed moon head) • immunosuppression (cane). o May reactivate latent infections, e.g. TB (TB cacti with reactivation in upper lobes) • Hypokalemia d/t mineralocorticoid cross reactivity (banana peel) 4.1 - "JAK Stat and the Beanstalk": Growth Hor Hormone, mone, Meca Mecasermin, sermin, Octreot Octreotide, ide, Pegvisomant Physiology • Growth hormone (GH) is an anterior pituitary secreted peptide (beans spilling from front of burlap pituitary sack). Secreted with prolactin, which has significant homology. • Effects: o enters circulation and binds GH receptor → Dimerization and recruitment of receptor-associated JAK tyrosine kinase → intracellular JAK/STAT pathway (Tire swing for tyrosine; JAK/STAT “jacks up cell growth”) o Effects on carbohydrate, protein, & lipid metabolism, mainly mediated through IGF1 produced in the liver (rock).– acts similar to insulin with similar tyrosine kinase receptor (“welcome Inside” mat). In contrast with insulin, which stimulates sugar and fat storage, IGF1 is responsible for long bone growth (mat getting lifted by lanky bean sprout). ▪ High circulating levels with pubertal growth spurt (mat growing up). ▪ Required in childhood and adolescence for normal adult size & proper lean body mass & bone density () o GH has anabolic effects in muscle directly → muscle mass (striated muscle leaf on bulky vine). Catabolic effects in adipose tissues. Essentially shifts mass from fat to muscle (dumping donut jar for adipocyte lipolysis). • Excess serum GH most commonly seen in hormone secreting pituitary adenoma. Most commonly seen in adults → acromegaly (characterized by deep voice, Large hands and feet, Increased risk of colorectal polyps/cancer, Coarse facial features, impaired glucose tolerance or insulin resistance). Seen less commonly in children; before closure of growth plates, can cause gigantism. First line treatment is trans-sphenoidal resection. Rx • Somatotropin (exogenous GH) o Indications ▪ GH deficiency • Abnormal height increase + abnormal serum GH levels with appropriate stimulation (short kid holding up bean). • May be primary (genetic, developmental) or acquired (pituitary trauma, intracranial tumors, infection, radiation). ▪ Idiopathic short stature. Somewhat controversial. $$$ ▪ Increasing growth in Prader Willi syndrome (Padre Willi – missing father gene) →↓body fat and ↑lean muscle mass ▪ Increasing growth in Turner’s syndrome (turning X girl) o GH reduces insulin sensitivity, but IGF-1 exerts insulin like effects so the effects usually balance out. • Mecasermin(sermon) o recombinant IGF-1 o Indications ▪ Small number of children have growth failure d/t deficiencies in the IGF-1 rather than growth hormone. ▪ patients who are unable to respond to GH d/t resistance (e.g. anti-GH antibodies, receptor mutations). o May see hypoglycemia d/t exerting insulin effects (falling candy) • octreotide o Indications (generally counteract secretory effects of many hormone secreting tumors): ▪ Medical therapy for gigantism/acromegaly by inhabiting secretion of GH (octagon stop sign held up to giant). ▪ VIPoma & serotonin-secreting carcinoid tumors as well (crab sign over stop sign for “VIP customers only”). Generally used to reduce secretory diarrhea in these conditions, especially in incomplete resections. ▪ glucagonoma (ridiculously huge giant glucagon packet). Usually presents was weight loss & necrolytic migratory erythema ▪ insulinoma (big “welcome inside” mat – from excess). Fasting hypoglycemia ▪ Gastrinoma, with Zollinger-Ellison syndrome (massive gas tank) ▪ Can control bleeding of esophageal varices (decreased portal blood flow & variceal pressure). MOA poorly understood (exposed variceal pipes) o Adverse effects ▪ GI adverse effects (N/V, abdominal pain), steatorrhea d/t decreased pancreatic secretions & decreased gallbladder secretion (ill looking townsperson standing on yellow stool) • Cabergoline & bromocriptine o D2 receptor agonists o treat acromegaly by inhibiting secretion of GH from the pituitary (burglar with broomstick, climbing down two dope ropes). Also inhibit prolactin release (more effective than GH inhibition) (sac holding magic beans). • Pegvisomant: o GH Receptor antagonist; inhibits GH receptor preventing downstream effects (ants picking up beans off tire swing). May increase GH secretion d/t lack of feedback, and provoke adenoma growth. 4.2 - "Wat "Water er Hazard": Posterior pituitary regulation (ADH, DDAVP, ADH Receptor Antagonists) ADH (aka vvasopressin) asopressin) • responsible for regulating tonicity of plasma by regulating free water absorbed by the nephron ( water hazard). • Collecting duct is the site of ADH action & water resorption, as well as mineralocorticoid action & Na resorption (ADH boy). ADH released by posterior pituitary (water jug on posterior). ADH has antidiuretic properties and vasopressor properties. Act via two subtypes of receptors o V1 receptors are responsible for vasopressor activity. GqPCR, activates PLC → IP3 + DAG →↑intracellular Ca2+ (V1 hole on Q shaped green). Found in vascular smooth muscle cells → vasoconstriction & increased BP (angry golfer constricting golf club) o V2 receptors are GsPCR → activation of adenylyl cyclase →↑cAMP (V2 hole on S shaped green). Found on basolateral membrane of the collecting duct (location). Causes translocation of aquaporin 2 to the apical membrane of luminal cells → increased water permeability → reabsorption of free water (water boy at collecting duct translocating pure water). o There are extrarenal V2 receptors found in the vascular endothelium (endothelial tile). Activation →↑ release of coagulation factor VIII and vWF from endothelial cell Weibel-Palade bodies → increased platelet aggregation (8 ball on von Wille brand pool table). ADH activation of V2 stimulates factor 8. • Administered exogenously, directly constricts mesenteric arterioles, which can be useful in the management of esophageal variceal bleeding d/t reduction in portal pressure (bulging mucosal colored golf bag with blue veiny golf clubs) • DDAVP (desmopressin acetate) o Long acting synthetic analog of ADH (saving desert mobile). o High specificity for V2 receptor, which means minimal pressor activity (V2 engine). o Indications: ▪ Activity at vascular V2 Rs can be used to increase vWF release from vascular endothelium, useful for treating von Willebrand deficiency (scratched felt on pool table). • Von Willebrand disease will often present with increased bruising & mucosal bleeding (e.g. GI, oropharyngeal, uterine) (cue ball beating up player) ▪ Factor 8 deficiency (hemophilia A) (missing 8 ball & A-frame). • Usually presents with intramuscular bleeding, prolonged bleeding, hemarthrosis (bleeding knee) ▪ Night enuresis d/t ↓urine production (wet mattress) o May cause hyponatremia (falling peanuts) Diabetes insip insipidus idus • inability to concentrate urine (endless insipid trickle of a fountain shaped like a urinator) • Central (not producing sufficient ADH) (brain shaped dehydrating sand traps). Can be caused by number of processes (radiation, tumor, AI process) (crawling thirsty golfer). o Can administer DDAVP • nephrogenic (not responding to ADH) (brain & kidney shaped dehydrating sand traps). Usually d/t blockade by pharm agents, occasionally genetic (frustrated golfer ignoring water boy). Lithium is a common cause of nephrogenic DI (“lift-ium” balloons). Generally resolves with discontinuation of drugs. o Thiazide diuretic (pasty thigh guy) → volume reduction → proximal resorption of sodium & water, decreasing dependence on collecting duct activity. Treats polyuria & polydipsia. However, diuretics can decrease lithium clearance, increasing risk of toxicity. o Amiloride (K+ sparing diuretic) (almond snack cart) can treat lithium-induced nephrogenic DI. Blocks lithium entry into CD cells. o NSAIDs (fire extinguisher) Decrease PG production that normally antagonize ADH. SIADH (syndro (syndrome me of inappropri inappropriate ate ADH) • Overproduction of ADH resulting in excess water retention & hyponatremia (inappropriate water boy). May result from CNS disorders, traumas, ectopic production in lung cancer, or certain pharmacologic agents. • Treat with V2 receptor antagonisms, including conivaptan, tolvaptan (Vaporizer model water gun for -vaptan suffix). o Promote free water excretion by inhibiting aquaporin translocation. Can be used in conjunction with hypertonic saline & free water restriction. • Be careful in correcting hyponatremia too rapidly. May cause hypernatremia or, in severe cases, central pontine myelinolysis (osmotic demyelination syndrome) → irreversible CNS damage (salty peanuts being thrown at head) o Maximum rates of correction: less than 10 mEq/L at 24h and less than 18 mEq/L at 48 hours. Monitor sodium levels closely • Demeclocycline – a tetracycline – can be used to treat SIADH by interfering with V2 receptor activity. MOA not known. Not first line. Neuro & psych Drugs 1. 2. 3. 4. 5. Sedatives & hypnotics Anesthetics & analgesics Antidepr Antidepressants essants & anxiolytic anxiolyticss Mood st stabilizers; abilizers; ant antiepileptics iepileptics 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).