PK/PD Drug Interactions

PK/PD Drug Interactions

1. Pharmacokinetics= what the body does to the drug

   • Metabolism:ADME
     • What the drug does to the body Includes Absorption
     • Absorption
       • First step only in ExtraVascular
         • Oral Absorption
           • First Pass Effect
             • (GI tract to portal vein to Liver to general circulation (blood stream)
             • Gut-wall metabolism
               • poor bioavailability
             • Hepatic metabolism
       • Site of application to blood stream
       • Affective parameter is BIOAVALIABLITY (F)
         • Permeability of GI Tract
           • Active transport
     • DISTRIBUTION
       • Reversible from one location to another within the body
       • Parameter: Volume of Distribution (Vd, V, D)
         • Volume of body fluid in which drug dissolved
       • Protein Binding
         • Site of DDI
       • Systemic Circulation
         • target site (receptor): Drug Actions
         • (non receptors) tissues: side effect or adverse reactions occur
     • ELIMINATION (removal of drug from body)
       • Metabolism (liver or intestine)
         • Phase I reactions (oxidation, hydrolysis, & reduction)
           • Converts parent drug to more polar via CYP 450 enzymes
             • Polar & nontoxic excreted via kidney
             • CYP3A: present in GI tract, intestinal tract, and liver
               • Metabolizes: Calcium channel blockers, Benzodiazepines, HIV protease inhibitors, HMG CoA-reductase inhibitors, cyclosporine, most non-sedating antihistamines, and cispride
           • CYP DDI: predicts and provides understand for DDI
             • Inhibition: blocking one or more CYP
               • down regulation: reduces intestinal first-pass metabolism, increase in F and half life
                 • Reversible
                   • Concentration of substrates
                   • affinity for binding site (the one with highest affinity will slow metabolism of lowest)
                 • Irreversible: covalent and kills enzyme
                   • forms complex with Heme iron of CYP 450
                   • destruction of heme group (secobarbital)
               • PK parameters: (inc T-hallf & F, dec CL)
                 • 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
             • Inducers: increase CYP activity by increasing enzyme synthesis
               • results in accelerated biotransformation with reduction in unmetabolized (parent) drug
                 • 3A inducers: carbamazepine, rifampin, rifabutin, ritronavir, & St. John's wort
               • ie. Cigarette smoking increase substrate for CYP1A2
                 • may increase dose of metabolized drug
               • Autoinduction: drugs metabolized by same enzymes they induce
                 • ie. carbamazepine: low dose given, then inc dose weekly
         • Phase II reactions (conjugation reactions)
           • Non-CYP 450 enzyme system
             • toxic metabolite undergo detoxification w/ bile
         • Factors that alter: Concomitant medications, Food, and Herb
           • Affected PK parameters: F, CL, Half-life
       • Excretion
         • Renal (Majority)
         • Biliary (bile)
       • Parmaters
         • Half-life
           • period of time required for the drug amount in the body or drug blood concentration to decrease by half
         • Total body clearance (CLt)
           • measures of efficiency of all eliminating organs in metabolizing/excreting the drug
         • Organ CL
           • Hepatic CL (CLh)-metabolism
             • efficiency of liver in metabolizing drug
           • Renal CL (CLr)-kidney
             • efficiency of kidney in excreting the drug
   • Protein Binding
     • major determinant of drug distribution
     • efficacy may be affected
     • Blood: Bound/unbound
       • free/unbound drug interacts with receptors
         • can enter or leave tissue&/or blood
         • can only be distributed
       • bound
       • Blood proteins: albumins (acidic drugs) & globulins (basic drugs)
     • dynamic state
     • stie of DDI
       • Competition: displaces and replace one drug from another to binding site
         • Reversible
           • displacer most occupy most binding sites, lowering number of set available for binding
           • increase concentration, inc/override affinity
         • Irreversible
           • alteration of. protein by other substance modifies affinity of drug for protein
   • Active Transport Interactions
     • Active transport: carrier molecule, energy, against concentration gradient
       • determinant of drug efficacy and toxicity
       • Membrane Transporters: Efflux & influx
         • GI tact
           • serve as defense with metabolizing enzyme against toxic effect of xenobiotics
           • GIT Active Absorption
             • Influx: PEPT1 & OATP
               • inc metabolism, absorption & F
               • i.e.: Quinidine inhibits Pgp, inc digoxin BA
             • Efflux: Pgp, MRP, BCRP
               • dec absorption, metabolism, F
         • Liver, CNS, & kidney
         • cause change in PK and changes in drug activity
         • Uptake (influx) transporters: Soluble carrier family (SLC); outside to inside cell
           • 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
         • Efflux transportors : ATP binding cassette (ABC) family; inside to outside cell
           • Pgp, BCRP, MRPs
             • Pgp: hydrophobic substrates; mostly cationic
             • BCRP: broad range of substrates (statins and phytoestorgens)
             • MRPs: organic anions & neutral drugs
           • expressed throughout body
           • 1st found in human cancer cells
         • exhibit genetic polymorphism & encoded by genes, genotype predict substrate concentration and correct dosing
       • DDI: Induction & Inhibition: modulate influx and Efflux ( affect PK, efficacy, safety of substrates)
       • Drug- food interactions
       • Drug-herb interaction
     • site for DDI interactions
     • ADME
       • Absorption: affects intestinal permeability (F)
       • Distribution: affects tissue permeability
       • Excretion: Renal and biliary affect (CL and T-half)
       • Metabolism: affected by AT
   • PK graph: conc vs time)

2. Pharmacodynamics= what drug dose to body

   • 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
   • Drug-Receptor Interactions
     • afffinty= propensity of drug to bind receptor; its attractiveness
       • receptor that bind slightly, produce a slight therapeutic effect
     • Irreversible= covalent bonds are stable
     • Reverisible= electrostatic bonds
     • Types of PD interactions
       • Additive
         • effect of two drugs is the sum of the effects of each
           • BP decreases when ACE inhibitor added to calcium channel blocker
       • Synergistic
         • Effect of two drugs is greater than sum of their individual effects
           • diuretic added to an ACE inhibitor (enalapril or captopril)
       • Anatagonistic
         • Effect of two drugs is less than the sum of their individual effects
           • NSAIDS increase BP, inhibit anithypertensive effect of ACE inhibitors