Pharmacology I Flashcards
Define volume of distribution and recite the equation
Vd = administered drug/desired concentration
-Vd describes the relationship between a drug’s plasma concentration following a specific dose. A theoretical measure of how a drug distributes throughout the body.
What are the implications when a drug’s Vd exceeds TBW?
> 42 L
0.6 L/kg
The drug is lipophilic. And it requires a higher dose to achieve a given plasma concentration. I.e., propofol, fentanyl
What are the implications when a drug’s Vd is less than TBW?
< 42 L
< 0.6 L/kg
The drug is hydrophilic. Rocuronium, albumin.
How do you calculate a loading dose for an IV medication?
= Vd x (desired concentration/bioavailability)
-an IV drug always has a bioavailability of 1.
What is clearance? What increases or decreases it?
Increased by: increased blood flow, increased drug dose, increased extraction ratio
Decreased by: half life and drug concentration in central compartment
Clearance = the volume of plasma that is cleared of a drug per unit time.
How many 1/2 times for a steady state to be achieved?
5
what is the alpha vs beta distribution phases on the plasma concentration graph
alpha - distribution (from plasma to the tissues)
beta - elimination (begins as plasma concentration falls below tissue concentration). the concentration gradient reverses, which causes the drug to re-enter the plasma
context sensitive half time of opioids
fentanyl > alfentanil > sufentanil > remifentanil
what is the difference between a strong and weak acid?
the degree of ionization. if you put a strong acid or a strong base in water, they will completely ionize.
what is ionization? what 2 factors determine how much a molecule will ionize?
the process where a molecule gains a positive or negative charge. its dependent on pka of the drug and pH of the solution
non-ionized
= lipophilic, will be hepatically biotransformed
what happens if you put an acid in a basic solution
weak acids will be more ionized and water soluble
how can you tell if a drug is an acid or base based on its name?
DRUGS ARE PREPARED AS A SALT THAT DISSOCIATES IN A SOLUTION
weak acid is paired with a positive ion (sodium, calcium, magnesium)
-sodium thiopental
weak base is paired with negative ion (chloride, sulfate)
-morphine sulfate, lidocaine hydrochloride
name 3 key plasma proteins
albumin (acidic drugs)
alpha 1 acid glycoprotein (basic drugs)
beta globulin (basic drugs)
what reduces albumin concentration?
age
pregnancy
malnutrition
renal/liver dx
what decreases a1acid
pregnancy
neonates
what increases a1acid
elderly
chronic pain, RA
surgery, MI
how do you calculate changes in plasma protein binding?
new - old / old
a new anesthetic drug is cleared from the body at a rate proportional to its plasma concentration. what kind of kinetic order describes this?
first order
When there is more drug than enzymes….
zero order
aka: ETOH, phenytoin, ASA, theophylline, warfarin, heparin
what is the function of a phase 1 reaction? list three examples
MODIFICATION (lipophilic > hydrophilic)
hydrolysis (typically a water molecule breaks an ester bond)
reduction (add an electron)
oxidation (remove an electron)
what is the function of phase 2 reaction?
conjugation
-glucuronic acid, glycine, acetic acid, sulfuric acid, methyl group
discuss enterohepatic circulation and give 2 examples
conjugated compounds excreted into bile > reactivated in intestine > reabsorbed into systemic circulation
diazepam & warfarin
what is the extraction ratio?
how much drug is delivered to a clearing organ vs how much drug is removed
arterial concentration - venous concentration / arterial concentration
what is perfusion-dependent elimination
ER > 0.7, dependent on Q
-fent/sufent/morphine/meperidine
-naloxone
-ketamine/prop/lido
-bupi
-metoprolol, propanolol
-nifedipine, diltiazem, verapamil
what is capacity-dependent elimination
ER < 0.3, dependent on enzymes or protein binding
-rocuronium, diazepam, lorazepam, methadone, thiopental, theophylline, phenytoin
Name hepatic inducers (6)
tobacco, ETOH
barbs
phenytoin
rifampin
caarbamazepine
Name hepatic inhibitors (7)
grapefruit juice
SSRIs
cimetidine
omeprazole
erythromycin
ketoconazole
isoniazid
What drugs are metabolized by nonspecific esterases?
esmolol
clevidipine
remifentanil
remimidazolam
atracurium
etomidate (+hepatic)
what drugs are metabolized by pseudocholinesterases?
succinylcholine
mivacurium
ester LA (cocaine + liver)
What is Lusedra?
fospropofol (prodrug)
what is pharmacobiophysics?
considers the drug’s concentration in the plasma and the effect site (biophase)
what does a steep sleep on the dose-response curve tell you?
small increase in dose can have a profound clinical effect.
therapeutic index
TD50/ED50
what is chirality?
one carbon with tetrahedral bonding (bonds with 4 different atoms)
1 chiral carbon = 2 enantiomers
what is an enantiomer?
chiral molecules that are non-superimposable mirror images
what are the cv and respiratory effects of midaz?
cv = at sedation doses, nothing. at induction doses … drops the SVR and BP
respiratory= sedation doses, shifts co2 response curve to the right (esp. with fentanyl).
pt with copd are more senstiive to the respiratory depressant doses
cns effects of midazolam
induction dose = drops cmro2 and cbf.
cannot produce an isoelectric EEG (barbs and propofol can)
anticonvulsant, anxiolysis, antispasmotic
what are the unique features of remimazolam?
vial protected from light and discard 8 hours
metabolized by plasma esterases
c/i with patients with a hypersensitivity to dextran
how long does flumazenil last
30 - 60 mins
0.2 mg, 0.1 mg q1m
how many flourine ions are in each volatile agent
iso = 5 Fl
des = 6 Fl
sevo = 7 Fl
halothane - 3 flourine and one bromine
which volatile agents are most identicle
iso and des.
des has a flourine atom instead of a chlorine
what does full fluorination do
decreases potency
increases vapor pressure
decreases hepatic biotransformation
why is sevo more potent than des
BULKY PROPYL SIDE CHAIN
what is vapor pressure and how is it affected by ambient temperature?
the pressure exerted by a vapor when it is in equilibrium with its liquid or solid phase.
increase temperature increases vapor pressure
how is anesthetic delivery affected by altitude? when does this matter?
vol % x ambient pressure
so if you are at high altitude, you can underdose des b/c it does not have a temperature compensating valve like sevo and iso
vapor pressure of sevo, des, iso, n2o
sevo - 157 mmHg
des - 669 mmHg
iso - 238 mmHg
n2o - 38,770 mmHg
which inhalational anesthetics are stable in soda lime? whaat byproducts can each agent produce in soda lime?
sevo - not stable, compound A (happens in function and dried soda lime)
des- not stable (CO)
iso - not stable (CO)
N2O - stable (none!!)
what is solubility? how do we measure it?
the tendency of a solute to dissolve into a solvent. aka the agent’s ability to dissolve in the blood and tissues.
blood:gas solubility
how much of the gas is in the blood vs alveoli.
___ part per blood vs. 1 part per alveoli
b/g solubility for sevo, des, iso, n2o
sevo = 0.65
des = 0.42
iso = 1.4
n2o = 0.46
how do we establish an anesthetic concentration inside the alveolus?
-vaporizer on = Fi
-ventilation washes anesthetic agent into alveoli = FA
-buildup of anesthetic partial pressure inside the alveoli is opposed by the continuous uptake of the anesthetic into to the blood. = uptake
-CO distributes it throughout the body = distribution
what increases the rate of FA/FI via delivery
-increased vaporizer setting (increased FGF)
-decreased time constant of the delivery system
-decreased anatomic dead space
-increased alveolar ventilation
-decreased FRC
what increases the uptake
-low blood gas solubility
-low CO
-low partial pressure gradient between the alveolar gas and mixed venous
what are the four tissue groups?
-VRG - heart, brain, kidneys, liver, endocrine glands = 10%, receives 75% of CO
-Muscle - skeletal muscle, skin 50%, receives 20% of CO
-Fat = 20%, receives 5% of CO
-VPG = 20%, receives < 1% of CO. bones, tendons, cartilage
how are inhalational anesthetics removed form the body?
- alveoli (ventilation)
- hepatic biotransformation
- percutaneous loss (minimal)
discuss the hepatic biotransformation of the inhaled anesthetics
- n2o = 0.004
- des = 0.02
- iso = 0.2
- sevo = 2
- halothane = 20
what is 1 mac hour
sevo at 2% for 1 hour
sevo at 1% for 2 hours
which volatile agents are metabolized to trifluouracetic acid?
halothane
isoflurane
desflurane
potential consequence = immune mediated hepatic dysfunction (especially in a patient with previous TFA exposure)
theoretical consequences of sevoflurane metabolism
liberation of flouride ions d/t high degree of metabolism
-high output renal failure
-polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, inability to concentrate the urine
what is the concentration effect
increased alveolar uptake as the concentration of a gas is increased. d/t two mechanisms.
- concentraTING effect: n2O volume going from alveolus to pulmonary blood is much higher than the amount of nitrogen moving in the opposite direction. this causes the alveolus to shrink. the reduction in alveolar volume = relative increase in FA.
- augmented gas inflow: on the subsequent breath, the concentrating effect causes an increased inflow of tracheal gas containing the anesthetic agent to replace the lost alveolar volume. this increases alveolar ventilation and augments FA. (temporary)
why does FA/FI rise faster for n2o than des
concentration effect.
alveolar partial presssure of N2O rises faster than desflurane. this is because we can safely deliver a higher inspiratory concentration which negates the small difference imposed by the slightly higher b/g coefficient
anesthetic overpressure results in a more profound effect for which agents
higher blood solubility
which IA are most greatly affected by a right to left shunt
low b/g solubility
DESFLURANE
why does n2o accumulate in closed air space?
34x more soluble than nitrogen.
n2o = 0.46
nitrogen = 0.014
where does n2o increase pressure
pulmonary blebs, air bubble sin blood, gas bubbles in eye (fast equilibration)
slow equilibration = bowel, pneumoperitoneum
fixed airspaces - middle ear, brain
how does nitrous affect a patient with an ocular gas bubble?
S56 bubble
-d/c nitrous oxide 15 mins prior to placement of bubble. post placement, do not use nitrous for 7 - 10 days
air bubble
-do not use nitrous for 5 days
silicone bubble
-ok to use nitrous
perfluoropropane
-do not use nitrous for 30 days
what is the mac for nitrous
104
what is mac bar
1.5
MAC required to block autonomic response after a supramaximal pain stimulus
what is mac awake
during induction = 0.3 - 0.4 MAC
emergence = 0.15 MAC
this is the MAC when a patient willl open their eyes
what factors increase MAC
-hypernatremia
-MAOIs, ephedrine, amphetamines, acute cocaine, levodopa
-chronic ETOH
-red head (19%)
-infant 1 - 6 mo (sevo is the same for neonates and infants)
-hyperthermia
what factors decrease MAC
-hyponatremia
-acute ETOH
-lithium, lidocaine, hydroxyzine, opioids (etc.)
-hypothermia
-preemies and elderly (6% decrease per decade post 40)
-hypotension (MAP < 50)
-hypoxia, anemia (<4.3 mL O2/dL)
-CPB
-metabolic acidosis
-hypoosmolarity
-pregnancy —> PP 24 - 72 hours
-PACO2 > 95
what factors do not affect MAC?
potassium
magensium
thyroid problems
gender
PaCO2 15 - 95 mmHg
HTN
what is meyer-overton rule?
lipid solubility is directly proportional to the potency of an inhaled anesthetic.
-the number of anesthetic molecules that are dissolved in the brain determine the depth of anesthesia
what is the unitary hypothesis?
all anesthetics share a similar MOA although each at a different site
most important site of halogenated anesthetic action?
GABAa
increases the duration it is open
what cerebral receptors are stimulated by nitrous oxide
nmda antagonism
potassium 2p-channel stimulation
NO GABA
where do halogenated agents produce unconsciousness
thalamus
cerebral cortex
reticular activating system
where do halogenated agents produce amnesia
amygdala
hippocampus
how do halogenated agents decrease blood pressure
decrease intracellular calcium in VSM = vasodilation = decreased venous return
decrease intracellular calcium in myocyte = myocardial depression
how do halogenated agents affect HR
increased HR by desflurane, isoflurane, nitrous. no effect with ssevoflurane
-decreased SA node automaticity
-decreased conduction velocity through AV node, Purkinje fibers, ventricular conduction pathways
-increased duration of myocardial repolarization by impairing the outward current of potassium = increased QT interval due to prolonging AP
-altered baroreceptor function
why do des and iso increase HR 5 - 10%
SNS activation from respiratory irritation
-ne release at b1
how does nitrous oxide by itself affect hemodynamics
activates SNS.
increased MAP d/t increased SVR.
CVP may increase
also a myocardial depressant
how do halogenated agents contribute to hypercarbia
drop Vt and increase RR
decrease Mve = increased Vd
-shifts CO2 response curve down and to the right
-impair genioglossus muscle and thoracic muscles (decreased FRC)
what is CMRO2 a function of
60% = electrical activity
40% = homeostasis
at what MAC does isoelectricity occur
1.5 - 2 MAC
VA uncouple CMRO2 and CBF!
how do VA affect evoked potentials?
decrease amplitude
increase latency
which potential is most sensitive to VA
visual evoked
BAER most resistant
