Variability in Special Populations (Geriatrics, Women, Pregnancy)

• Change in baseline effects of drugs (increased)

• Change in sensitivity to drugs/drug effect (Increased)

Some common pharmacodynamic changes in geriatric population

• Decreased water content

• Increased body fat content

• Decreased muscle mass

• Altered Vd for high lipophilic or hydrophilic drugs

• Decrease overall in Kidney and Liver function

Aging impacts on physiology

• Unchanged passive diffusion and no change in oral bioavailability

• Some do have some decreased bioavailability (but less)

• Some decrease in first pass effect thus increase in bioavailability

Aging impacts on ADME (absorption)

• Decreased Vd and increase in Plasma concentrations of hydrophilic drugs

• increase in half-life of certain drugs (stays in or works longer)

Aging impacts on ADME (Distribution)

• Decreased hepatic and renal metabolism/clearance

• Increase in half-life! 

• Thus increase in AUC 

• Thus increase in C_SSavg

Aging impacts on ADME (Metabolism AND Excretion)

• Chronic inflammation and higher oxidative stress

• Excluded from clinical trials often

• DECREASE in CYP3A4 expression! 

Some key points about patients with obesity

• No difference in oral bioavailability

• Gastric emptying time is INCREASED (longer and lower curve)

Drug absorption in patients with obesity

• NO change in serum albumin

• 2x increase in alpha-1 acid glycoprotein

• INCREASE IN:

  • Adipose tissue

  • lean body mass

  • Organ mass

  • Cardiac output/Cardiac size

  • blood volume

Drug distribution in patients with obesity

• Livers typically have fatty infiltration

• Decrease in CYP3A4 mediated clearance (this is what metabolizes FAT)

• Increase in CYP2E1 clearance (Ethanol, APAP, toxic!)

• Increase in glucoronidation

• Increase in RENAL CLEARANCE! Increased GFR and tubular secretion!

Drug Elimination in patients with obesity

• Sex hormones influence gastric emptying rate and intestinal transit time

• Absorption rates MAY be slower in women

Drug absorption in women

• Vd only really important if utilizing Loading dose (Ex; Women have lower Vd for ethanol)

Drug Distribution in women

CYP3A4; CYP2DB; CYP1A2

Premenopausal women tend to have higher activity of _____ and ______ , while a decrease in _____ phase 1 enzymes

UGT; SULT

Women have decreased activity of _____ and ______ phase II enzymes

• Decreased GFR

• Decreased Tubular Secretion

• Decreased Tubular reabsorption 

• Generally decreased clearance! compared to men

Renal elimination in women

• Cardiovascular drugs (CV)

• Antipsychotic drugs (CNS)

Women are more sensitive to these drugs

• Best to avoid drug therapy in pregnancy

• HTN, epilepsy, asthma, and infection as well as other conditions may warrant medication therapy

• Antiepileptic drugs are eliminated more rapidly in pregnancy = MORE SEIZURES!!! BAD!!

Key points about drugs and drug therapy in pregnancy

• Clearance of drugs is generally increased in pregnancy

• Beta-lactam antibiotics are cleared quicker in pregnancy

• Clearance of caffeine is DECREASED! (due to CYP1A2)

• High levels of progesterone may inhibit some enzymes and increase others 

Additional points about drugs in pregnancy