Pharmacokinetics: Drug Elimination

• The lecture covers pharmacokinetics, specifically the elimination process.

Intended Learning Objectives

• Students should be able to list factors affecting drug clearance, differentiate types of elimination kinetics, and predict elimination kinetics analysis of pharmacokinetic parameters.
• Students should be able to calculate drug half-life based on clearance and volume of distribution and explain why drugs with saturation kinetics pose greater toxicity risks.
• Dosage adjustment calculation for patients with renal impairment should be understood.

Key Terms

• Elimination Half-Life (t1/2) refers to the time it takes to halve the plasma concentration of a drug.
• Steady State Concentration (Css)
• Loading Dose (L.D.)
• Maintenance Dose (M.D.)

Elimination Half Life

• Definition: time required to reduce the plasma concentration of the drug by half.
• Formula: t1/2 = 0.693 Vd / CLs (Clearance)
• Factors affecting elimination t1/2 include the condition of eliminating organs (liver & kidney) and drug delivery to these organs.
• Plasma protein binding limits renal filtration, and drugs with high Vd can escape elimination in tissues.

Value of determining elimination t1/2

• Dosage interval relies on it
• IV infusion may be required if drugs have very short t1/2, most drugs given at t1/2.
• Drug accumulation is more likely when drugs are given at intervals less than t1/2.
• Drug concentration drops between doses if given at intervals greater than t1/2
• Indicates Tss (time required to attain Css): about 4-5 t1/2.

Steady State Concentration (Css)

• The plasma concentration of a drug at which the rate of intake equals the rate of elimination.
• Clinical values include maintaining therapeutic drug levels and calculating loading and maintenance doses.

Types of Elimination Kinetics

• First Order Kinetics
• Zero Order Kinetics
• Saturation Kinetics

Kinetic Orders: 1st Order Kinetics (Linear)

• Metabolizing enzymes have unlimited capacity.
• Rate of elimination is proportional to drug concentration.
• A constant fraction of the drug is eliminated per unit of time, for example, 50%/h.
• t1/2 is constant.
• On repeated dosing, a steady-state concentration (Css) is reached.
• Css is proportional to dose, where increased dose leads to increased Css.
• Tss (time to reach Css) is approximately 4-5 t 1/2.
• Modest changes in dose or bioavailability are usually tolerated.
• Drug metabolites don't change with dose
• Most drugs follow this kinetic order

Kinetic Orders: Zero Order Kinetics (Non-Linear)

• Metabolizing enzymes have limited capacity.
• The rate of elimination is constant even with changing drug concentrations.
• A set amount of drug is eliminated per unit of time, such as 50 mg/h.
• t1/2 is not constant and increases with higher doses.
• No Css is reached; repeated dosing results in drug concentration overshoot.
• Modest changes in dose or bioavailability can lead to toxicity.
• Drug metabolites change with dose
• Ethanol is a well-known example

Kinetic Orders: Saturation Kinetics

• Drugs often follow first-order kinetics at smaller doses but transition to zero-order kinetics at larger doses; the elimination mechanism is saturated.
• Modest changes in drug dose or bioavailability can cause unexpected toxicity
• Drug interactions are riskier.
• Phenytoin and Theophylline are examples of drugs where saturation kinetics occurs.

Systemic Clearance (CLs)

• The volume of fluid cleared of drug per unit time; CLs = renal clearance (Clr) + non-renal clearance (Clnr).
• Factors affecting drug clearance include blood flow to the clearing organ (directly proportional), plasma protein binding (inversely proportional), and volume of distribution (inversely proportional).
• The activity of processes that remove drugs, such as hepatic enzymes and glomerular filtration, are directly related to CLs.

Significance of Drug Clearance

• Used to determine the maintenance dose (MD).
• Dosing schedules for medications cleared through glomerular filtration can be adjusted based on creatinine clearance.
• Gentamicin's dose in patient with normal kidney function is 160 mg/day with CrCl= 120 ml/min, in patient with Cr Cl= 60 ml/min is 80 mg/day

Key Terms in Pharmacokinetic

• Cmax = maximal drug level obtained with the dose.
• tmax = time at which Cmax occurs.
• Lag time = time from administration to appearance in blood.
• Onset of activity = time from administration to blood level reaching minimal effective concentration (MEC).
• Duration of action = time plasma concentration remains greater than MEC.
• Time to peak = time from administration to Cmax.