• can be toxic reactions to drugs (Drug reactions) or situations where one drug loses it therapeutic effect because of an interaction with another drug (Drug Interactions)
• Drug Interactions can be further divided into a) an Ý in pharmacological effect or b) a ß in pharmacological effect
• Ý response
• Pharmacokinetic mechanisms
• the concentration of a drug at the site of action is elevated and at the upper portion of the normal dose-response curve.
• the slope of the dose-response curve is steep, and small changes in dose = large changes in response.
• Pharmacodynamic mechanisms
• situations where receptor density is increased. (changes in the dose-response curve occur because of alteration at the site of action)
• cumulative- two or more drugs that affect the same site of action
• ß response
• Pharmacokinetic mechanisms- a lowered concentration of a drug at the site of action due to ß delivery
• Pharmacodynamic mechanisms – a ß in response at the site of action Þ a shift to the right in the dose-response curve.
• K_M Ý = affinity ß
• Since C_ss = ( AUC / t ) = [(dose)(F) / (Cl)(t )] t = dosage interval
• Changes in C_ss from predicted could be because
• (1) lack of compliance (changes dose or dosage interval)
• (2) a change in the amount absorbed (F)
• (3) a change in the Clearance of the drug (Cl)
• digoxin and quinidine
• quinidine inhibits digoxin secretion at proximal tubule (ß Cl_digoxin)
• displaces digoxin from peripheral tissues into the plasma (ß V_D)
• phenytoin and valproate - both WOA’s that bind albumin
• valproate ß C_SS of phenytoin but f is same; no need to Ý phenytoin
• if Ý phenytoin, then f Ý and becomes toxic

• Absorption – changes in pH and drug ionization, complexes formed by drugs, gastric emptying, GI motility, drug interactions with nutrient absorption, drugs metabolized in the GI tract, influence of food on drug absorption, and influence of antacids and alkali. A ß in drug absorption will delay the onset and lessen the intensity of a drug response.
• "First Pass" effect- some drugs are metabolized in the gut by bacteria or by a "first pass" through the liver via splanchnic circulation dumping blood into the portal system before it hits the systemic circulation.
• Distribution – the distribution of drugs to tissues depends on blood flow to tissues, mass of the tissue, binding of the drug to tissue macromolecules, and the binding of drug to plasma proteins.
• If the V_D is small and the drug is highly bound to plasma proteins, clinically significant drug interactions can occur if another drug is introduced that also binds to plasma proteins. With decreased binding of drug the free-drug concentration will increase. If the V_D is small this increased free drug will influence the concentration in a theoretically small space, but if V_D is large the increase in free-drug will be diluted by the large volume available for its dispersal. The ß in binding will lead to an Ý in Clearance until a new steady state is reached where [free-drug] is the same and [total drug] is reduced.
• Elimination – the elimination of a drug from the body can be considered as clearance. Total systemic clearance = the sum of renal and metabolic clearances.
• Metabolic Clearance- Cl_int = "total intrinsic clearance" and is a measure of the capacity of the liver to irreversibly remove drugs from the plasma in the absence of flow limitations.
• Drugs with low Cl_int are limited by enzyme activity and are not affected by alterations in hepatic blood flow. These drugs can Ý clearance and shorten T_1/2 by induction (increased # or activity) of the enzymes that metabolize this drug.
• Drugs with high Cl_int will not be greatly affected by induction but changes in hepatic blood flow will have an impact. These drugs typically have a large "first pass" effect and need to be administered parenterally.
• Renal Clearance- occurs by Glomerular Filtration, Tubular Secretion, and is influenced by Tubular Reasorption.
• Drugs that are secreted can act as competitors and impair renal excretion of other drugs and endogenous compounds. (e.g. Probenecid ß Tubular Secretion thereby ß excretion of penicillin, salicylate, indomethacin, and furosemide)
• probenecid also ß reabsorption of urate Þ treatment for gout

• Interactions occurring at the receptor site: competitive, leading to ß response (e.g. Atropine, although not an agonist when it associates with the ACh receptor it competitively prevents ACh from associating and producing a response) or Cumulative: combined drugs leading to an Ý response (e.g. alcohol and barbiturates)
• Changes in the receptor: the response to one drug may lead to alterations in the receptor for another drug. (e.g. Thiazide diuretics lead to urinary K⁺ loss and may result in an increased Digitalis toxicity)
• Interactions with components other than the receptor at the site of action:
• Effects on different components of a system: If at the same time one drug increases input into the system and another drug ß output at a different part of the same system, the combined effect may be greater than one alone.

Drug Reactions – toxicity resulting from actions not related to the primary pharmacological activity of the drug