Therapeutics – branch of pharmacology that deals with clinical applications

• fundamental therapeutic questions: what drug?; what dose?; what formulation?; how long?
• drug administration requires:
• dose-response relationship
• determined clinical endpoint - exactly what effect are we trying to achieve? (qualitative and quantitative)
• monitoring of efficacy and toxicity
• a dose that is effective but not toxic (the correct dose is: enough)
• pharmacologic effects are only modifications of intrinsic physiology - we modify responses, we don’t create them
• therapeutic effects are a function of the pharmacodynamics and pharmacokinetics
• therapeutics is complicated because these parameters are not constant between individuals
• dynamics and kinetics can be altered by disease states, age, pregnancy, genetic determinants, etc.
• we test drugs on healthy humans and animals Þ how useful is this information?

• Absorption
• affected by:
• altered gastric emptying
• decreased GI blood flow
• ileus (gastric obstruction)
• exongenous buffers
• i.e. absorption of aspirin is impaired during a migraine attack Þ aspirin isn’t therapeutic for migraines
• diarrhea, thyroid dysfunction, CHF, CF, and many other diseases affect absorption
• Distribution
• affected by:
• hemodynamic instability
• inflammation
• altered protein levels
• synthesis of acute phase reactions
• extravascular fluid collections
• drug-drug interactions
• disease states that affect distribution
• decreased plasma protein: affects total drug concentration but not free drug concentration
• nephrotic syndrome; malnutrition, short bowel syndrome; celiac disease; liver failure
• decreased protein affinity or displacement
• uremia; hyperbilirubinemia; drug-drug interactions; genetic alterations in albumin
• increased tissue water: changes volume of distribution
• congestive heart failure; renal failure; liver failure with ascites
• Metabolism
• affected by:
• hemodynamic instability (altered delivery to liver and kidneys)
• hypoxemia: oxygen may become limiting in some reactions
• drug-drug interactions
• hormone or autocoid use as pharmacologic rather than physiologic agents
• i.e. viral illness (especially influenza) can decrease drug metabolism via the release of cytokines
• disease states that affect metabolism
• viral infections
• inborn errors of metabolism
• congestive heart failure
• bacterial sepsis
• cystic fibrosis
• malnutrition
• chemical intoxicants
• Excretion
• affected by:
• altered vascular volume
• altered renal blood flow
• hypoxemia
• nephrotoxic agents
• Pharmacodynamics
• affected by: altered receptor affinity or number; up or down regulation of receptors
• Pharmacogenetics
• mostly relates to altered drug metabolism
• genetic differences can be further modified by other factors (see above)
• may lead to alterations in intensity or duration of drug effect; or uncommon/abnormal effects
• types of pharmacogenetic disorders
• decreased or defective proteins
• succinylcholine apnea; acetylation polymorphism; inc susceptibility to drug induced hemolysis
• P450 polymorphisms (i.e. altered ratios of isoforms
• Þ altered metabolism; prolonged or exaggerated or altered drug effect; drug-drug interations
• increased drug resistance
• induction Þ altered drug response
• abnormal drug distribution