UNIT 4 Pharmacology I Flashcards
define volume of distribution & recite the equation
Vd describes the relationship b/n a drug’s plasma concentration following a specific dose. It is a theoretical measure of how a drug distributes throughout the body.
Vd assumes two things:
1. drug distributes instantaneously (full equilibration occurs at t=0)
2. drug isn’t subjected to biotransformation or elimination before it fully distributes
Vd = amount of drug/desired plasma concentration
What are the implications when a drug’s Vd exceeds TBW? What is Vd if less than TBW?
If Vd>TBW, the drug is assumed to be lipophilic:
- it distributes into TBW & fat
- it will require a higher dose to achieve a given plasma concentration
- ex: propofol, fentanyl
If Vd
How do you calculate the loading dose for an IV medication? For a PO medication?
loading = Vd*desired plasma concentration/bioavailability
for an IV drug, the bioavailability is always 1
for a PO drug, the bioavailability will be <1 d/t first pass metabolism
What is clearance? What factors increase/decrease it?
clearance is the volume of plasma that is cleared of drug per unit time
increased by:
- increased blood flow to clearing organ
- increased extraction ratio
- increased drug dose
decreased by
- increased half life
- increased drug concentration in central compartment
What is steady state?
occurs when the amount of the drug entering the body is equivalent to the amount of drug being eliminated from the body- there is a stable plasma concentration. Each of the compartments has equilibrated, although the total amount of drug may be different in different compartments
steady state is achieved after 5 half-times
compare and contrast the alpha and beta distribution phases on the plasma concentration curve
graphical depiction of the biphasic decrease of a drug’s plasma concentration following a rapid IV bolus
alpha phase: describes drug distribution from the plasma to the tissues
beta phase: begins as plasma concentration falls below tissue concentration. Concentration gradient reverses, which causes the drug to re-enter the plasma. B phase describes drug elimination from the plasma by the clearing organs
You have administered 30mg of esmolol to a patient after a sudden (and profound) elevation in HR. After 3 half-lives, what percentage of your initial dose remains in the patient’s bloodstream?
12.5%
What is context sensitive half-time?
the time required for the plasma concentration to decline by 50% after discontinuing the drug infusion
Discuss the CS1/2t of fentanyl, alfentanil, sufentanil, adn remifentanil. Which has the longest? Which has the shortest? Why?
The CS1/2t for a fentanyl infusion increases as a function of how long it was infused (since it has more time to fill up the peripheral compartments). This is also true for alfentanil & sufentanil to lesser degrees.
Remifentanil is the exception. Although it’s highly lipophilic, it is quickly metabolized by plasma esterases & has a similar CS1/2t regardless of time infused.
What is the difference b/n a strong and weak acid or base?
the difference is the degree of ionization:
- if you put a strong acid or base in water, it will ionize completely
- if you put a weak acid or base in water, a fraction of it will be ionized and the remaining fraction will be unionized
What is ionization? What 2 factors determine how much a molecule will ionize?
ionization describes the process where a molecule gains a positive or negative charge
the amount of ionization is dependent on two things:
- the pH of the solution
- the pKa of the drug
Finish this sentence: When pKa and pH are the same, _____
50% of the drug will be ionized and 50% will be unionized
How does ionization affect solubility, pharmacologic effect, hepatic biotransformation, renal elimination, and diffusion across lipid bilayers?
ionized:
- water solubility
- not pharmacologically active
- less hepatic biotransformation
- more renal elimination
- no diffusion across lipid bilayers (BBB, GI, placenta)
nonionized:
- lipid solubility
- pharmacologically active
- more hepatic biotransformation
- less renal elimination
- diffusion across lipid bilayers (BBB, GI, placenta)
What happens when you put an acid in a basic solution? How about an acidic solution?
“like dissolves like”
acid in a basic solution:
- acidic drug will be highly ionized in a basic pH
- acidic drug wants to donate protons & basic solution wants to accept
acid in an acidic solution
- acidic drug will be highly unionized in an acidic pH
- acidic drug & acidic solution both want to donate protons
Can you tell if a drug is an acid or a base by looking at it’s name? if so, how?
most drugs are weak acids or weak bases. They are usually prepared as a salt that dissociates in solution.
Weak acid is paired w/ a positive ion such as sodium, calcium, or magnesium (ex. sodium thiopental)
weak base is paired w/ a negative ion such as chloride or sulfate (ex. lidocaine hydrochloride, morphine sulfate)
Name the 3 key plasma proteins. Does each bind acidic drugs, basic drugs, or both?
albumin: binds primarily acidic drugs, but does bind to some neutral and basic drugs
a1-acid glycoprotein: binds basic drugs
B-globulin: binds to basic drugs
What conditions reduce albumin concentration
liver disease renal disease old age malnutrition pregnancy
What conditions affect alpha1 acid glycoprotein concentration?
increased:
- surgical stress
- MI
- chronic pain
- RA
- advanced age
decreased:
- neonates
- pregnancy
How do changes in plasma protein binding affect plasma drug concentration?
decreased PB –> increased plasma concentration
increased PB –> decreased plasma concentration
How do you calculate changes in plasma protein binding?
[free drug] + [unbound PB sites] [bound drug]
if a drug is 98% PB and the bound fraction is reduced to 96%, the unbound or free fraction has increased by 100%!
A new anesthetic drug is cleared from the body at a rate proportional to its plasma concentration. What kinetic model best describes the elimination of this drug?
first order kinetics (a constant fraction of drug is eliminated per unit time)
most drugs follow this model
alcohol is cleared from the body via zero order kinetics. How ill this drug’s rate of elimination change as plasma drug concentration changes?
it won’t
a constant amount of drug is eliminated per unit time. Said another way, the rate of elimination is independent of plasma drug concentration.
Other examples:
- aspirin
- phenytoin
- warfarin
- heparin
- theophylline
What is the function of a phase 1 reaction? List 3 examples.
Phase 1 reactions result in small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for a phase 2 reaction - it creates a location on the molecule that will allow the phase 2 reaction to take place. Most phase 1 biotransformations are carried out by the P450 system.
oxidation: adds oxygen to a compound
reduction: adds electrons to a compound
hydrolysis: adds water to a compound to split it apart (usually an ester)
What is the function of a phase 2 reaction? List 5 common substrates.
conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water soluble, biologically inactive molecule ready excretion
common substrates:
- glucuronic acid
- glycine
- acetic acid
- sulfuric acid
- methyl group
some drugs do not require preparation by phase I reactions & may proceed directly to phase II reactions
Discuss enterohepatic circulation & list 1 drug example.
some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
example: diazepam
What is the extraction ratio?
a measure of how much drug is delivered to a clearing organ vs. how much drug is removed by that organ.
ER of 1.0 means that 100% of the drug delivered to the clearing organ is removed
ER of 0.5 means that 50% of the drug delivered to the clearing organ is removed.
Extraction ratio = (arterial concentration-venous concentration)/arterial concentration
Regarding hepatic clearance, what is flow limited elimination?
flow limited elimination (ER >0.7)
- for a drug w/ high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow
- HPF greatly exceeds enzymatic activity, so alterations in hepatic enzymes has little effect
- increase in HBF = increased clearance, decrease in HBF = decreased clearance
Regarding hepatic clearance, what is capacity limited elimination?
capacity limited elimination ( ER<0.3)
- for a drug w/ a low hepatic extraction ratio(<0.3), clearance is dependent on the ability of the liver to extract drug from the blood. Changes in hepatic enzyme activity or PB have a profound impact on clearance of these drugs
- changes in the liver’s intrinsic ability to remove drug is influenced by the amount of enzyme present.
- enzyme induction –> increased clearance and vice versa
Theophylline has a low hepatic extraction ratio. Which will have a greater effect on it’s metabolism: prolonged hypotension or CYP inhibition?
CYP inhibition. Given it’s low hepatic ratio, prolonged hypotension will not impact its rate of metabolism to the same degree that CYP inhibition will.
List drugs w/ low, intermediate, and high hepatic extraction ratios.
low:
- roc
- diazepam, lorazepam
- methadone
- TPL
- theophylline, phenytoin
intermediate:
- midazolam
- vec
- alfentanil
- methohexital
high
- fentanyl, sufentanil, morphine, meperidine
- naloxone
- ketamine, propofol
- lidocaine, bupivacaine
- metoprolol, propranolol, alprenolol
- nifedipine
- diltiazem, verapamil
Whats the difference b/n a hepatic enzyme inducer & enzyme inhibitor? List examples of each.
inducers: increase clearance, decrease plasma drug level –> dose increases may be required
- tobacco smoke
- barbiturates
- ethanol
- phenytoin
- rifampin
- carbamazepime
inhibitors: decrease clearance, decrease plasma drug levels –> dose decreases may be required
- grapefruit juice
- cimetidine
- omeprazole
- SSRIs
- erythromycin
- ketoconazole
- isoniazid
List 2 drug classes & 7 drugs that are metabolized by pseudocholinesterase.
some NMB:
- succinylcholine
- mivacurium
ester LA
- chloroprocaine
- tetracaine
- procaine
- benzocaine
- cocaine
list 6 drugs that are metabolized by non-specific plasma esterases.
esmolol remifentanil aspirin clevidipine atracurium (+ Hoffman) etomidate (+ hepatic)
list 1 drug that is biotransformed by alkaline phosphatase hydrolysis.
fospropofol (propofol prodrug under the trade name Lusedra)
define pharmacokinetics, pharmacobiophysics, and pharmacodynamics. How do they relate to each other?
pharmacokinetics: “what the body does to the drug.” It explains the relationship b/n the dose that you administer and the drug’s plasma concentration over time. Affected by absorption, distribution, metabolism, and elimination.
pharmacobiophysics: considers the drug’s concentration in the plasma & the effect site (biophase)
pharmacodynamics: “what the drug does to the body.” It explains the relationship b/n the effect site concentration and the clinical effect.
What is potency, and how is it measured?
potency = dose required to achieve a given clinical effect
the ED50 & ED90 are measures of potency. They represent the dose required to achieve a given effect in 50% & 90% of the population respectively.
How is potency measured on the dose response curve?
dose response curve:
x axis = log [dose]
y axis = intensity of effect
R shift = more potent
what is efficacy, and how is it measured on the dose response curve?
efficacy is a measure of the intrinsic ability of a drug to produce a clinical effect.
the height of the plateau on the Y axis represents efficacy (higher plateau = greater efficacy)
once the plateau phase is reached, additional drug doesn’t produce additional effect, it will only increase the risk of toxicity.
what does the slope of the dose response curve tell you?
how many of the receptors must be occupied to elicit a clinical effect.
steeper slope = small increase in dose can have profound clinical effect
flatter slope = higher doses are required to increase the clinical effect.
what are the differences b/n a full agonist, partial agonist, antagonist, and inverse agonist?
full agonist: binds a receptor & turns on a specific cellular response
partial agonist: binds a receptor, but is only capable of partially turning on a cellular response (less efficacious)
antagonist: occupies the receptor and prevents agonist binding to it. Doesn’t tell the cell to do anything (does not have efficacy)
inverse agonist: binds the receptor & causes an opposite effect to that of an agonist (it has negative efficacy)
What is competitive antagonism? Give an example.
reversible
increasing the [agonist] can overcome competitive antagonism
ex: atropine, vecuronium, rocuronium
what is noncompetitive antagonism? give an example.
not reversible (usually covalent binding) increasing [agonist] cannot overcome noncompetitive antagonism, it can only be overcome by producing new receptors
ex: aspirin & phenoxybenzamine
define ED50
effective dose 50 = dose that produces the expected clinical response in 50% of the population. It is a measure of potency
define LD50
lethal dose 50 = dose that will produce death in 50% of the population
define therapeutic index
helps us determine the safety margin for a desired clinical effect.
TI = LD50/ED50
drug w narrow TI = narrow margin of safety
What is chirality?
division of sterochemistry. Deals w/ molecules that have a center of 3D asymmetry. In biologic systems this type of asymmetric stems from the tetrahedral bonding of C (when C binds to 4 different groups)
molecule w/ 1 chiral C will exist as two enantiomers. The more chiral C in a molecule = more enantiomers created
What is an enantiomer? What is the clinical relevance?
chiral molecules that are non-superimposable mirror images of one another.
different enantiomers can produce different clinical effects. For example, the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug
What is a racemic mixture? List some commonly used examples.
A racemic mixture contains 2 enantiomers in equal amounts.
About 1/3 of the drugs we administer are enantiomers, and just about all of these are prepared as racemic mixtures. Common examples: bupivacaine, ketamine, isoflurane, and desflurane (not sevo)
What is the mechanism of action of propofol?
direct GABA-a agonist –> increased Cl- conductance –> neuronal hyperpolarization
What is the dose, onset, duration, and clearance mechanism for propofol?
dose:
induction = 1.5-2.5mg/kg
gtt = 25-200mcg/kg/min
onset 30-60sec
duration 5-10min
clearance P450 (liver) + extrahepatic (lungs)
What are the CV & respiratory effects of propofol?
CV:
- decreased BP d/t decreased SNS tone & vasodilation
- decreased SVR
- decreased venous tone –> decreased preload
- decreased contractility
resp:
- CO2 response curve shift = less sensitive to CO2 –> respiratory depression or apnea
- inhibition of hypoxic ventilatory drive
What are the CNS effects of propofol?
decreased CMRO2 decreased CBF decreased ICP decreased IOP no analgesia anticonvulsant properties
What is the formulation of propofol? Is there a patient population where this is a problem?
Propofol is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol
probably safe to administer to those allergic to egg, soy, and/or peanuts.
What is propofol infusion syndrome?
contains long chain TGs & an increased long chain TG load impairs oxidative phosphorylation & fatty acid metabolism. This starves cells of oxygen, particularly in cardiac and skeletal muscle. Associated w/ a high mortality rate.
What are the risk factors for propofol infusion syndrome?
dose >4mg/kg/hr (67mcg/kg/min) duration >48hrs children >adults inadequate O2 delivery sepsis significant cerebral injury
What is the clinical presentation of propofol infusion syndrome?
acute refractory bradycardia –> asystole + at least one of:
- metabolic acidosis (bse deficit >10)
- rhabdomyolysis
- enlarged or fatty liver
- renal failure
- HLD
When must a propofol syringe be discarded? How about an infusion?
syringe = 6hrs infusion = 12hrs
propofol supports bacterial & fungal growth; use strict aspectic technique
What preservatives are used in brand & generic propofol? What patient populations are at risk?
Diprivan (branded propofol), contains EDTA (disodium ethylenediamine tetraacetic acid) as a preservative. It’s not a problem for any specific patient population
generic formulations contain different preservatives:
- metabisulfate can precipitate bronchospasm in asthmatics
- benzyl alcohol should be avoided in infants (few case reports of toxicity & death)
How can propofol injection pain be minimized?
injecting into larger & more proximal vein
lidocaine
giving an opioid prior to propofol
Discuss the antipruritic effects of propofol.
10mg IV can reduce itching by spinal opioids & cholestasis
Discuss the antipruritic & antiemetic effects of propofol.
10-20mg IV can be used to treat PONV. An infusion of 10mcg/kg/min can also be used
How is fospropofol converted to its active form?
alkaline phosphatase converts fospropofol to propofol
- explains why it has a slower onset (5-13min) & longer DOA (15-45min) than propofol
- another byproduct is formaldehyde & phosphate
