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).
alendronate (Fosamax) dosing
70mg PO qwk
risedronate (Actonel) dosing
35mg PO qwk
steroid use, low calcium intake (<1000 mg /d, 1200 if 50+), vitamin D deficiency (1000 U??), lifestyle (alcohol/tobacco)
zolendronate (Reclast) info
once-yearly treatment (every other year for prevention)
vitamin D pathway
typically skin produces cholecalciferol (D3), liver converts this to calcifediol (25-hydroxyvitamin D3), kidney converts this to calcitriol (1,25-dihydroxyvitamin D3 -- ACTIVE FORM).
vitamin D MOA
calcitriol is essential in the regulation of calcium and phosphorus (facilitates absorption, decreases excretion, regulates osteoclasts/osteoblasts, negative feedback loop c PTH).
vitamin D IND
vitamin D monitoring
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
parathyroid hormone MOA
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.
parathyroid hormone IND
parathyroid hormone SE
long term tx (>2yrs) unknown. BBW for osteosarcoma.
RANKL inhibitors MOA
when RANKL binds to the RANK receptor on osteoclasts, there is increased bone breakdown/resorption. denosumab inhibits this.
RANKL inhibitors PK
SC. long T1/2 (dosed q6mo by health professional).
RANKL inhibitors IND
osteoporosis (Prolia -- not first line), bone mets of solid tumors (Xgeva)
RANKL inhibitors CI
hypocalcemia (correct prior to therapy)
RANKL inhibitors SE
skin reactions including eczema
denosumab (Prolia) dosing
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)
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)
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).
NSAIDs in renal pts
COX2 selective may be safer for older pts c worry of renal injury (COX1 constricts AA)
NSAIDs GI risk
ketorolac highest GI risk. ibuprofen lowest GI risk.
NSAIDs and HTN
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 inhibitors MOA
xanthine oxidase converts typoxanthine to xanthine to uric acid. the inhibitors prevent this.
xanthine oxidase inhibitors PK
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.
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).
inhaled anesthetics solubility
solubility (as well as vascularity of tissue) has effects speed of onset: desflurane (lowest/fastest induction+elimination) < sevoflurane < isoflurane < halothane (highest/slowest induction+elimination).
inhaled anesthetics IND
general anesthesia, severe refractory status asthmaticus
inhaled anesthetics CI
family or personal hx of malignant hyperthermia (inhaled anesthetics are one of two triggers -- the other is succinylcholine)
maintenance of physiologic homeostasis, amnesia, analgesia, neuromuscular blockade.
IV anesthetics MOA
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.
IV anesthetics PK
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.
IV anesthetics IND
induction/maintenance of general anesthesia, sedation, intubation
IV anesthetics SE
hypotension (best indicator of oversedation), respiratory depression, addiction. propofol/etomidate pain on injection, etomidate adrenal suppression (use as single bolus only).
IV anesthetics dosing by population
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.
IV anesthetics GABA mimetics vs NMDA antagonists
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).
most common IV anesthetic
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)
local anesthetics MOA
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).
local anesthetics nerve differences
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).
local anesthetics SE
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.
local anesthetics PK
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 bonus
local anesthetics are weak bases, so acidic environments (abscess/infection) ionize drug and make anesthetizing more difficult.
NONdepolarizing neuromuscular blockers MOA
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).
mivacurium hypotension (due to histamine release). pancuronium tachycardia (due to vagolytic effects).
NONdepolarizing neuromuscular blockers bonus
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!)
DEpolarizing neuromuscular blockers MOA
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).
DEpolarizing neuromuscular blockers PK
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!)
hyperkalemia, muscle pain (due to transient fasciculations), bradycardia (more pronounced in kids, if concerned prevent by pretreatment c atropine)
DEpolarizing neuromuscular blockers bonus
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.
analine analgesics MOA
has analgesic and antipyretic effects but no antiplatelet/antiinflammatory effects, most likely through inhibition of PGE2 centrally and COX enzymes peripherally
analine analgesics PK
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).
analine analgesics IND
analine analgesics SE
increased risk for asthma
NSAIDs vs APAP
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.
acetaminophen at risk
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)