PK/PD Drug Interactions - created from Mind Map

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Pharmacokinetics= what the body does to the drug

Pharmacodynamics= what drug dose to body

Metabolism:ADME

What the drug does to the body

Includes Absorption

2. Protein Binding

3. Active Transport Interactions

PK graph: conc vs time

Absorption

DISTRIBUTION

Reversible from one location to another within the body

ELIMINATION (removal of drug from body)

First step only in ExtraVascular

Site of application to blood stream

Affective parameter is BIOAVALIABLITY (F)

Oral Absorption

First Pass Effect

(GI tract

to portal vein to Liver to

general circulation (blood

stream)

Gut-wall metabolism

Hepatic metabolism

poor bioavailability

Permeability of GI Tract

Active transport

Parameter: Volume of Distribution (Vd, V, D)

Protein Binding

Systemic Circulation

Volume of body fluid in which drug dissolved

Site of DDI

target site (receptor): Drug Actions

(non receptors) tissues: side effect or adverse reactions occur

Metabolism (liver or intestine)

Excretion

Parmaters

Phase I reactions (oxidation, hydrolysis, & reduction)

Phase II reactions (conjugation reactions)

Factors that alter: Concomitant medications, Food, and Herb

Converts parent drug to more polar via CYP 450 enzymes

Non-CYP 450 enzyme system

CYP DDI: predicts and provides understand for DDI

Polar & nontoxic excreted via kidney

CYP3A

Metabolizes: Calcium channel blockers, Benzodiazepines, HIV protease inhibitors, HMG CoA-reductase inhibitors, cyclosporine, most non-sedating antihistamines, and cispride

present in GI tract, intestinal tract, and liver

toxic metabolite undergo detoxification w/ bile

Inhibition: blocking one or more CYP

Inducers: increase CYP activity by increasing enzyme synthesis

down regulation: reduces intestinal first-pass metabolism, increase in F and half life

Consequences

increase in plasma concentration, reduction of metabolite concentration, exaggerated and prolonged pharmacological effects, increase drug-induced toxicity, PK parameter (inc T-hallf & F, dec CL), and advantage of concomitant medications.

3A inhibitors: Azoles, cimetidine, macrocodes, and grapefruit

Reversible

Irreversible: covalent and kills enzyme

Concentration of substrates

affinity for binding site (the one with highest affinity will slow metabolism of lowest)

forms complex with Heme iron of CYP 450

destruction of heme group (secobarbital)

PK parameters: (inc T-hallf & F, dec CL)

results in accelerated biotransformation with reduction in unmetabolized (parent) drug

ie. Cigarette smoking increase substrate for CYP1A2

Autoinduction: drugs metabolized by same enzymes they induce

3A inducers: carbamazepine, rifampin, rifabutin, ritronavir, & St. John's wort

may increase dose of metabolized drug

ie. carbamazepine: low dose given, then inc dose weekly

Affected PK parameters: F, CL, Half-life

Renal (Majority)

Biliary (bile)

Half-life

Total body clearance (CLt)

Organ CL

period of time required for the drug amount in the body or drug blood concentration to decrease by half

measures of efficiency of all eliminating organs in metabolizing/excreting the drug

Hepatic CL (CLh)-metabolism

Renal CL (CLr)-kidney

efficiency of liver in metabolizing drug

efficiency of kidney in excreting the drug

major determinant of drug distribution

efficacy may be affected

Blood: Bound/unbound

dynamic state

stie of DDI

free/unbound drug interacts with receptors

bound

Blood proteins: albumins (acidic drugs) & globulins (basic drugs)

can enter or leave tissue&/or blood

can only be distributed

Competition: displaces and replace one drug from another to binding site

Reversible

Irreversible

displacer most occupy most binding sites, lowering number of set available for binding

increase concentration, inc/override affinity

alteration of. protein by other substance modifies affinity of drug for protein

Active transport: carrier molecule, energy, against concentration gradient

site for DDI interactions

ADME

determinant of drug efficacy and toxicity

Membrane Transporters: Efflux & influx

DDI: Induction & Inhibition: modulate influx and Efflux ( affect PK, efficacy, safety of substrates)

Drug- food interactions

Drug-herb interaction

GI tact

Liver, CNS, & kidney

cause change in PK and changes in drug activity

Uptake (influx) transporters: Soluble carrier family (SLC); outside to inside cell

Efflux transportors : ATP binding cassette (ABC) family; inside to outside cell

exhibit genetic polymorphism & encoded by genes, genotype predict substrate concentration and correct dosing

serve as defense with metabolizing enzyme against toxic effect of xenobiotics

GIT Active Absorption

Influx: PEPT1 & OATP

Efflux: Pgp, MRP, BCRP

inc metabolism, absorption & F

i.e.: Quinidine inhibits Pgp, inc digoxin BA

dec absorption, metabolism, F

OATP, OAT, PEPT, OCT

OCT: organic cationic

metformin, lamivudine, oxaliptan

OATP & OAT: organic anions

enalapril, temocaprilat, pravastatin, fexofenadine, and digoxin

PEPT: peptide & drug active transport

improves absorption of drugs with poor permeability: acyclovir, and gamcyclovir

Pgp, BCRP, MRPs

expressed throughout body

1st found in human cancer cells

Pgp: hydrophobic substrates; mostly cationic

BCRP: broad range of substrates (statins and phytoestorgens)

MRPs: organic anions & neutral drugs

Absorption: affects intestinal permeability (F)

Distribution: affects tissue permeability

Excretion: Renal and biliary affect (CL and T-half)

Metabolism: affected by AT

relationship between drug concentration and pharmacological response

effects of drug result in concentration at site of action: only in Blood

drug's effect in the absence of corresponding change in plasma concentration

change in therapeutic effect, not in concentration

when two or more drugs have mechanisms of action that result in the same/opposing physiological outcome

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