Pharm Flashcards
phase 1 reactions
oxidation, reduction, hydrolysis
phase 2 reactions
conjugation
oxidation and reduction occur via what
cytochrome p450
how does cytochrome p450 work
hydroxylation, dealkylation, deamination, desulfuration, epoxidation, dehalogenation
inducers p450
phenobarbital and phenytoin
inhibitors p450
amiodarone and CCB
what is conjugation
conjoins hydrophobic drug molecules with polar moities to increase solubility and renal clearence
morphine metabolism
metabolized in liver to form M3G and M6G
M3G inactive, M6G is potent and can’t be cleared in renal disease
Rate of metabolism
rate = Q(Cin - Cout), Q blood flow to liver
hepatic extraction ratio
ER = Cin-Cout/Cin
clearence equation
Q * ER
if a drug has a high extractino ratio, what does clearance depend on
Q, blood flow to liver
GA decreases hepatic blood flow
less important in drugs that have low extraction ratio
examples of tissue clearance
esmolol, succ, remi - ester hydrolysis in tissue and plasma
drugs that undergo butylcholinesterase/pseudocholinesterase metabolism in plasma
succ, mivacurium, chloroprocaine
what undergoes nonspecific ester hydrolysis in muscle and intestine
remi, atracurium
hofmann degradation
plasma, cis
major protein binding for anesthesia drugs
albumin and alpha 1 acid glycoprotein
free fraction
ratio of unbound drug to total amount of drug,
free raction of 1 means 100% of drug is free in plasma - would not be impacted by changes in protein conc
decrease in protein binding results in an increase in the conc of free form of drug, artifically decreased Vd
zero order kinetics
occurs at constant rate, rate independent of conc of drug
first order kinetics
dose dependent, rate of clearance proportional to conc, log
3 compartment model
body has central plasma compartment, rapid equilibrating comp (vessel rich like brain and GI) and slow equilibrating compartment (vessel poor like fat)
IV injection –> all in plasma —> rapid distribution phase, down conc gradient into surrounding tissue –> slow distribution phase, equilibrate with slow uptake tissue –> elimination
where do epidural opioids have site of action
outside of epidural space in dorsal horn
two main processes that interfere w opioid ability to reach CSF from epidural space
clearance of drug into plasma, partioining of drug into other tissues
dependent on lipid solubility
highly lipid soluble drugs (fentanyl, sufentatil) reach ____ peak concentrations in CSF
lower, compared to hydrophilic drugs like morphine
lipophilic drugs partition into epidural fat, more rapidly cleared into plasma which occurs in dura matter
epinephrine reduces clearance rate bc reduces dural blood flow
why don’t spinal lipophilic opiates cause resp depression
move out of CSF into epidural fat so limited bioavail at spinal cord rostral to site
intrathecal bioavailability of epidurall administered LA ____ with lipophilicity
increase , opposite of opioids
hyperbaric solutions, how to make them denser
greater density than csf, glucose
achieve considerable spread
travel to most dependent part of spines
isobaric
limited subarachnoid spread , not affected by gravityu
more profound motor block and more prolonged duration
three most important factors in determining neuraxial spread
baricity, position, dose
drug tolerance refers to changes in what 2 things
potency (higher effective dose)
effectiveness (decreased maximal effect)
4 key characteristics of drug tolerance
- reversible, once exposure to drug dc
- dependent on dose and frequency of drug exposure
- variable time course and extent of tolerance development between different drugs
- not all drug effects develop same amt of tolerance
dispositional/metabolic tolerance
repeated use of a drug reduces amount of drug available at target tissue
alcohol, opiates, barbiturates
accelerated drug clearance due to induction of enzymes
reduced responsiveness tolerance
when repeated use of drug alters nerve cell function, days/weeks to develop
caffeine
increased receptor activation by agonistic drugs –> receptor downregulation
reduction in receptor activations due to antagonism results in receptor upregulation
behavioral tolerance
repeated drug use reduces effect in environemnt where administered, learned behaviors
tachyphylaxis
not dose dependent, neurotransmitter depletion
to be excreted drugs need to be more _____
hydrophilic
to be reabsorbed drugs need to be more ______
lipophilic
two types of biotransformation
phase I nonsynthetic and phase II synthetic
what are phase I reactions
oxidation, reduction, hydrolysis
what are phase II reactions
conugation reactions
glucuronyl transferase, sulfotransferase, transacylases, glutathione transferase, acetylases, ethylases, methylases
total clearance equation
clearance = volume * rate constant
three processes of renal excretion
glomerular filtration, active secretion, passive reabsoprtion
net renal excretion
equals amount filtered at glomerulus plus amount secrete minus amount reabsorbed
= U * V/P
U is concentration, v = volume of urine p=plasma conc
two ways drugs can alter by two main mechanisms
increasing or decreasing cardiac output, displacing the drug from protein binding sites
naloxone MOA
binds to opiate receptors and blocks effect of narcotics
flumazenil MOA
blocks effects of alc/benzos at GABA receptor
ACh inhibitors MOA
antagonize breakdown of Ach molecules
Opiate agonist-antagonist compounds MOA
agonists at kappa=opiate receptor and antagonists at mu opiate receptor
serotonin syndrome
mental status changes, muscle twitching, excessive sweating, shivering, fever
inhaled anesthestics are affected by ?
central catecholamine levels
anaphylaxis
antigen-antibody, type I hypersensitivity rxn, antigen binding to IgE antibodies on the surface of mast calls initials release of various chemical mediators
anaphylactoid rxns
resemble anaphylaxis but IgE does not mediate them , clinically indistringuishable
local anesthestic allergy
ester - common, amide - rare, usually related to PABA preservative
ephedra
potential interactions with cardiac glycosides, MAOIs, oxytocin, MI, stroke, hypertension, tachy, arrythrmias
echinacea
hepatotoxicity
feverfew
inhibit platelets
garlic
potentiate warfarin, heparin, aspirin
ginger
potentiate anticoagulant effects, inhibit thromboxane synthetase
ginkgo biloba
potentiate nsaids, warfarin, decrease effects of anticonvulsants, lower seizure threshold, hyphem and bleeds
ginseng
sleepiness, hypertonia, edema, hypoglycemia, tachy, HTN, mania, SJS, epistaxis, inhibition of platelet aggregation
goldenseal
paralysis, htn, electrolyte abnormalities
kava-kava
potentiate barbituates, benzos, ethanol, increased suicide risk, decreased mac, hepatotxicity, hallucinations
licorice
HTN, hypoK, edema, renal, hypertonia
saw palmetto
headaches, GI
st john’s wort
interact with MAOIs, prolonged anesthesia, photosensitivity, restlessness, dizziness, fatigue
valerian
barbituates, benzo withdraw syndrome, prolonged effects of anesthesia
mechanism of anesthetic gases
enhance inhibitory receptors (GABA and glycine) and dampen excitatory pathyways (nicotinic and glutamate)
suppresiom of nociceptive motor responses w/in spinal cord and supraspinal suppresion causing amnesia
MAC increases (decreases in potency)
hyperthermia, stimulants, chronic alcohol, infants aged 6-12m
mac decreases
hypothermia, hypoNa, opioids, barbituates, alpha 2 blockers, ca2 blockers, acute alcohol, pregnancy, prematurity, aging
____ partition coefficient = ____ solubility = ____ rate of induction
____ partition coefficient = ____ solubility = ____ rate of induction
blood gas coefficient for des
0.4
blood gas coefficient for sevo
0.6
blood gas coefficient for iso
1.4
speed of induction slowest to fastest
iso –> sevo –> des
solubility highest to lowest
iso –> sevo –> des
boiling point highest to lowest
sevo/en > halothane > iso > des > nitric
vapor pressure highest to lowest
Nitrous > des > halothane > iso > en > sevo
MAP ____ with use of all volatile agents except halothane
decreases, decreases SVR
nitrous unchanged or increased MAP
HR ____ with all volatile agents at a MAC of 0.25 for iso, 1 for desflurane, 1.5 for sevo
increases
all volatile anesthestics sensitize myocardium to ____ and _____ myocardial contractility
epi and depress contractility
effect of gas on TV and RR and MV
decrease TV, increase RR, little effect on MV
PaCO2 increases
blunt vent stimulation caused by hypoxemia and hypercarbia
decrease FRC, cause bronchodilation
gas effect on cerebral blood flow and CMRO2
increase blood flow, decrease cerebral metabolic rate for oxygen (except nitrous with increases CMRO2)
but inhibit autoregulation (iso maintains it the best)
Iso effect on CSF
no effect on CSF production, decreases resistance to CSF absorption
des effect on CSF
increases CSF production without affect absoprtion
ICP with volatile
increased ICP, counteracted by hypocapnia
blunted by narcotics
gases ____ amplitude and ____ latency of SSEPs
decrease and increase
EEG tracings with gas
more gas, more amplitude and synchrony of EEG
ED50/MAC
50% do not move in response to stimulus, 1 SD is about 10% of the MAC value
iso mac
1.15
sev mac
2
des mac
6
pain is transmitted by a what system
3-neuron system
At periphery, noxious stimuli mainly received and tramsitted by
A beta, A delta, C fiber
First order neurons
first order neurons synapse with 2nd order neurons where
dorsal horn spinal cord
second order neurons travel up spinal cord via
dorsal column and spinothalamic tract and synapse with 3rd order in thalemus —> cerebral cortex —> pain
bradykinin
macrophages and plasma kininogen, activates nociception
serotonin
from platelets, activates nociception
histamine
from platelets and mast cells - vasodilation, edema, pruritis
prostaglandin
COVX pathway, sensitizes nociception
leukotriene
LOX pathway, sensitizes nociception
H+ ions
tissue injury, ischemia, hyperalgesia
cytokines/TNF/interleukins
from macrophages, snesitive nociception
adenosine
from tissue injury, activates nociceptors, hyperalgesia
glutamate
injured nerve terminals, activates nociceptors
substance P
injured nerve terminals, activates macrophages and mast cellsn
nerve growth factor
macrophages, stimulates histamine and serotonin release
major receptors activated by opioids
mu, delta, kappa
G protein coupled receptors - cAMP
located at periphery, dorsal horn, brainstem and cortex
three major mechanisms of action of opioids
inhibiton of presynaptic Ca2+ influx (depolarizes, inhibits release of neurotransmitters)
increases postsynaptic K+ efflux deploarizes and inhibits cellular signal transmission
activation of descending inh pain pathway via inihibito of GABAergic receptors in brainstem
peripheral Mu
decreased GI secretions, biliary spasm, pruritis, muscle rigidity, urinary retention
mu1
supraspinal
decreased GI transit, prolactin release, catalepsy
mu2
spinal and supraspinal, resp depression, decreased GI transit, cardiovascular effects
Mu3
decreased inflammation
kappa peripheral
decreased ADH, sedation
kappa1
spinal, antipruritic
kappa3
supraspinal
delta peripheral
resp depression, decrease GI transit, urinary retention
delta1 and 2
1 - spinal, 2 - supraspinal, 1 - dopamine turnover
MOA barbituates
depress nerve synapses in reticular activating system, inibit excitatory neurotransmission (acetylcholine and NMDA) and enahnce inhibitor neurotransmission like GABA
GABA receptor is a ____ channel
chloride ion channel, increases chloride ion conductance when GABA binds and membrane hyperpolarizes
barbituates on cerebral physiology
dose dependent cerebral vasoconsition and cerebral metabolic rate
reduce ICP and blood flow
preserve autoregulation
dose dependent EEG depression
minimal effect on SSEP and MEP
dose dependent depression of BAEP
neuorprotection for focal cerebral ischemia (not global)
barbituates good for this type of surgery
space occupying cranial lesions
barbituate effect CVS
depression of medullary vasomotor center vasodilates periphery
decreased preload
decrease contractility
tachycardia
resp effects barbituates
resp depression, decreased MV, decreased response to hypercap and hypoxia, airway obstruction, bronchospasm/laryngospasm
contraindication barbituates
porphyria
hypnotic effects propofol
agonism of beta subunit of GABA in CNS
inhibits Ach release in hippocampus and prefrontal cortex
inhibit NMDA subtype of glutamate receptors
propofol effect on ICP
decrease 30-50%, decreases CMRO2 and CBF
propofol effect on myocardial blood flow and oxygen consuption
decreases both so supply and demand remains the same
euphoria mechanism propofol
increased dopamine in nucleus accumbens
etomidate mechanism
potentiation of GABAa receptors, increases cl ion conduction leading to neuronal hyperpolarization and depression of reticular activating system
etomidate endocrine side effects
inhibits 11-beta-hydroxylase (cholesterol to cortisol), can lead to adrenal insufficiency for up to 8 hours after dose
etomidate CNS effects
reduces CBF and ICP due to cerebral vasoconstriction
can look like seizures on EEG
decreased IOP
etomidate and heme effects
inhibits platelet function
benzo MOA
enhance inhibitory neurotransmission via GABA receptors
alpha 1 - sedation, amnesia, anticonvlusion
alpha 2 - anxiolysis and muscle relaxation
benzo receptor affinity
lorazepam > midaz > diazepam
ketamine MOA
within thalamus and limbic system, binds NMDA receptors, nonceompetitive antagonism
catalepsy, high amplitude slowing of EEG
where else can ketamine bind
my opioid receptor
sigma opioid resulting in dysphoria
miscarinic and nicotinin receptors producing dose dependent potentiation of paralytics
ketamine CNS effects
increase ICP, increase CBF
precedex MOA
selective alpha 2 adrenergic agnoist
reduction of pain signaling in spinal cord, hypnosis at locus coeruleus, reduction of CNS sympathetic activity
two groups of LA
esters and amides
ester LA
benzocaine, 2-chloroprocaine, cocaine, procaine, tetracaine
amide LA
bupi, etidocaine, lidocaine, mepivacaine, prilocaine, ropi
highest to lowest absorption/vascularity LA
IV > trachea > intercostal > paracervical > caudal > epidural > brachial plexus > sciatic > subq
protein binding and duration of action LA
greater protein binding, longer duration - free drug is slowly made available for metabolism
amides LA elimination
liver by P450 microsomal enzymes (hydroxylation and N-dealkylation)
amides have longer half life
ester LA metabolism
hydrolyzed by pseudocholinesterases
LA are weak/strong acid/bases
weak bases
LA MOA
inhibit electrical conduction through nerves by blocking voltage gated soidum channels with nodes of ranvier
must cross axonal membrane into cystosol of neuro by diffuseing through lipid bilayer
decrease rate of depol in response to excitation, preventing ahcievement of action potential
DO NOT alter resting potential or threshold potential
are myelinated or unmyelinated nerves blocked first by LA
myelinated
A alpha
myelinated, proprioception, large motor
A beta
myelinated, small motor, touch, pressure
A gamma
myelinated, muscle tone
A delta
myelinated, pain, temp, touch
B fibers
myelinated, preganlionic autonomic
C fibers
unmyelinated, dull pain, temp, touch
LA potency determined by
lipid solubility, directly proportional
LA speed of onset determined by
pKA, closer Pka to tissue pH the more rpaid onset time
LA that cause methemoglobinemia
prilocaine, benzocaine
transient neurologic symptoms
transient direct neurotox of lumbosacral nerves, severe pain and dysesthesia in lower back, butt, lower extremities with 12-24hr after uneventful spinal
NO sensory loss, motor, bowel/bladder dysfxn
lidocaine, higher doses, lithotomy
resolve within a week
tx: NSAIDs
cauda equina syndrome
direct neurotoxicity of sacral nerves
tetracaine
slow onset, profound motor blockade, potential neurotoxicity when administered at high doses, spinal anesthesia for long cases
chloroprocaine
can impair action of subsequent epidural bupi and opioids
ropivicaine
S(-) enantiomer of bupi, less pronounced motor block, reduced cardiotoxicity probably bc of vasoconstriction
prolong duration of succ
liver disease, pregnancy, malnutrition, malignancy, hypothyroid
electrolyte abnormalities that prolong duration/potentiate muscle relaxants
magnesium, hypoK, hyperCa, resp acidosis, metabolic alkalosis
drugs that potentiate muscle relaxants
volatiles, LA, CCB, BB, aminoglycosides, mag, lithium, chronic steroids, dantrolene
myasthenia gravis effect on paralytics
resistant to succ, sensitive to nondepolarizing
lambert eaton effect on paralytics
more susceptible to succ and nondepolarizing
what are cholinesterase inhibitors
neostigmine, pyridostigmine, physostigmine, edrophonium
cholinesterase inhibitors side effects (muscarinic side effects)
bradycardia, bronchospasm, secretions, cerebral excitation, GI spasm, increased salivation, increased bladder tone, pupillary constriction
