pharm - MSK info.txt

similar to pyrophosphate (PPi), a natural circulating inhibitor of mineralization, just modified (carbon for oxygen) to better penetrate and attach to bone matrix.

two actions: first their structure allows for enhanced calcium binding, and they also prevent bone breakdown (via inhibition of osteoclast activity, mevalonate pathway).

low oral bioavailability

Paget's disease, osteoporosis

hypocalcemia, vitamin D deficiency, hypoparathyroidism, severe renal insufficiency (monitor serum Cr)

dysphasia, nausea, heartburn, esophageal irritation (to reduce, take first thing in the morning c 8oz H2O, NPO p x 30min, upright p x 30min). rare osteonecrosis of the jaw, atypical subtrochanteric/femoral shaft fracture (due to antiresorptive effects).

70mg PO qwk

35mg PO qwk

steroid use, low calcium intake (<1000 mg /d, 1200 if 50+), vitamin D deficiency (1000 U??), lifestyle (alcohol/tobacco)

once-yearly treatment (every other year for prevention)

typically skin produces cholecalciferol (D3), liver converts this to calcifediol (25-hydroxyvitamin D3), kidney converts this to calcitriol (1,25-dihydroxyvitamin D3 -- ACTIVE FORM).

calcitriol is essential in the regulation of calcium and phosphorus (facilitates absorption, decreases excretion, regulates osteoclasts/osteoblasts, negative feedback loop c PTH).

osteoporosis/osteomalacia, hyperparathyroidism

measure calcifediol (25-hydroxyvitamin D3) -- less variables influence its levels, therefore its a more accurate indicator of intake/production

hormone secreted by the thyroid gland that inhibits osteoclasts (and may also increase osteoblasts), in essence enhancing calcium retention in bone and "toning down" serum calcium levels

endogenous hormone that acts to increase serum calcium, decrease serum phosphate, and increase osteoclast activity via RANKL (increased bone remodeling, increased resorption). also stimulates calcitriol production in the kidney.

severe osteoporosis

long term tx (>2yrs) unknown. BBW for osteosarcoma.

when RANKL binds to the RANK receptor on osteoclasts, there is increased bone breakdown/resorption. denosumab inhibits this.

SC. long T1/2 (dosed q6mo by health professional).

osteoporosis (Prolia -- not first line), bone mets of solid tumors (Xgeva)

hypocalcemia (correct prior to therapy)

skin reactions including eczema

60mg SC q6mo

BMD > 2.5 SD below young adult mean. severe osteoporosis = osteoporosis + hx of fx.

binds microtubules, suppressing immune functions including decreased inflammatory mediators, decreased neutrophil adhesion/chemotaxis, and decreased phagocytosis of urate crystals by neutrophils.

narrow TI (CYP3A4 / P-GP substrate)

gout

hepatic or renal impairment c concomitant CYP3A4 or P-GP inhibitor use (higher rates of toxicity)

diarrhea, myelosupression, myopathy, neuropathy

block cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins and leukotrienes, helping to reduce inflammation.

pain, inflammation, fever, acute gout

NSAIDs + ASA (block antiplatelet effect -- give non-coated ASA 1 h prior to NSAID)

naproxen lowest CV risk.

CNS (HA, tinnitus, dizziness, confusion, hallucinations), GI (pain, dyspepsia, N/V, ulcers/bleeding), CV (fluid retention, HTN), renal dysfunction, pulmonary (asthma), rash

200-800 mg q4-6h, MDD 1200 fever, 2400 normal, 3200 osteoarthritis

375-500mg q12h

7.5-15mg qd

200mg qd

COX 1/TxA2 thought to play maintenance/protective role (stomach mucous), COX 2/PGI2 expressed primarily in inflammatory cells (selective blockade helps prevent inflammation while maintaining COX1 stomach protection). However, COX2 inhibits platelet aggregation while COX1 promotes it (so COX2 selective isn't always ideal, may lead to CV events).

COX2 selective may be safer for older pts c worry of renal injury (COX1 constricts AA)

ketorolac highest GI risk. ibuprofen lowest GI risk.

NSAIDs can increase BP (though effect varies widely) -- take in smallest dose for least amount of time. If on antihypertensive/diuretic and become uncontrolled, consider switch to CCB (least affected by NSAIDs).

lower serum uric acid levels by increasing excretion (UA filtered freely at glomerulus, 90% reabsorbed in proximal tubule. probenecid competes with this transporter).

half life varies based on dosage (500mg = 3-8h, >500mg = 6-12h)

renal insufficiency, kidney stones, peptic ulcer, blood dyscrasias, age >60.

kidney stones (increased excretion of UA -- encourage hydration). also HA, GI, rash.

250mg BID x1wk, then increase to 500mg BID. continue up to MDD of 2-3g/d if needed (target sUA <6mg/dl)

begin 1-3wks post-acute attack. when initiating therapy, all uric acid-lowering therapies (ULTs) have the ability to actually increase gout flares (co-prescribe with colchicine 0.6mg qd/BID or low dose NSAIDs for prophylaxis -- begin 2-3 wks prior and continue for up to 6 months).

xanthine oxidase converts typoxanthine to xanthine to uric acid. the inhibitors prevent this.

allopurinol half life T1/2 is 1-3h, but active metabolite T1/2 is 18-30h. hypouricemic effect onset 1-2 days, peak 1-2 wks, duration 1-3 wks.

gout, renal stones

febuxostat + azathioprine (inhibits metabolism, increases toxicity), febuxostat + mercaptopurine (inhibits metabolism, increases toxicity)

discontinue drug at the first sign of a rash! (could be start of severe hypersensitivity rxn such as SJS, TEN). febuxostat has higher rate of cardiovascular events than allopurinol.

200-800mg/d qd-QID. adjust c renal impairment.

40-80mg qd. do NOT need to adjust c renal impairment.

buildup of xanthine/hypoxanthine may cause feedback inhibition of purine synthesis (purines -> hypoxanthine).

muscle relaxant (but not a paralytic). binds to GABA-B receptors, opening K+ channels. K efflux results in hyperpolarization, inhibiting depolarization. (secondary mechanism = inhibiting calcium channels).

poor lipid solubility (so doesn't cross BBB -- intrathecal administration if needed there)

muscle spasticity (MS, spinal cord lesions, CP)

CNS (drowsiness, vertigo, slurred speech, ataxia), neuromuscular (weakness, hypotonia), cardiac (CP, dyspnea, palpitation, syncope), urinary.

avoid abrupt withdrawal due to severe spasticity, rhabdomyolysis, fever. OD can mimic brain death.

central inhibition of neurotransmitter release (inhibition of presynaptic NE release via autoreceptor negative feedback loops)

clonidine oral/TD, dexmedetomidine IV

HTN (not first line), sedation, (glaucoma)

severe bradyarrhythmia, hypotension

alpha-2 agonists + MAOIs (MAOIs prevent NE breakdown, can lead to potentiation and extreme HTN)

oral use dry mouth, sedation, bradycardia, hypotension.

binds to GABA-A receptors, opening chloride channels. Cl influx causes hyperpolarization, inhibiting depolarization.

newer drugs very low amount undergoes metabolism (route of elimination = exhalation). more vascular tissues quick to take up/release drug, less vascular the opposite (can act as a sink, prolong the anesthesia).

solubility (as well as vascularity of tissue) has effects speed of onset: desflurane (lowest/fastest induction+elimination) < sevoflurane < isoflurane < halothane (highest/slowest induction+elimination).

general anesthesia, severe refractory status asthmaticus

family or personal hx of malignant hyperthermia (inhaled anesthetics are one of two triggers -- the other is succinylcholine)

hypotension, respiratory depression, halothane hepatic damage (very rare), sevoflurane kidney damage.

maintenance of physiologic homeostasis, amnesia, analgesia, neuromuscular blockade.

GABA mimetics bind to GABA-A receptors, opening chloride channels. Cl influx causes hyperpolarization, inhibiting depolarization. NMDA antagonists inhibit glutamate (excitatory NT) release by blocking glutamate's binding to NMDA receptors, inhibiting the subsequent calcium influx / cell depolarization.

fast onset (begin working within one "arm to brain" circulation time). however, vessel-rich organs also quickly uptake drugs reducing their levels in the blood (and therefore the brain) in a matter of minutes. therefore, termination action of single bolus is more the result of redistribution than metabolism/elimination.

induction/maintenance of general anesthesia, sedation, intubation

hypotension (best indicator of oversedation), respiratory depression, addiction. propofol/etomidate pain on injection, etomidate adrenal suppression (use as single bolus only).

larger doses needed for alcoholics (even as little as one drink/day), children (greater mg/kg needed). lower doses for elderly, sick, those taking opioids.

GABA mimetics do not have analgesic properties, cause apnea, and lower cerebral blood flow / ICP. NMDA antagonists do have analgesic properties, do not cause apnea, and increase cerebral blood flow / ICP (bad for those with brain injury).

propofol (favorable recovery profile, short elimination half life, less prolonged sedation/nausea then pentothal).

water-soluble prodrug, causes less injection site irritation than propofol though suffers from lack of familiarity/comfort among practitioners.

preferred when vasodilation and cardiac depression are undesirable (least risk of hypotension -- use with severe cardiac disease or acute trauma/blood loss). higher rates of postoperative nausea.

dysphoric (produces unpleasant sensations/hallucinations -- commonly coadministered c benzodiazepine), causes a dissociative state, SNS activation (incr. HR/BP therefore less hypotension risk), and bronchodilation (good for intubation of pts c severe bronchospasm like asthma)

bind voltage-gated sodium channels, inhibiting AP propagation. work on the intracellular side so must be able to cross cell membrane (increased lipid solubility = bigger/faster/longer effect).

large-diameter nerves and myelinated nerves both more difficult to block, require higher doses and are blocked for shorter durations (autonomic smallest/nonM therefore easiest, motor largest/M therefore hardest, sensory intermediate however have higher basal rate so signaling actually blocked earlier than motor).

CNS toxicity (numbness/tingling, tinnitus, blurred vision, AMS, seizure, coma), CV toxicity (heart block, VT, VF especially bupivacaine) -- both more common with accidental intravascular injection. pain on injection (initially activated Na channels). intraneural injection nerve damage.

onset time/duration of action both dose dependent. can also be improved by low-dose epinephrine (also reduces bleeding, but additional risk of tachycardia/HTN)

local anesthetics are weak bases, so acidic environments (abscess/infection) ionize drug and make anesthetizing more difficult.

cause muscle relaxation/paralysis. the NONdepolarizers competitively antagonize ACh at the NMJ. partial blockade decreases strength (vs complete). selective for skeletal muscle (no effect on smooth/cardiac muscle -- also do not affect consciousness).

paralysis (surgery, intubation)

conscious patient

nondepolarizing muscle relaxants + inhaled anesthetics (prolonged effects). mixing nondepolarizing muscle relaxants (synergistic effects).

mivacurium hypotension (due to histamine release). pancuronium tachycardia (due to vagolytic effects).

degree of paralysis can be measured with nerve stimulator -- partial = small twitch c TOF fade, compete = no contraction. zero contractions with train of four test will not respond to reversal medication, will only cause side effects (bradycardia, salivation/mucous, bronchospasm, N/V/D, urination -- also OD causes paradoxical reparalyzes!)

cause muscle relaxation/paralysis. DEpolarizers irreversibly bind postsynaptic ACh receptors, locking sodium channels open / depolarization (contraction not held b/c sarcoplasmic reticulum sucks up internal Ca after initial contraction/fasciculation). this also results in an efflux of potassium, typically raising sK levels 0.5-1 mEq/L (normal 3.5-5).

shortest acting paralytic drug currently available (onset 45 sec, duration 4-5 min). metabolized by pseudocholinesterase (can't be reversed with anti-cholinesterases -- rarely someone is pseudocholinesterase deficient, and duration of action can be >12h!)

intubation, ECT

conscious patient, risk of hyperkalemia (renal failure) or hyperresponders (esp burn pts, spinal cord paralysis pts, muscular dystrophy pts), myotonic dystrophy (prolonged effect), malignant hyperthermia (c volatile anesthetics)

hyperkalemia, muscle pain (due to transient fasciculations), bradycardia (more pronounced in kids, if concerned prevent by pretreatment c atropine)

degree of paralysis can be measured with nerve stimulator -- partial = small twitch c NO TOF fade (not competitively bound -- does fade with phase 2 blockade / multiple doses), compete = no contraction.

has analgesic and antipyretic effects but no antiplatelet/antiinflammatory effects, most likely through inhibition of PGE2 centrally and COX enzymes peripherally

CYP2E1 enzyme pathway basis for acetaminophen toxicity (CYP2E1 metabolizes APAP to NAPQI, which is toxic. typically reduced by glutathione/GSH, however when GSH stores are depleted injury can occur).

pain, fever

increased risk for asthma

APAP more selective for CNS, different COX binding (NSAIDs act at COX site, APAP acts at peroxidase site), APAP inhibited by hydroperoxide (produced by macrophages/platelets, likely why it has no antiinflammatory/antiplatelet effects)

toxic dose 10x greater than therapeutic dose. tx targeted at replenishing GSH stores by giving NAC, a precursor.

Chronic alcoholism -> increased 2E1 activity -> faster generation of NAPQI. Low GSH stores due to young age or malnutrition. Reduced liver conjugation leaving more to be metabolized by 2E1.

bind to opioid receptors (G-protein coupled) located in the brain and spinal cord. The main opioid receptor is the Mu receptor, of which there is over 100 polymorphisms (variation in response! -- may also be incomplete cross tolerance between opioids)

pain, cough, diarrhea, dyspnea

decreased LOC, elderly, hepatic/renal impairment, addiction hx

opioids + sedatives (respiratory depression)

respiratory depression, NV, pruritis, urinary retention/constipation, miosis, truncal rigidity, sphincter of Oddi spasm.

hydrocodone/acetaminophen, 2.5-10mg hydrocodone PO q4-6h PRN

oxycodone/acetaminophen, 2.5-10mg oxycodone PO q6h PRN

ER oxycodone, 10mg PO q12h

tramadol, 50-100mg PO q4-6h PRN

apnea/hypoventilation/hypoxia, miosis, decr LOC, track marks

rhinorrhea/lacrimation, yawning, chills/piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, V/D, anxiety/hostility

does not cross BBB, so useful for peripherally mediated SE (like constipation) w/o reducing analgesic effects

Mu1 = sedation, analgesia, euphoria. Mu2 = constipation, respiratory depression.

hydrocodone, hydromorphone, morphine, oxycodone

fentanyl TD, ER morphine, ER oxycodone, methadone

ONLY FOR CONTINUOUS PAIN CONTROL FOR AN EXTENDED PERIOD (not PRN). do not cut/crush/chew/dissolve tablets (risk of OD due to faster release -- alcohol can also speed release from capsules).

"gold standard" -- metabolites include morphine-6-glucoronidate (more potent, renally cleared so adjust dose if needed).

pro-drug metabolized to morphine by 2D6 (genetic variability / interactions). don't use in kids (URMs)

morphine 1, hydromorphone 10, fentanyl 80

BBW seizures, serotonin storm. Nucynta (tapentadol) is a more potent version that is not metabolized by glucuronidation and does not mess with CYP450 enzymes.

titrate slowly to effect (full effect takes 3-5 days). BBW pts tolerant to opioids may be incompletely tolerant to methadone, QT prolongation.

spontaneous breakdown (no hepatic/renal needed). atracurium and cisatracurium (NNBs -- mivacurium pseudocholinesterase-metablized).

300-800mg TID-QID

400mg q4-6h PRN

200-400mg q4-6h PRN

600mg QID x 7-14d