Pharmacokinetics: Drug Elimination

Elimination half life

• Half life the length of time required for the concentration of a drug to decrease to a half of its starting concentration in the body
• Plasma half life is same as half life but more precise expression
• Biological half life is the time needed to eliminate 50% of drug from tissues
• Half life calculated by two methods:
• first by giving the drug to patient and calculating plasma conc of drug and plotting it into concentration time curve and finding the half life;;
• by the equation clearance= 0.7*vd/ t1/2
• Half life is the time when the drug is taken again like amoxicillin q12h means half life 12 hours

Clinical significance of half life

• Determination of dosing frequency of a drug
• Determination of drug dose taken by pt. who is unconscious if the timing when dose was taken is known , there is another way to identify the dose taken by unconscious patient from volume of distribution

Kinetics of drug elimination

• Kinetics of drug elimination refers to the study of the rate at which a drug is eliminated from the body
• We have two orders of drug elimination kinetics, first order and zero order.
• The main factors affecting the kinetics by which the drug eliminated is the chemical properties of the drug itself, and the dose of the drug given.
• Understanding the kinetics of drug elimination is important to predict the duration of action of a drug, It can also help to determine appropriate dosing regimens for different patient populations, and to predict the likelihood of side effects associated with a particular drug.

Steady state plasma concentration Css

• Steady state plasma concentration means the steady drug level in the circulation and that is achieved when rate of administration equals rate of elimination
• Means we supply the eliminated part of the drug

General facts about the Css

• we reach Css after 5 half lives
• if we change the dose , the new Css reached after 5 half lives
• If dosing stops, complete elimination of the drug from plasma occurs after 5 half lives
• Css is 1.5 the dose you give
• you can reach the Css with 1 half life and that is by using the loading dose

Loading dose

• We can reach the Css with 1 half life instead of 5 and that is by using the loading dose
• Loading dose is needed in serious infections or arrhythmias (Emergency conditions)
• Disadvantage of loading doses include increased risk of drug toxicities and a longer time for the plasma concentration to fall if drug accumulation occurs

Clinical significance of zero order elimination

Important points to look for in zero order elimination

• Modest change in drug dose may produce unexpected toxicity
• Elimination of drugs or attainment of Css takes long time
• If patient change formulations by buying another type this might lead to toxicity too because other formulations might have additives or have another drug combined with or wrong dose
• Drug accumulation and drug to drug interactions are common

Clearance

• Clearance is the volume of plasma become cleared from some substance per unit time
• For example: drug clearance is 100 ml/min , means 100 ml of plasma cleared from that drug in 1 minute
• We have multiple routes of elimination like kidney, liver , sweat, tears, breast milk, lungs …
• Kidney is the primary organ of drug elimination
• Lungs primarily involved in elimination of anesthetic gases (like isoflurane)
• Drug eliminated through breast milk might expose infant to medications and metabolites taken by mother and lead to side effects in infants
• Drugs that conjugated in the liver are excreted through bile and into feces

Clinical significance of clearance

• avoid injury of diseased organ by avoiding drugs that are cleared by that organ. Solved by giving drugs that cleared by another organ, if there is no alternatives then dose adjustment is the solution
• CL=0.7 *Vd/t1/2 , through this formula you can identify the half life and subsequently the dose of the drug you should give if you know clearance of that drug thus avoiding accumulation.
• if drug cleared by certain organ , you can make it a targeted therapy to that organ. E.g. in UTI we use antibiotics that are cleared by the kidney like nitrofurantoin
• Ion trapping: manipulating urine PH to trap drugs that are (accumulated in the body) in urine and excrete them
• weak acids can be eliminated by alkalinization of the urine
• weak bases may be increased by acidification of the urine

Drug monitoring

• Drug monitoring is monitoring of drug level in plasma to optimize therapy and avoid toxicity
• Not all drugs are monitored
• Drug monitoring is calculated by either:
• calculating the drug level itself in blood
• calculating the effect of the drug like in warfarin (anticoagulant) we calculate INR of the blood (level of coagulation of blood: the usual number Is 1.2 and when giving warfarin it increases )

Drug monitoring clinical significance

• Avoid toxicity while using drugs with narrow therapeutic index (meaning the dose gap between therapy and toxicity is small) like digoxin, warfarin and lithium
• Avoid toxicity in patient who have renal impairment or liver impairment , by monitoring the level of the drug and adjusting it.
• Differentiation between drug resistance and patient non compliance (if drug level is low means non compliance, if normal dose it is resistance)

Course Menu

This lecture is part of the Clinical Pharmacology Basic Principles Free Course; this course also include these lectures:

• Routes of drug administration
• Pharmacokinetics 101: Drug absorption
• Pharmacokinetics 101: Drug distribution
• Pharmacokinetics 101: Drug elimination
• Drug targets: Receptors, ion channels, enzymes and carrier molecules
• Pharmacodynamics 101: Agonist dose response curves
• Pharmacodynamics 101: Types of antagonists
• Drug factors affecting patient response
• Patient factors affecting response to drugs