Pharmacokinetics and Pharmacodynamics Flashcards
What is pharmacokinetics
uses math to describe the fate of a drug with dosing schedule and route of administration
what is pharmacodynamics
the interaction of a drug on the body receptors
What is LADME
Liberation
Absorption
Distribution
Metaboilsm
Elimination
What is the concept of LADME
determine how rapid, in what concentration and how long the drug takes to reach the target organ
T/F - availability is a function of liberation and absorption
T
What factors affect absorption of drugs in the GI
food
pH
surface area
enzyme and microflora
what factors influences absorption
GI factors
physiochemical drug properties
transporters
route of administration
how do large charged molecules cross the lipid bilayer
active transport
How does the Henderson Hassel Balch predict the absorption capacity of a drug
calculate the pH to determine if pH of environemnt < pKa of drug. charged molecules = less absorbed
If pH< weak acid pKa = not ionized
If pH < weak base pKa = ionized
Is aspirin (pKa = 3.5) absorbed in the stomach or intestines more?
stomach - acidic nature turns aspirin neutral as pH < pKa = easier to absorb
What is the best indicator of total exposure to a dose of drug
Area Under the curve
What is bioavailability
amount of drug that reaches the circulation
How to calculate bioavailability?
ratio of AUC (alternative) / AUC (intravenous)
what is first pass metabolism
liver and intestine reduce administered drug bioavailability
What does a F =1 mean
complete absorption (intravenous)
F <1 = extra vascular
What is F and S in the effective dose calculation
S = chemical form = active form of drug salts
F = bioavailability factor = dose that reaches circulation
T/F - bioavailability estimates extent and rate of absorption
F - bioavailibity only estimates extent and NOT rate of absorption
what does a large volume of distribution mean (Vd)
concentration in tissues > concentration in plasma
what is the relationship of Vd and water solubility and plasma concentration
increase water solubility = increase plasma conc = DECREASE Vd
What is the relationship of plasma protein binding (PPB) and plasma concentration and Vd
low PPB = low plasma conc = INCREASE Vd
eg. liver cirrhosis = less albumin is made = high Vd for an albumin bound drug in the tissue than plasma
why is Vd important?
- determines if dialysis of a drug is benefitial
- estimates body burden of drug (amount)
- Calculates loading dose
how to calculate amount of drug
amount = Vd x weight x Cp (concentration of plasma)
what are the units of Vd
ug/L
ug to mg conversion
ug / 1000 = mg
what factors effect Vd (2)
- drug solubility
- plasma protein binding
clearance definition
volume of plasma (NOT VOLUME OF DRUG) cleared of drug per unit time through metabolism and excretion
what are the components in the clearance equation Cl= Vd x Kel
Vd = volume of distribtion
Kel = elimination constant
how to figure out Kel from graph
log of AUC elimination phase slope gives - Kel
how does half life relate to time to steady state
steady state is assumed to be reached in 5 half lives
time to acheive steady state influenced by half life
what is steady state concentration determined by
dose and frequency of dose
what must the time units be in steady state
mg/ minute
what is first order elimination
rate of drug clearance is proportional to drug concentration. the drug PERCENTAGE is removed at constant rate
what is zero order elimination
drug clearance is CONSTANT regardless of drug concentration
when is zero order elimination seen
when drugs saturate elimination mechanism (enzymes/transporters)
eg. alcohol and aspirin
what is used to sop up drugs that undergo enterohepatic circulation
activated charcoal
what is enterohepatic recirculation
when the drug gets reabsorbed in the small intestine to the liver over and over again
what are the two phases of hepatic elimination of drugs
phase 1 chemical reaction
phase 2 conjugate reaction
process of renal elimination of drugs
- glomerular filtration - passive
- proximal tubular secretion - active
- distil tubular reabsorption - passive
what factors affect renal excretion
PPB
urine pH
kidney function
If a patient overdosed on amphetamines (basic), would you acidify or alkalinize the urine to clear the drug?
acidify - it ionizes the drug to promote elimination
(if it was alkalinized, the nonionized drug will get reabsorbed)
what factors affects pharmacokineteic properties
- AGE
- gender
- pregnancy
- disease
what are xenobiotics
organic compounds foreign to the body
eg drugs, pesticides, pollutant, toxins
what is the goal of xenobiotic metabolism
harmful molecules can be lipophilic = reabsorbed in the body. We want to excrete these molecules
How can xenobiotics be metabolized
biotransformation = enzymatic transformation by functionalization (phase 1) and conjugation (phase 2) into water soluble
functionalization (phase 1) process
- introduction
- exposure or modification (eg oxidation reduction)
- (optional) conjugation in phase 2
T/F - increase polarity / hydrophilicity dissolves xenobiotics in urine for elimination
T
Process of acetaminophen metabolism
CYP2R1 converts APAP into NAPQI
NAPQI destroys liver cells unless bound to glutathione
glutathione removed = damage to liver
Where can biotransformation occur
Major = liver
but all tissues can metabolize
what enzymes are used for biotransformation
cytosolic enzyme or membrane anchored enzymes in ER
what are CYP enzymes structural components and function
- hemoprotein - oxygen binding due to protoporphyrin IX containing heme
- flavoprotein - cofactor NADPH
- heat stable lipid component - holds everything together
where did the name CYPP450 come from
P = red liver pigment
450 = max light absorption
what is CYP450 used for
detoxify, generate energy, create hormones, abosorption/digestion
How can host factors modify metabolism
can inhibit or induce CYP metabolism based on diet and disease
How do brassica (brocoli) affect CYP1A2
increase activity
how do apiaceous (celery /carrots) affect CYP1A2
decrease activiity
how does grapefruit juice affect CYP3A4
stops actvitiy
how does aging affect CYP
slight decrease activity
Define pharmacogentics
study of genetically determined variation in drug metabolism
What are extensive metabolizers (EM)
person who metabolizes a drug at similar rate as to the population
what are poor metabolizers (PM) and what is the consequence?
person who responses drug at a slower rate than population
lack response = inability to convert drug into active form = toxic side effects of prodrug accumulation
what are ultra rapid metabolizers (URM) and what are the consequences
person who metabolizes drugs rapidly due to multiple copies of CYP2D6 gene
fail to respond to normal doses of drug = need very high doses for effects
How does the CYP2D6 impact codeine metabolism
Fluoxetine is a codeine drug that uses CYP2D6 to turn into morphine
URM mother breastfeeding complications without CYP2D6 mutation
Taking codeine at higher dose for effect. CYP2D6 converts all into morphine (hydrophobic/nonpolar) and leaks into breastmilk. Baby drinks all the morphine
Does CYP2C9 metabolize S or R warfarin
CYP2C9 metabolizes S-warfarin (5x stronger than R-warfarin)
What are the allelic variants of warfarin metabolism and what do they mean
CYP2C91 = wildtype
CYP2C92 and CYP2C9*3 = slow metabolism
how does warfarin get metabolized
S warfarin utilizes CYP2C9 to metabolize
or
inihibtion on K for activation of clotting factors for efficient warfarin clotting
how to resolve excess warfarin?
give more vit K
T/F Clopidogrel is a prodrug
T - Clopidogrel is a prodrug as it has to be metabolised into its active form
What gene impacts codeine metabolism
CYP2D6
what gene impacts warfarin metabolism
CYP2C9
what gene impacts clopidogrel metabolism
CYP2C19
How does the CYP2C19 gene impact clopidogrel metabolism
No gene = wt
detection of gene = altered enzymatic activity and slow clopidogrel metabolism
how does enzyme induction work
increase CYP enzyme expression by increasing synthesis and decreasing degradation
what process is seen in ethanol abuse in acetaminophen metabolism
enzyme induction
What happens when ethanol abuse occurs with acvetaminophen
- ethanol induces CYP2E1 enzyme which increases acetaminophen metabolism of NAPQI (toxic)
- ethanol depletes glutathione stores
3 Types of inhibition from drugs or xenobiotics
- substrate (reversible)
- non substrate (reversible)
- metabolite inhibition (irreversible / suicide)
What happens when terfenadine is administered with an inhibitor
cardiac arrest
3 types of immunosuppressants
cyclosporin
tacrolimus
sirolimus
how does cyclosporin work
- based from fungi amino acids (tolypocladium inflatum)
- used as first line immunosuppressant
- inhibiting calcineurin to block NFAT-mediated transcription of IL-2
how does sirolimus work (rapamycin)
- binds FKBP12 to inhibit mTOR = block signaling of IL-2
- used with cyclosporin
how does Tacrolimus work (FK506)
- isolated from bacterium (streptomyces tsukubaensis)
- 100x more potent than cyclosporin
- inhibits calcinerurin
- current first line immunosuppressant drug in US
Which families of CYPP450 are the most important for metabolism
11, 17, 21
