Module 1: Pharmacokinetics Flashcards
Pharmacogenetics
- genetic variations in drug response
- genes that determine drug metabolism
***Individual Gene Level***
Pharmacogenomics
- look at the whole genome
- study of how a person’s genetic makeup may determine their drug response
***Whole Genome Level***
High Extraction Ratio
- HIGH: 0.7- 1
- Intermidiate: 0.3-0.7
- Low: <0.3
Drug Effect Graph
- Onset of Effect
- Peak Effect
- Duration of Action
- MEC for adverse response
- therapeutic window
- MEC for the desired response
- MEC = minimum effective concentration
Extensive vs. Poor Metabolizers
- Genetic make-up affecting outcomes:
- can increase or decrease drug metabolism
- decrease or increase efficacy of drug
- can increase or decrease drug metabolism
AUC
(Area under the curve)
- tells you the total amount of exposure to the drug
Drug Clearance
- the removal of a drug from the body expressed as volume divided by time
- removal of a drug from a volume of plasma in a given time
- **Does NOT** indicate amount of drug being used
Cytochrome P450 Enzymes
- Liver Metabolism (CyP450)
- Major enzymes responsible for drug metabolism to transform lipophilic drugs into water-soluble molecules that can then be filtered by the kidneys
- some drug substrates inhibit CYP450
- inducers = increase CYP450 = increased metabolism of the drug = decreased bioavailability
- inhibitors = decrease CYP450 = decreased metabolism of the drug = increased bioavailability
CYP450 Inhibitors
GPACMAN
- Grapefruit
- Protease Inhibitors
- Azole antifungals
- Cimetidine (antihistamine and antacid; H2 antagonist)
- Macrolides (except azithromycin)
- Amiodarone (anti-arrhythmic)
- Non-DHP CCBs (non-dihydropyridine calcium channel blockers)
CYP450 Inducers
PCRABS (induce CYP450 to cut up with its claws the medications that it acts on)
- Phenytoin (anticonvulsant)
- Carbamazepine (anticonvulsant)
- Rifampin (TB drug)
- Alcohol (chronic)
- Barbituates
- St. John’s Wort
MEC
Minimum Effective Concentration
How many half-lifes to eliminate a single dose?
5 half-lifes = 97% eliminated
Protein Binding
drugs will bind to proteins which makes it more challenging to monitor
-clinically relevant in high clearance drugs with narrow therapeutic windows
Modes of Absorption
- Paracellular: between cells
- Transcellular: across cell bodies
- passive
- active transport by carrier
- drug transporters
- facilitated
- active transport by carrier
- endocytosis
- passive
Significances of Drug Metabolism
- gets rid of undesirable foreign compounds
- providing a means for producing active compounds
- some drugs are given as inactive “prodrugs”, which then convert to active form
Extraction Ratio
- the ability of an organ to remove a drug
- increased extraction ratio = drug cleared very efficiently by organ
- Clearance is only high if BOTH blood flow and extraction ratio are high
Volume of Distribution
How much volume the drug is theoretically being distributed into
- Vd = amount of drug in the body/ concentration of the drug in blood or plasma
- drugs with higher Vd = higher concentration in extracellular tissue
- drugs with lower Vd = high concentration in intravascular space
- limited drug distribution
- **does not indicate WHERE the drug is being distributed into**
First Order Elimination
- most drugs are eliminated in this way
- elimination is proportional to amount of drug in body
- amount of drug in body increases –> increased amount of drug elimination and vice versa
- **FRACTION** of drug eliminated over time remains constant *fixed percentage from previous number*
*
Zero Order Elimination
Drug eliminated in each time interval is constant regardless of amount of drug in body
- fixed % from original
Fraction of Dose Remaining
Fraction of Dose Remaining = (1/2)n
n = # of half-lifes
Prodrugs
- inactive compounds designed to max the amount of active species at the site of action
- a biologically inactive compound which can be metabolized in the body to produce an active compound
2 Phases of Metabolism
- Phase 1: occurs first
- usually involve oxidation, reduction, hydrolysis
- generally loss of pharmacological activity
- Phase II: Conjugation
- covalently link function group with endogenous glucuronic acid, sulfate, glutathione, amino acid, or acetate
**Some drugs only undergo Phase II reactions**
Pharmacokinetics vs. Pharmacodynamics
- Pharmacokinetics: what the body does to the drug
- Pharmacodynamics: what the drug does to the body
Bioavailability
amount of drug available in the body to cause pharmacological effects
First Pass Loss/ Effect
- the loss of a drug before getting to the site of action when it first passes through the GI and Liver
- **Drugs with a much high first pass loss require much larger oral than IV doses to achieve same effects**
Most Common Metabolic Reactions
- oxidations: loss of electron
- reduction: gain of electron
- hydrolysis: breaking a bond by using H2O
- Conjugation:
- glucuronidation: adding glucuronic acid to molecule
- sulfation: adding sulfate to another molecule
- acetylation: adding an acetyl group to another molecule
Phenytoin and First Order vs. Zero Order Elimination
Normally is first order elimination but at high doses has zero order elimination
- elimination has reached max capacity and can only eliminate a fixed amount at a time rather than a fixed percentage
- **anticonvulsant nad antiarhythmic**
Clearance Equation
- CL (total)= CL (r) + CL(L) + CL(b) + CL(other)
- r = renal, L = liver, b = biliary
- determined by blood flow and extraction ratio
Central Compartments
- highly perfused
- heart
- liver
- lungs
- kidney
- blood
Peripheral Compartments
- lower perfusion
- Fat tissue (including brain)
- Muscle Tissue
- Cerebrospinal Fluid
- Bone
