PK of drug interactions and pathophysiology of disease + obesity/bariatric surgery case

pharmacodynamic interactions result in…

change in effect

pharmacokinetic interactions result in

one drug altering the kinetics of another leading to alterations in plasma drug concentrations

pharmaceutical incompatibility

a result of physical or chemical incompatabilities

PK parameters involved in absorption

F, ka, AUC

PK parameters involved in distribution

free/unbound fraction

Vd (tissue binding displacement)

AUC

PK parameters affecting metabolism

Q, T1/2, CLint, Cssavg

PK parameters affecting excretion

Cl, Cssavg, AUC

Functions of a healthy liver

• metabolism of lipid soluble drugs via phase I/II

• P-glycoprotein actively secretes products into bile

• Oral meds must pass thru liver before entering systemic circulation (first pass effect)

• produces albumin and AAG

• endogenous substances (ex: bilirubin) are cleared

Effects of hepatitis/cirrhosis in general

• inflammation of liver leading to reduced function/death of hepatocytes = impaired metabolism and hepatic CL

• Decreased portal blood flow (due to hepatocytes being replaced by CT)

• decreased plasma protein production

• decreased CL of bilirubin

• Disease sequelae- hepatorenal syndrome + cholestasis

Hepatic disease effects on absorption

Increased F due to diminished first pass effect (= increased AUC)

• Reduced portal blood flow (Q is Imp for high E drugs)

• Reduced number/activity of hepatic enzymes (CLint → important for low E drugs)

Hepatic disease effects on distribution

Increased free-fraction (fu)/decreased protein binding

• decreased albumin and AAG synthesis

• increase endogenous compounds such as bilirubin

Increased Vd

• if ascites present, increase in Vd of water soluble drugs esp

Metabolism effects in hepatic disease

decreased enzymatic activity of CYP450 system (decreased CLint)

increased T1/2, increased Cssavg

hepatic disease effects on excretion

potential impairment in biliary excretion in end stage liver disease

hepatorenal syndrome: unexplainable progressive decline in renal fxn in the setting of chronic liver disease

**Low muscle mass combined with impairment in converting creatine → creatinine in this pts may provide inaccurate CrCL with cockgroft gault

heart failure key physiologic changes

decrease cardiac output = decreased hepatic/renal blood flow

edema fluid in GI tract

peripheral vasoconstriction = decreased ability to reach binding sites or target tissues = drugs remain in plasma

HF effects on absorption

GI edema interferes with absorption

• decreased blood flow to GI tract

• decreased F

HF effects on distribution

vasoconstriction (sympathetic activation) interferes w/ drug distribution

decreased Vd- drug remains trapped in plasma

HF effects on metabolism

decreased hepatic blood flow (decreased Q)= decreased metabolism of int-high E drugs

HF effects on excretion

decreased renal blood flow, decreased renal Cl (increased t1/2)

do HF effects effect high E or low E drugs more & why

High E- may be less responsive (due to decreased metabolism)

why may IV drugs be better in HF

if acutely ill, decreased F may be problem

general PK changes in obesity

changes to regional blood flow, hormone release, increased obesCO, fat vs lean body mass, pro inflammatory cytokine expression (chronic low grade inflammation)

obesity absorption changes

despite alterations to intestinal blood flow and gastric emptying, oral absorption of drugs does not seem to be affected by excess body weight

subcutaneous and transdermal absorption has been shown to be affected for some drugs (not all!), leading to decreased F due to increased adipose tissue which has decreased blood flow

obesity distribution changes

increased overall Vd but:

• increase in TBW and fat free mass but different proportions than lean individuals causes weight adjusted Vd to be smaller than for normal weight patients

lipophillic drugs = increased Vd

increased AAG therefore increased protein binding for basic drugs

metabolism obesity changes

expression of hepatic enzymes can be influenced by cytokines- which explains some observed changes

• decreased CYP3A4 expression/activity

• increased UGT1 and UGT2, xanthine oxidase, N-acetyltransferase and CYP2E1 activity

possible changes in extra hepatic metabolism (clinical data lacking)

excretion obesity changes

increased renal blood flow may suggest increased renal clearance- chronic obesity and htn can lead to renal injury which can be reflected by decreased GFR

decreased expression of intrahepatic transport proteins = decreased biliary excretion

increased half life (but varies based on if Vd and Cl change proportionally)

roux-en-y gastric bypass surgery absorption changes

increased gastric pH, decreased intestinal surface, decreased transit time, decreased mixing of drugs and biliopancreatic secretions

***expect decreased absorption

roux-en-y gastric bypass surgery distribution changes

not anticipated

gastric bypass surgery metabolism changes

decreased CYP3A4 metabolism in the small intestine (and other same changes as obesity I think)

gastric bypass excretion changes

decreased bile salt mixing