Lecture 2: Pharmacokinetics Flashcards
What is the ADME pneumonic for Pharmacokinetics?
A - absorption (oral/GI, inhalation, injection)
D - distribution
M - metabolism (liver - bile or kidney - urine)
E - excretion
What are the 3 main Enteral routes of drug administration?
- Oral (most convenient, slow and uniform)
- Rectal (when oral route precluded)
- limited first-pass metabolism; irregular absorption
- Sublingual (rapid, no first-pass metabolism)
- can only absorb small amounts
What is are key differences between Intravenous and Intramuscular drug administation?
Intravenous
- most direct route that skips barriers
- NOT suitable for oily substances
- inc. risk of adverse effects immediately after inject
Intramuscular
- suitable for oily substances
- can lead to nerve injury
What is a key advantage and disadvantage of Subcutaneous drug injections?
its suitable for suspensions and pellets but large amounts cannot be given
What is the most common method for drugs to be transported across the lipid bilayer?
Simple DIffusion
What is a major transporter of drugs OUT of the cell?
P-glycoprotein 1
- active transport pump that requires energy
When can weak acids and bases move across cell membranes?
only when they are in their unionized forms
What is the equation for Bioavailability (F) of a drug?
F = AUC (route used) / AUC (intravenous)
F = fraction of drug that reaches blood stream
- is < 1
AUC = area under curve
What is the equation for Concentration in Plasma (Cp) of a drug?
Cp = (S x F x Dose) / Vd
S = "salt factor" (less than or equal to 1) F = bioavailability Vd = volume of distribution
S and F should be 1 if not provided in question
What is the equation for Volume of Distribution (Vd) of a drug?
Vd = amount of drug in body / plasma concentration
How do you calculate Total Body Water for lean males and females?
Lean males = 60% of their bodyweight (kg)
Lean females = 55% of their bodyweight (kg)
What do you calculate Extracellular Volume and Plasma Volume?
ECV = 1/3 x TBW
Plasma volume = 25% x ECV
ECV = plasma volume + interstitial volume
What is the only condition in which polar or ionized drugs can move across the BBB (and placenta)?
they can only move across the membrane barriers if their is a TRANSPORTER for them
What are 4 classic examples of inducers that increase the metabolism of drugs? (PCEC)
Phenobarbital, Carbamazepine, Ethanol, Cigarette smoke
What are 4 classic examples of inhibitors that decrease the metabolism of drugs? (EKMG)
Erythromycin, Ketoconazole, Metronidazole, Grapefruit Juice
grapefruit juice is a CYP3A4 enzyme inhibitor
What does Phase II Conjugation do to drugs and what two processes does it use to achieve this?
- makes drugs MORE water soluble and MORE excretable (adds highly polar molecule)
- Glucuronidation
- in endoplasmic reticulum and is inducible
- Sulfation
- in cytoplasm
What does Phase II Acetylation and Methylation do to drugs?
- makes drugs LESS water soluble
- transferases tend to reduce drug activity which can inactivate the drug
What are 4 non-renal routs of drug excretion?
bile, sweat, breath, and breast milk
What are 3 major factors that modify renal drug excretion?
- pH-dependent ionization
- competition for active tubular transport
- age (GFR falls as we age)
What is the difference between Excretion Rate and Clearance, and how do these relate to first order kinetics?
ER = mass eliminated per unit time
- inc. as plasma conc. increases
CR = plasma vol. from which all of the solute is removed per unit time (ml/min or FLOW RATE)
- remains constant as plasma concentration changes
What is the equation for estimated GFR?
eGFR = ((140-age) x (body weight (kg))) / (72 x serum creatinine)
multiply by 0.85 if female
What are 3 common drug types that are commonly seen in drug allergies or hypersensitivities? (PAS)
penicillin (most serious reactions)
also aspirin and sulfonamides
What drug causes problems for individuals that lack plasma esterase?
Succinylcholine
- causes long duration apnea
What drugs cause problems for individuals that lack NADH methemoglobin reductase? (NSP)
nitrites, sulfonamides, primaquine
- causes hereditary methemoglobinermia
What drug causes problems for individuals that lack liver acetyl transferase?
Isoniazid
- causes inc. toxicity from drugs
What drug causes problems for individuals that lack G6P dehydrogenase?
Primaquine (dec. GSH)
- causes drug-induced hemolytic anemia (favism)
What drugs cause problems for individuals with porphobilinogen deaminase deficiency? (BESC)
barbiturates, estrogens, sulfonamides, chloroquine
- acute intermittent porphyria
What are 3 things you must see that identifies a drug as a teratogen?
- characteristic malformations
- drug given during specific window of vulnerability
- incidence inc. with dose and duration of exposure
Diethylstibesterol (DES) and Drug-induced Carcinogenesis
- drug originally used to prevent spontaneous abortion in high-risk pregnancies, but later found that daughters exposed in utero had a high incidence of vaginal and uterine cancers
What is absorption, distribution, hepatic metabolism, and renal excretion like for neonates and infants?
A - inc/dec from GI tract, dec/erratic from IM injection
D - low albumin, BBB no fully developed
HM - decreased
RE - decreased
What is absorption, distribution, hepatic metabolism, and renal excretion like for children > 1 yr old?
A, D, RE similar to that of adults
HM - much faster than adults but declines from peak at 2 years old
What is absorption, distribution, hepatic metabolism, and renal excretion like for geriatrics?
A - no change, dec. from GI tract
D - plasma albumin falls, influence by body composition
HM - decreases but widely variable
RE - decreases progressively
What are Zero Order Kinetics for drugs?
- a constant amount is eliminated per unit
- elimination process is saturated
- amount of eliminated drug independent of drug concentration
What is an example of a drug that abides by Zero Order Kinetics?
ethanol
- rate of metabolism is rapidly saturated, so it is basically first order
What are First Order Kinetics for drugs?
- constant fraction is eliminated per unit of time
- elimination process is NOT saturated
- mass of drug eliminated is directly related to the drug concentration
How much of a drug is eliminated in 5 half-lives if it follows first-order kinetics?
97%
each half-life BACKWARDS doubles the concentration, while each half-life FORWARDS halves the concentration
What is the equation for the First Order Elimination Rate Constant Kel?
Kel = Cl / Vd
Cl = clearance (volume drug is eliminated from / time) Vd = apparent volume of distribution
What is the equation for Clearance?
Cl = (S x F x (Dose/interval)) / Cp
S = salt factor F = bioavailability Cp = plasma concentration
What is the equation for Rate of Elimination?
RE = (Vmax x C) / (Km + C)
Vmax = max elimination capacity C = plasma concentration Km = drug conc. at which elimination rate is 50% of Vmax
What is the equation for the Mean Plasma Concentration at Steady State (Cpss)?
Cpss = (1.44 x S x F x D x t1/2) / (interval x Vd)
What is a loading dose?
- dose needed to rapidly achieve therapeutic drug concentrations for drugs with a very long half-life
What is the equation for Loading Dose?
LD = Cpss x Vd / (S x F)
S and F = 1 unless otherwise stated in equation
