1. Clinical Pharmacokinetics
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
Clinical Pharmacokinetics
PHCY 350
Lecture-2 Basic Concepts of Clinical Pharmacokinetics Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
explain the basic concepts of pharmacokinetics & dynamics,
apply the concepts of drug potency, drug tolerance and its clinical correlates,
describe linear versus non-linear pharmacokinetics including Michaelis-Menten pharmacokinetics.

3. Basic Concepts
Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs.
When drugs are given extravascularly (e.g., orally, intramuscularly, applied to the skin via a transdermal patch, etc.), absorption must take place for the drug molecules to reach the systemic circulation.
Distribution occurs when drug molecules that have entered the vascular system pass from the bloodstream into various tissues and organs such as the muscle or heart.

4. Metabolism is the chemical conversion of the drug molecule, usually by an enzymatically mediated reaction, into another chemical entity referred to as a metabolite.
The metabolite may have the same, or different, pharmacological effect as the parent drug, or even cause toxic side effects.
Excretion is the irreversible removal of drug from the body and commonly occurs via the kidney or biliary tract.
Others, particularly volatile substances, are excreted in the breath.
Elimination occurs by excretion and metabolism.

5. Pharmacodynamics is the relationship between drug concentration and pharmacological response.
The effect of a drug present at the site of action is determined by that drug’s binding with a receptor. (Eg. opiate receptors).
Drug potency
By acting on same receptor-amount of drug needed to produce response-a little dose of one produces the effect that more of another drug would = more potent.
Drug potency can be compared by concentration at which 50% of the maximum effect is achieved (50% of effective concentration or EC 50).
When 2 drugs of same pharmacological class tested in same individual, the drug with a lower EC 50 would be more potent.

6. A lesser amount of a more potent drug is needed to achieve the same effect as a less potent drug.

8. A drugs effect is often related to its concentration site of action, so it would be useful to monitor this concentration.
The receptor sites for digoxin are within myocardium and hence cannot directly sample drug concentration in this tissue.
Measure it in blood or plasma, urine, saliva and other easily sampled fluids.
Changes in plasma drug concentration reflects changes in drug concentrations at receptor site, as well as other tissues (directly proportional).
Clinical Correlate: Drugs concentrate in some tissues because of physical or chemical properties. Eg- digoxin concentrates in myocardium, and lipid soluble drugs like benzodiazepines concentrate in fat.

9. Effectiveness of a drug can decrease with continued use.
Tolerance
Effectiveness of a drug can decrease with continued use.
May be due to pharmacokinetic factors like increased metabolism (that decrease concentrations achieved with a given dose).
Pharmacodynamic tolerance occurs when same concentration at receptor site results in reduced effect with repeated exposure.
Eg:- Use of opiates in management of chronic pain.
Clinical Correlate: Tolerance can occur with commonly used drugs. E.g. continued use of organic nitrates like nitroglycerin cause hemodynamic tolerance. For this drug, tolerance can be reversed by drug-free intervals with long term use.

11. LINEAR VERSUS NONLINEAR PHARMACOKINETICS
When medications are given on a continuous basis (continuous intravenous infusion or an oral medication given every 12 hours), serum drug concentrations increase until the rate of drug administration equals the elimination (drug metabolism and excretion) rate.
At that point, serum drug concentrations become constant.
For example, if theophylline is given as a continuous infusion (Intravenous) at a rate of 50 mg/h, theophylline serum concentrations will increase until the removal of theophylline via hepatic metabolism and renal excretion equals 50 mg/h.

12. In this case, the solid line shows serum concentrations in a patient receiving intravenous theophylline at a rate of 50 mg/h (solid line) and oral theophylline 300 mg every 6 hours (dashed line).
Since the oral dosing rate (dose/dosage interval = 300 mg/6 h = 50 mg/h) equals the intravenous infusion rate, the drug accumulation patterns are similar.

13. For the intravenous infusion, serum concentrations increase in a smooth pattern until steady state is achieved.
During oral dosing, the serum concentrations oscillate around the intravenous profile, increasing during drug absorption and decreasing after absorption is complete and elimination takes place.

14. Regardless of the mode of drug administration, when the rate of drug administration equals the rate of drug removal, the amount of drug contained in the body reaches a constant value.
This equilibrium condition is known as steady state .
Steady-state serum or blood concentrations are used to assess patient response and compute new dosage regimens.
If a plot of steady-state concentration versus dose, yields a straight line, the drug is said to follow linear pharmacokinetics.
While most drugs follow linear pharmacokinetics, in some cases drug concentrations do not change proportionally with dose.

15. If a plot of steady-state concentration versus dose is not a straight line and the drug is said to follow nonlinear pharmacokinetics

16. When steady-state concentrations increase more than expected after a dosage increase, the most likely explanation is that the processes removing the drug from the body have become saturated.
This phenomenon is known as saturable or Michaelis-Menten pharmacokinetics.
Both phenytoin and salicylic acid follow Michaelis-Menten pharmacokinetics.

17. When steady-state concentrations increase less than expected after a dosage increase, there are 2 typical explanations.
Some drugs like valproic acid and dysopyramide, saturate plasma protien binding sites so that as the dosage is increased steady-state serum concentrations increases less than expected.
Other drugs such as carbamazepine, increase their own rate of metabolism from the body as dose is increased so steady-state concentrations increase less than anticipated.
This process is called as autoinduction of drug metabolism.
Drugs that shows non-linear pharmacokinetics are very difficult to dose correctly.

19. Clinical Application
Steady-state serum concentrations/dose plots for medications are determined in humans early during the drug development process.
It is usually known if the drug follows linear or nonlinear pharmacokinetics, and is not necessary to determine this relationship in individual patients.
The clinician treating a patient will be alert to expect linear or nonlinear pharmacokinetics and can assume the appropriate situation when adjusting drug doses.
Dealing with drugs that follow linear pharmacokinetics is more straightforward and relatively easy.

20. A dosage adjustment is required because of lack of drug effect or the presence of drug toxicity in a patient, steady-state drug concentrations will change in proportion to dose for drugs that follow linear pharmacokinetics.
For example,
if a patient is taking sustained-release procainamide 1000 mg every 12 hours for the treatment of a cardiac arrhythmia, but is still having the arrhythmia.
A clinician could obtain a steady-state procainamide serum concentration.
If the procainamide concentration was too low (e.g., 4 μg/mL before the next dose), a dosage increase could help suppress the arrhythmia.

21. Apply linear pharmacokinetic principles
One could determine that a dosage increase to 1500 mg every 12 hours would increase the steady-state procainamide serum concentration to 6 μg/mL
(e.g., new steady-state concentration = (new dose/old dose) × old steady-state concentration)
New steady-state concentration = (1500 mg/1000 mg) × 4 μg/mL = 6 μg/mL.