PK/PD Flashcards
PK diagram
Check diagram on notes
- population and individual tailoring
- predicting toxicity: review all medications
PK requirements- factors for approval
Bioavailabity T1/2 Drug elimination Inter-subject availability Drug-stud reactions Safe dose->plasma conc-> right tissue
Pk requirements- factors to consider
New drug repurposed? Alcohol/smoke Age/sex/diet Infection/preg etc Liver/CVD function
Bioavailabity- definition
Check graph
Measure of drug absorption where it can be used
Vd= AUC oral/AUC IV *100%
Drug-> systemic circ vs IV route
Drug admin IV= 100% Vd
Other routes= fraction of IV (1> eg oral)
Vd affected by
Absorption: Formulation age(luminal changes) food (chelation and gastric emptying) vomit/malabsorption (Crohn’s)
1st pass metabolism- metab b4 reaching systemic circ= gut lumen/wall/liver
Rate of absorption
Dictate visibility of distribution and elimination phase
Fast abs- see D/E phase, slow =D phase masked= see diagram
Modified release preparation
Change PK parameters- change coating/tweaking drug- less/more freq dosing
Modified release form of metformin
- take less often, Better adherence
-abs slower: plasma conc shift towards rate of abs
Expensive
Distribution
Adequate plasma levels and reach target organ
Factors affecting therapeutic agents
Blood flow and capillary structure:
Simple diffusion
Junctions
Active transport
Lipophilicity/hydrophylicity
Protein binding: Albumin-acidic drug Globulins-normal Lipoproteins- basic drug Glycoproteins- basic drug
Rate of distribution and equilibrate on from IV administration- multiple compartments
- IV dose admin- 1st compartment
- Equilibrate between 2 volumes
- distribute and equilibrate between v1 and v2
- elimination from v1:Conc in V1 and V2 parallel
- look at 2 graphs
Drug-protein binding and distribution
Free drug: resp/eliminated
Bound: stays in compartment
Clinically important:
Highly protein bound
Narrow therapeutic index
Low Vd
Increased free drug
- 2nd drug displace 1st from binding proteins=bind more efficiently
-increase free drug= resp:
harm potential-preg(change fluidbalance)/renal failiure/ hypoalbunemia(less protein drug can bind to= increase free drug, less response elicited)
Calculations
Vd=dose/[drug]plasma
- Vd in adipose tissue increase as drug sequestered into it
- Vd decrease as increase [drug]plasma
Conc=amount/vol (mg/L)
-protein binding in plasma= increase free drug in plasma= conc increase
Apparent Vd
Smaller- drug confined in plasma and ECF (warfarin)
Larger- drug distributed throughout tissues (Digoxin)
Dose= Vd x [drug]plasma
Metabolism- Phase 1 enzymes cytochrome P450 expose polar regions of drug by:
Oxidation
Alkylation
Reduction
Hydrolysis
Metabolism-phase 2 enzymes add a covalent bond, this adds:
Glucuronide
Sulphate
Glutathione
N-acetyl
These will: change size and dictate if excreted by kidney/ bile=faeces
Metabolism- last part
Phase1/2 products conjugated
Kidney-> urine
Gall bladder -> Bile
Structural complexity affects route of metabolism
Size
Lipo/hydro philicity/phobicity
Phase 1: convert drugs to lipophilc, metabolites May alter PK/PD
Cytochrome p450 (CYPs)
Phase 1 catalysed reactions
Genes encode enzymes
- CYP1A:smoking induced: smoke and take drug can increase/decrease metab of drug stimulate/inhibit it
- CYP2C:inhibitor
- CYP20:metab many drugs
- CYP2E:alcohol metab
- CYP3A:~50% therapeutics
Cytochrome P450 importance:
Active drug become inactive MOST
Inactive drug become active
ACEI
Levadopa->dopamine
perindopril->perindoprilat
Active drug become another active structure
Codeine->morphine
Diazepam->oxazepam
CYPs induced/inhibited- these things affect phase 1
Age
Hepatic disease
Blood flow to hepatic system
Alcohol/smoking
CYP2D6
Not in 7% Caucasians
Hyperactive/ increase induction: 30% East Africans= increase drug metab
Substrates:BB/SSRI/opioids
Inhibited by some SSRIs/other antiarrythmic/other antidepressants
CYP3A4 inhibition
grape fruit juice and statin therapy
CYP3A4 metabs lovastatin.
Conc of this in pt high more than not have grape fruit w statin= more muscle fatigue
Clinical importance of CYP
Drug prescribing
Over the counter drugs
Race/sex/species
Carbamazepine- increase metab of drug (more metab of drug)= mood stabiliser
Drug elimination
Primary:kidney
Fluids:sweat/tear/saliva
Solids:faeces/hair
Gases:volatile compounds
Drug elimination: renal
Lower molecular weight polar metabolites
CYP450 exposes the polar region
Affected by:
- GFR and protein binding: gentamicin, tubular secretion, renal clearance
- competition for transporters:penicillin
- lipid sol/pH (chnage ph: increase/decrease drug elimination, reducing:poisoning) flow/ rate:aspirin
Clearance of drug from body: all routes
(Metab and excretion)=mL/min
Drug elimination: hepatic
High molecular weight with glucoronic acid (pz)
Bile:conjugates
Elimination-faeces/reab
Enterohepatic circ:
Drug-intestine-portal v.-liver
Intestinal lumen:
increase metab/change drugs (may be excreted/reab)
Antibiotic drug interactions-warfarin/morphine
Drug elimination; order
Look at 3 graphs
Zero order- drug elimination specific amount/time Drug conc 4 time change Slope= -k Mass/time
First order:
Change [drug]/t = constant rate, concentration dependent
Increase [drug] body= increase elimination
Steep at first
Exponential equation- learn
Natural log of first order
Slope=-k
T1/2=0.693/k
K=0.693/T1/2
T1/2-1st order kinetics
Independent of [drug]
Diff for diff drug/PK processes
Elimination T1/2 ranges: min-days/weeks
Reduce [drug] by 50%
CL
Constant proportion vol blood cleared/t
Rate of elimination from body/drug conc in plasma
mL/min
Increase drug conc increase drug in same vol cleared
Increase elimination rate = amount/Time mg/min
Elimination 4 1/Vd
K=CL/Vd=0.693/T1/2
