-
chloroform, cyclopropane, ethylene
- inhaled anesthetics - volatile halogenated hydrocarbons
- not used anymore.
-
halothane:
- inhaled anesthetics - volatile halogenated hydrocarbons
- not used anymore.
- highest blood/gass partition coeff (2.3) = more insoluble in gas than blood, therefore more molecules needed to dissolve in blood before increase PP significantly, and so arterial tension of gas and brain conc increases less rapidly.
- 15-20% metabolized; mostly to trifluoracetic acid (TFA). clin sig: halothane hepatitis, nephorotox
-
diethyl ether
- inhaled anesthetic - volatile ether
- not used anymore.
-
enflurane
- inhaled anesthetic - volatile halogenated ether
- not really used anymore.
-
methoxyflurane
- inhaled anesthetic - volatile halogenated ether
- not really used anymore.
- 40-50% metabolized; mostly to fluoride. clinical sig: nephrotox, hepatotox
-
isoflurane
- inhaled anesthetic - volatile halogenated ether
- one of 3 most commonly used ethers now (+ sevoflurane and desflurane)
- higher Blood/Gas Partition Coeff (1.4) = more insoluble in gas than blood, therefore more molecules needed to dissolve in blood before increase PP significantly, and so arterial tension of gas and brain conc increases less rapidly.
- 0.2% metab'd, mostly to trifluoracetic acid (TFA). low potential for tox.
-
fluroxene
- inhaled anesthetic - volatile halogenated ether
- not really used anymore.
-
sevoflurane
- inhaled anesthetic - volatile halogenated ether
- one of 3 most commonly used ethers now (+ isoflurane and desflurane)
- low-med Blood/Gas Partition Coeff (0.6) = very insoluble in blood, gets to brain very fast b/c fewer molecules needed to increase partial pressure in blood.
- 3% metabolized; mostly to fluoride (short lived). Low potential for toxicity.
- But increased degradation by soda line (C02 absorbent in gas machine) to vinyl ether (Cpd A) --> nephrotox to rats
-
desflurane
- inhaled anesthetic - volatile halogenated ether
- one of 3 most commonly used ethers now (+ sevoflurane and isoflurane)
- low Blood/Gas Partition Coeff (0.42) = very insoluble in blood, gets to brain very fast b/c fewer molecules needed to increase partial pressure in blood.
- very resistant to metabolism (0.02%). high molecular stability, no sig tox
-
nitrous oxide
- inhaled anesthetic - inorganic gas
- incomplete: rapid onset and rapid recovery.
- important as adjuvant to volatile agents (so that can use less of the volatile drug), but use is less because:
- 1) green house gas
- 2) induces post-op N&V
- 0.0004% metabolized...to nitrogen. toxicity of free radicals?
- low Blood/Gas Partition Coeff (0.47) = very insoluble in blood, gets to brain very fast b/c fewer molecules needed to increase partial pressure in blood.
-
xenon
- inhaled anesthetic - inorganic gas
- not used much - too expensive.
-
thiopental
- intravenous anesthetic - barbiturate
- rapid induction of hypnosis ("arm-brain circulation time", less than 20 seconds)
- facilitates inhibitory neurotransmission via GABAa receptors
- redistribution to other tissues -> pt wakes up 5mins after single IV bolus.
- but when tissues are saturated after infusion/repeated doses, t1/2 elimination = 11 hours.
- SE: hypotension (Pearl Harbor experience), resp depression, histamine release, arterial occlusion.
-
propofol
- intravenous anesthetic - most popular one now (alternative to thiopental)
- used for sedation, induction, and maintenance of anesthesia (total IV anesthesia). smooth induction...pleasant dreams.
- also antiemetic
- facilitates inhbitory neurotransmission via GABAa receptors
- rapid induction of hypnosis like thiopental, even more rapid awakening after IV bolus (3mins)
- but rapid liver metab (t1/2 = 1h), no redistb --> useful for infusion
- SE: resp depression and apnea, hypotension (more than thiopental), injection pain, sepsis (formulation in egg lecithin and soy bean oil, supports bacterial growth)
-
ketamine
- intravenous anesthetic - only IV anesthetic that is anesthetic + analgesic. phencyclidine-derivative. psychomimetic drug "Angel Dust"
- dissociative anesthesia: conscious, but cannot process/respond to sensory input (catatony, amnesia, analgesia)
- little cardioresp depression, maintains airway reflexes, bronchodilator properties...unpleasant dreams.
- for induction of anesthesia in trauma or shock, battlefield surgery, analgesia in burn patients, i.m induction in children.
- MoA: antagonist at NMDA receptors (excitatory glutamate)
- rapid induction after IV bolus (but slower than thiopental and propofol)
- causes increased cerebral bf, oxygen consumption, ICP...dangerous when ICP high (similar to volatile anesthetics).
- hepatic metab t1/2 3h.
- SE: post-op disorientation, illusions, vivid dreams.
-
pentazocine
- opioid, agonist at K receptor, weak antagonist or partial agonist at u receptor.
- opioid with lower abuse potential
- high doses cause dysphoric and psychotomimetic effects (confusion, hallucinations)
- does not block resp effects of other opioids (e.g. morphine)
- has ceiling effect to analgesia
- can precip withdrawal if given to a pt dependent on a u agonist
- can be used in pts allergic to morphine
- (K receptor agonists more effective analgesics in women than men)
-
nalbuphine
- opioid, agonist at K receptor, antagonist at u receptor
- similar to pentazocine, but with less dysphoric effects
- (K receptor agonists more effective analgesics in women than men)
-
buprenorphine
- opioid, partial agonist at u receptor (limited intrinsic activity), antagonist when used with a full agonist
- analgesia similar to morphine
- can precip mild withdrawal if given to pt receiving u agonist long-term
- unknown whether there is a ceiling to resp depression (not major problem)
- when d/c'd, can cause withdrawal similar to morphine but not as severe.
- injection = analgesic; SL = tx of opioid dependence
- metabolized by CYP3A4
-
codeine
- opioid, "weak"
- converted to morphine by CYP2D6 (polymorphic gene: ultra-rapid=more SE and toxicity, slow 5-10% Caucasians=not as much analgesia as expected).
- Drug interactions with CYP2D6 can be significant.
- - inhibitors (amiodarone, cimetidine, SSRIs, venlafaxine, methadone)
- - inducers rare
- antitussive at dose >15mg q4-6h
- chronic use in severe renal dysfunction can lead to accumulation of toxic metabolites (likely switch to hydromorphone)
- - morphine-6-glucuronide = active metabolite: more analgesia, but more toxicity
-
oxycodone
- opioid, agonist at u and K receptors
- recent high rate of abuse, but weaker than heroin in terms of high
- CYP3A4 interactions:
- - inhibitors: macrolides, azoles, protease inhibitors, cimetidine, grapefruit, dilt
- - inducers: cbmzp, phenytoin, phenobarb, primidone, rifampin, St John's wort
-
tramadol
- opioid, centrally acting analgesic, weak u agonist
- blocks reuptake of 5-HT and NE...not scheduled as narcotic yet
- not studied in peds
- reduces seizure threshold - increases risk of seizures (caution if recent head trauma, epilepsy)
- parent compound: serotonergic effects (inhibition of CYP2D6/decrease activity INCREASES parent coompound, increase risk of serotonin syndrome esp if pt is on other serotonergic drugs SSRI, SNRI, TCA)
- --> e.g. avoid tramadol with SSRI, but ok to give together if pt aware of sx to look for
- active metabolite via CYP2D6: opioid actions (weak u agonism)...genetic variations and drug interactions affect analgesia
- CI with MAOI
- renal: decrease dose of CrCl <30ml/min
- SE: dizziness, N/V, constipation, h/a, somnolence.
-
morphine
- opioid, strong u agonist
- morphine-6-glucuronide: active, toxic metabolite
- renal dysfxn: accumulation of toxic metabolite --> SE
-
hydromorphone
- opioid, strong u agonist
- safe for renal dysfxn (palliative, end-of-life)
- less SE than morphine in some pts (sedation, N, constip)
- given po, sc, im iv, pr
-
meperidine
- opioid, u agonist and NMDA antagonist, 5-HT reuptake blocker
- rapid onset, short duration, not for chronic pain, but for acute pain/alternative in cases of morphine allergy
- NOT to use in renal dysfxn: toxpic metabolite normeperidine accumulates.
- serotonin syndrome can occur if also taking antidepressants (TCA, SSRI, SNRI)
- CI with MAOI
- safe in morphine allergy
- cardiovascular SE: antimuscarinic (tachycardia), negative inotropic effects.
-
fentanyl
- opioid, strong u agonist
- transdermal: onset is delayed initially...wait for 6 days before adjust dose.
- not for opioid naive pts or acute pain
- not studied in peds
- heat increases absorption from patch
- if pain irritates skin: use steroid spray or wait 1min for alcohol in patch to evaporate.
-
methadone
- opioid, agonist at u and delta receptors, NMDA antagonist
- blocks reuptake of 5-HT and NE
- used tor treatment of opioid dependence, good for both pain and addiction, or pts in pain with hx of addition
- works better for difficult-to-treat pain e.g. cancer/neuropathic (b/c of activity at other receptors)
- long t1/2 - wait 4 days before changing dose
- resp depression possible
- SE: usual opioid SE as well as QT prolongation, swearing, antichol effects, arrhythmias, MI, seizures
- interactions: CI with amiodarone (b/c methadone QT prolong + amio pro-arrhythmic = increase risk of sig vent arrhythmias that cause death)
- other interactions: cleared through CYP3A4, CYP2D6 inhibitor, serotonin syndrome
-
COX non-selective
- inhibit both COX-1 and COX-2
- risk of GI ulceration
- inhibit platelet aggregation
-
COX-2 selective
- limit GI ulceration because homeostatic GI protection is mediated by COX-1.
- older COX-2 NSAIDs showed increased CVD rates...COX-2 inhibitors do not inhibit platelet aggreg.
- newer evidence: Swedish cohort - COX-2 inhibs no increased risk of MI, stroke, or heart failure without prior CVD dx.
- Increased risk of afib, but also seen in traditional NSAIDs too.
-
ASA
- NSAID
- irreversibly blocks COX enzymes by acetylation
- low doses (<325mg) preferntially blocks COX-1 on platelets...blocks TXA2 production, and decrease platelet aggregation and vasodilation. Duration of effect is related to platelet lifetime = 7 days.
- Therefore, stop ASA 7-14 days before major surgery.
-
acetaminophen
- analgesic and antipyretic activity, but no anti-inflamm
- raises threshold to painful stimuli
- MoA
- 1) weakly inhibits COX-1 and COX-2 by reducing cyclooxygenase to inactive form and block prostaglandin synth.
- 2) inhibit COX-3, found in high concs in brain and heart...but unlikely to be main mechanism because only a weak producer of PGE2.
- 3) activate descending endogeous opioid pathways + synergistic action at level of spinal cord.
- 4) endogenous serotonergic descending pain inhibitory pathway originating from periaqueductal gray in midbrain.
- 5) inhibition of NO pathway...which facilitates transmission of nociception.
- 6) metabolite of acetam blocks reuptake of endocannabinoid...indirectly activating cannabinoid CB1 receptors and --> analgesic, antipyretic
- 7) metabolite activates transient receptor potential vanilloid 1 in vitro...antinociceptive.
- SE rare at therapeutic doses: rash, neutropenia, thrombocytopenia.
|
|
