Drug Dose and Interactions

Drug Dose and Drug Interaction

• This lecture covers drug dose, drug interaction, pharmacokinetics as part of BMS161 (5)
• The student should be able to calculate and predict drug dosages, effects, interactions and adjustments at the end of this lecture

Optimization of the Dose: Loading Dose

• Loading dose is the dose administered to achieve the desired plasma level rapidly
• The intravenous loading dose (IV LD) is calculated as the volume of distribution (Vd) multiplied by the desired steady-state concentration (Css) (IV LD = (Vd) × (desired Css))
• The oral loading dose is calculated as Vd multiplied by the desired Css divided by F (Bioavailability): Oral Loading dose = (Vd) × (desired Css) /F (Bioavailability)
• Loading doses can be administered as a single dose or over a series of doses
• Disadvantages of loading doses can include an increased risk of drug toxicity
• Using loading doses is most useful for drugs that have a relatively long half-life and shorten the time to reach Css

Optimization of the Dose: Maintenance Dose

• Maintenance dose is the dose given to maintain a Css within the therapeutic window
• The intravenous infusion maintenance dose (MD) is calculated as clearance (Cl) multiplied by Css: I.V. infusion MD = Cl X Css
• The intravenous injection MD is calculated as Cl multiplied by Css multiplied by the time interval: I.V. injection MD = Cl X Css X time interval
• The oral MD is calculated as Cl multiplied by Css multiplied by the time interval, divided by F (bioavailability): Oral MD = Cl X Css X time interval / F (bioavailability)

Washout Period of Drug

• Clinical significance of washout period is risk of drug interaction

Dosing in Renal Impairment

• Dose in Cr Cl 120 mL/minute = 120 mg/12 hours
• How to manage a patient with CrCl 60 mL/minute: give 60 mg/12 hours instead of 120 mg/24 hours

Summary

• Continuous or repeated administration of fixed doses results in accumulation of the drug until a steady state occurs
• Plasma and tissue levels remain relatively constant
• The time required to reach the Css is 4-5 times the half-life
• The time required to wash out the drug is 4-5 times the half-life.
• Clinical significance includes the residual effect of a drug even after withdrawal and serious drug interactions that may occur if one drug is stopped and replaced by another immediately

Drug-Drug Interactions

• High-risk drug-drug interactions include drugs that possess a steep dose-response curve, low therapeutic index (TI), enzyme-inducing or inhibiting properties, and saturation kinetics
• High risk patients include those receiving multiple drugs, severely ill patients with impaired liver or kidney function, and patients at extremes of age
• Important examples include, oral anticoagulants, oral hypoglycemics, cardiac glycosides, and antiepileptics.

Types of Drug Interactions

• Pharmaceutical incompatibilities occur outside the body, such as precipitation when drugs are mixed in solution for IV administration
• Pharmacokinetic interactions occur at absorption, distribution, metabolism, and excretion
• Pharmacodynamic interactions occur at the sites of action or nearby

Pharmacokinetic Interactions

• Interactions at the site of absorption include tetracyclines chelate metals, decreasing its absorption by calcium, iron, or antacids (Mg2+, & Al3+)
• Drugs that alter GI motility or change the pH of the gut contents can also effect absorption

Displacement Interaction at Plasma Protein

• Clinically important protein binding interactions necessitate that more than 90% of the drug is plasma-protein-bound and have a low therapeutic index
• Examples of displacement interactions are; aspirin displaces warfarin, which leads to bleeding; sulfonamides & vitamin K displace bilirubin which leads to hyperbilirubinemia and kernicterus in newborns

Interactions Involving Metabolism

• Enzyme induction by enzyme inducers leads to an increase in metabolism of other drugs, leading to decreased levels and effects, resulting in failure of therapy.
  • Rifampicin increases the metabolism of oral contraceptives, which leads to pregnancy.
  • Phenytoin increases the metabolism of vitamin D, which leads to osteomalacia
• Enzyme inhibition by enzyme inhibitors leads to a decrease in metabolism of drugs given simultaneously, which leads to increased levels, resulting in potentiation/toxicity
  • Erythromycin inhibits the metabolism of theophylline
  • Ciprofloxacin inhibits the metabolism of theophylline and warfarin

Interactions at Site of Excretion

• Alkalinization of urine leads to increased ionization of acidic drugs (aspirin)
  • This leads to decreased tubular reabsorption and increased excretion, useful in the treatment of toxicity
• Acidification of urine leads to increased ionization of basic drugs (amphetamines)
  • This leads to decreased tubular reabsorption and increased excretion, useful in the treatment of toxicity
• Probenecid competes with penicillin for renal tubular excretion
  • This inhibits its excretion, which prolongs its action

Pharmacodynamics Interactions

• Enhancement Interactions
  • Summation (1+1=2); additive where drug A lowers BP 5 mmHg and drug B lowers BP 5 mmHg, so both lower BP 10 mmHg
  • Synergism (1+1=5); Sulfonamides (static antibiotic) + trimethoprim (static antibiotic) where the combination is bactericidal
  • Potentiation (0+1=>1); a drug with no effect intensifies the action of the other
    • Beta lactamase inhibitor has no antibacterial effect, but it intensifies the antibacterial effect of amoxicillin (antibiotic)
• Antagonistic Interactions (1+1=0) where β Blockers + β agonist