Pharmacokinetics Flashcards
pharmacokinetics
- how a drug molecule moves through your body from administration to elimination
pharmacodynamics
- how a drug molecule affects its target to produce the desired physiological effect
- also includes toxic side effects
4 subprocesses of pharmacokinetics
- drug absorption
- drug distribution
- drug metabolism
- drug clearance
absorption
- how does a drug get into the body
distribution
- how does a drug get to the target site
metabolism
- how is a drug molecule chemically altered by the body
clearance/elmination
- how is a drug molecule removed from the body
how do drugs enter the body
- must cross epithelial or endothelial cell layers
how drugs cross plasma membranes
- passive diffusion
- facilitated diffusion
- or active transport
- based on physical properties
charge of drug molecules
- must be neutrally charged to cross plasma membrane by diffusion
- hydrophobic
pH of environment
- affects the charge state of a drug molecule
- alters its absorption
bioavailability
- how much of the drug is absorbed
how drugs are distributed effectively
- most reach the blood
- topical drugs are an exception
how oral drugs enter the body
- enter GI tract and cross epithelium to interstitial space
- cross endothelium of capillaries to enter plasma (intravenous space)
how inhalation drugs enter the body
- cross epithelial layers at alveoli
how topical drugs enter the body
- only cross epidermis
how IM/SC drugs enter the body
- skip through epithelial layer
how IV drugs enter the body
- direct injection into bloodstream
absorption properties of the patient
- surface area
- drug transit time
- pH of lumen
which has the most surface area for the most absorption
- small intestine
- 25-40 m^2
surface area of mouth, esophageal, stomach
1 m^2
surface area of large intestine
2 m^2
drug transit time of mouth/esophagus
- rapid
drug transit time of stomach
- variable, but less rapid
- food slows transit
drug transit time of small intestine
- slow
pH of mouth
neutral
pH of stomach
acidic
pH of large intestine
neutral
pH of small intestine
neutral
best place for acidic drugs
- stomach
best place for drugs overall
- small intestine
non-saturable processes
- diffusion
saturable processes
- facilitated diffusion
- active transport
what does it mean to be a saturable process?
- limited by amount of transport protein present
weak acid drugs absorbed well in stomach
- aspirin
- furosemide
weak base drugs absorbed well in small intestine
- imipramine
- metoprolol
which drugs reach the general circulation at 100%
- IV drugs
bioavailability
- the fraction of a drug dose that reaches the systemic circulation
bioavailability of other drugs
- lower than IV
area under curve
- a measure of total drug exposure that you get by administration
how to calculate bioavailability
area under curve (drug)
___________________
area under curve (IV)
first pass effect
- drugs need to pass through liver before they pass through general circulation
- generally concentration is reduced
- this is due to portal circulation
when is bioavailability of drugs measured
- after the first pass effect
oral drugs and intestinal bacteria
- decrease absorption and bioavailability
drug binding to serum proteins
- affects both distribution and clearance
volume of distribution
- the distribution of a drug across the three body water compartments
- crucial when calculating rate of drug clearance
xenobiotics
- molecule that is alien to your body
- like a drug
where are drugs metabolized
- lungs
- liver
- small intestines
- kidneys
why are drugs metabolized?
- to inactivate them
- facilitate elimination via urine or feces
ways of drug elmination
- phase I then phase II
- phase I only
- phase II only
- NEVER PHASE II THEN PHASE I
Phase I
- functionalization phase
- drug converted to functionalized metabolite
- possibly still active
- makes easier to conjugate to in next week
Phase II
- conjugation phase
- chemically inactivate the drug
- increase chemical polarity (hydrophobicity) of the molecule
- facilitate renal and hepatic clearance
acetominophen phase I reactions
- oxidation
acetaminophen phase II reaction
- glutathionation - addition of glutathione group
types of phase I reactions
- oxidation
- reduction
- hydrolysis
most common phase I reaction
- oxidation
phase II reactions
- glucuronidation
- glutathione-conjugation
- glycine-conjugation
- sulfation
- acetylation
- methylation
most common phase II reaction
- glucuronidation
oxidation/reduction catalyzed by
- cytochrome P450 families
hydrolyses catalyzed by
- epoxide hydrolase families
glucuronidation catalyzed by
- UDP-glucouronosyltransferase families
glutathione conjugation catalyzed by
- glutathione-s-transferase families
sulfation catalyzed by
- sulfotransferases
acetylation catalyzed by
- N-acetyltransferases
methylation catalyzed by
- methyltransferases
which families are responsible for Phase I metabolism of xenobiotics
- CYP families 1-3
drug metabolized via multiple mechanisms
- Acetaminophen
- APAP
- Phase I creates the toxic intermediate
pro-drug activated by phase I reaction
- clopidogrel
- plavix (anticoagulant)
zero-order kinetics
- drug in excess. have maxed out enzymes
- clearance rate independent of drug concentration
- constant mg/hr
- T1/2 decreases as concentration decreases
- linear decrease
- Rx rate = Vmax
first order kinetics
- enzymes in excess
- clearance rate dependent on drug concentration
- constant % per hour (half life curve)
- T1/2 constant
- most drugs eliminated at this rate
- Rx rate < Vmax
where do you see first order kinetics on MM curve?
- on the left side before you reach Vmax
where do you see zero order kinetics on MM curve
- on right side when you’ve reached Vmax
enterohepatic circulation
- bacteria in intestines chemically reverse phase I and phase II metabolic changes of drug and turn it back to its original form
- instead of being eliminated, drug is reabsorbed back into blood stream
- increases biological half life of drugs
- estradiol
- valproic acid (anti-epileptic)
antibiotics on enterohepatic circulation
- may disrupt glut flora and block effect of EHC
antibiotics and oral contraceptives
- may increase the elimination of oral contraceptives by inhibiting EHC
- increase rate at which birth control is metabolized and reduce efficacy of drug
- recommend to be on a different birth control
antibiotics that block EHC
- amoxicillin
- ampicillin
- sulfamethoxazole
- trimethoprin
- tetracyline
- metronidazole
T MASTA
drug doses for elderly patients
- reduced due to reduced Vd
- reduced hepatic and renal function
best source for changes in dosing of drugs to elderly patients
- Beers criteria for potentially inappropriate medication use in older adults
importance of genetic polymorphisms
- affect activities of various proteins involved in pharmacokinetics for a large part of the variability in drug response among individuals
drug interactions that affect absorption of each other
- Omeprazole and Cefpodoxime
- Digoxin and antibiotics
Cefpodoxime
- antibiotic
- becomes more absorbable in stomach
Omeprazole
- proton pump inhibitor to reduce stomach acid
- increases pH of stomach
- makes Cefpodoxime less absorbable
Digoxin and antibiotics
- antibiotics prevent degradation of digoxin by gut microflora
- more digoxin absorbed into blood can lead to overdose and toxicity
drug interactions that affect distribution
- NSAIDS and warfarin
warfarin use
- anticoagulant
- prevent thrombotic and embolic strokes and MI
NSAIDs use
- prevent clotting
- used as analgesics
NSAIDS and warfarin
- albumin binds warfarin because it is acidic
- NSAIDs also bind albumin at some site
- outcompete warfarin and cause it to be free in active form in body
- can cause serious bleeding
drugs and CYP systems
- drugs interact with each other through CYP systems
- can cause each other to be active or inactive
omeprazole and clopidogrel
- omeprazole inhibits CYP2C19 that converts clopidogrel to active form
- reduces efficacy and increases clotting risk
verapamil use
- used for hypertension, cardiac arrhythmia, and angina
digoxin use
- used for Afib and heart failure
verapamil and digoxin use
- P-gp eliminates digoxin (transporter protein that pumps out drug molecules into urine to be eliminated)
- Verapamil inhibits P-gp
- too much digoxin is in the blood and you have to worry about associated toxicities
pharmacokinetics affected by
- age
- body composition
- health status
- genetic profile
how age affects absorption
- reduce small intestine surface area
- increased gastric pH
- increase dosing?
how age affects distribution
- reduced body water content
- increased body fat content
- decrease dosing
how age affects metabolism
- reduce liver function
- decrease dosing
how age affects clearance
- reduce renal function
- decrease dosing
drug transporters that are affected by genetic variation
- p-glycoprotein (ABCB1)
drug distribution affected by genetic variation
- serum proteins
drug metabolism affected by genetic variation
- phase I/II enzymes
- CYP2D6
- CYP2C9
- CYP2C19
clearance transporters affected by genetic variation
p-glycoprotein (ABCB1)
role of p-glycoprotein
- transmembrane protein that pumps drugs out of cells
- absorption/clearance of many drugs
- clearance via bile
- absorption from Gi tract
- clearance via urine
