1. Clinical Pharmacokinetics
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
Clinical Pharmacokinetics
PHCY 350
Lecture-12 Drug Dosing in Special Populations- Drug-Drug Interactions Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outline
Upon completion of this lecture the students will be able to
explain the outcomes of drug-drug interactions,
analyze the pharmacokinetic drug interactions in clinical conditions,
manage the drug interactions.

3. Drug interaction can be defined as “a measurable modification (in magnitude and/or duration) of the action of one drug by the prior or concomitant administration of another substance, including prescription, non-prescription drugs, food, alcohol, cigarette smoking or diagnostic tests
Outcomes of drug interactions:
Loss of therapeutic effect
Toxicity
Unexpected increase in pharmacological activity
Beneficial effects (e.g. additive & potentiation or antagonism (unintended).
Chemical or physical interaction e.g. I.V incompatibility in fluid or syringes mixture

4. High Risk Drugs
Narrow therapeutic index
– Aminoglycosides
– Digoxin
– Phenytoin
– Lithium
– Warfarin
Steep dose-response curve
– Carbamazepine
– Quinidine
– Oral Contraceptives

5. High Risk Patients
Multiple drug therapy
Severely ill patients
CV disease
Epilepsy
GI disease
Psychiatric disease
Clinical Significance
Most interactions result in little clinical significance
Only a small number have major consequences such as
being life threatening
Consequences can usually be averted by awareness

6. MECHANISM OF DRUG INTERACTION
Pharmacokinetic interactions
Absorption
Distribution
Biotransformation
Excretion
Pharmacodynamic interactions
Receptor interaction
Receptor sensitivity
Neurotransmitter release/Drug transportation
Electrolyte balance
Physiological interactions
Pharmaceutical interactions

7. Pharmacokinetic Interactions
Altered GIT absorption due to
Altered pH
Altered bacterial flora
Formation of drug chelates or complexes
Drug induced mucosal damage
Altered GIT motility
Altered pH:
The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does
E.g. Antacids, H2 blockers delay the absorption of Ciprofloxacin and Ketaconazole

8. Altered intestinal bacterial flora:
Antibiotics kill a large number of the normal flora of the intestine that influences the absorption of other drugs.
E.g. In 10% of patients receive Digoxin…..40% or more of the administered dose is metabolized by the intestinal flora that increases the concentration and toxicity of the drug
Complexation or chelation:
E.g. Tetracycline interacts with iron preparations
Milk (Ca2+ ) forms insoluble complexes of drugs
Antacid (aluminum, magnesium, ferrous) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

9. Drug-induced mucosal damage:
Antineoplastic agents (Cyclophosphamide, Vincristine, Procarbazine) Inhibit absorption of several drugs (E.g. Digoxin)
Altered motility:
Metoclopramide (antiemetic) increase absorption of cyclosporine due to the increase of stomach emptying time and increase the toxicity of Cyclosporine, Digoxin

10. Altered Distribution:
Displaced protein binding:
It depends on the affinity of the drug to plasma protein
The most likely bound drugs is capable to displace others
The free drug is increased by displacement by another drug with higher affinity
E.g. Phenytoin (90%), Tolbutamide (96%) and warfarin (99%) are highly bound to plasma protein and displaces drugs like Aspirin, Sulfonamides, Phenylbutazone
Effect is transient as clearance returns free levels to pre-interaction levels
Hence, clinically not much important

11. Altered Metabolism:
The effect of one drug on the metabolism of the other is well documented
The liver is the major site of drug metabolism but other organs can also do e.g., WBC, skin, lung, and GIT
CYP450 family is the major metabolizing enzyme in phase I (oxidation)
% drugs metabolized by CYP enzymes
3A %
2D %
1A %
2C Small no. but significant interactions
2C Small no. but significant interactions

12. Enzyme induction:
A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself
Most CYPs are inducible but not CYP2D6
Time course of interaction depends on half-life of inducer
Rifampicin has short half-life and induction apparent with 24 hours
Phenobarbitone has longer half life so time to complete induction takes longer

13. Known induction by
Rifampicin
Phenobarbitone
Carbamazepine
Cigarette smoke
e.g., Carbamazepine (antiepileptic drug) increases its own metabolism
Phenytoin increases metabolism of Theophylline and decreases its level leading to poor therapy outcome
Phenobarbital increases the metabolism of Warfarin, resulting in reduced anticoagulation
Enzyme induction involves protein synthesis, therefore, it needs time up to 3 weeks to reach a maximal effect

14. It is the decrease of the rate of metabolism of a drug by another one.
This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity.
Inhibition of the enzyme may be due to the competition on its binding sites, so the onset of action is short may be within 24h.
When an enzyme inducer (e.g. Carbamazepine) is administered with an inhibitor (Verapamil) The effect of the inhibitor will be predominant.
E.g. Erythromycin inhibit metabolism of Astemazole (anti – histaminic) and Terfenadine Increase the serum concentration of the antihistaminic leading to increasing the life threatening cardio toxicity.

15. Cimetidine reduces the clearance of Theophylline
Cimetidine reduces the clearance of Theophylline causing an increase in adverse effects
Omeprazole Inhibits oxidative metabolism of diazepam
First-pass metabolism:
Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action.
This is more clear when such drug is an enzyme inducer or inhibitor.
E.g. Rifampin lowers serum concentration of Verapamil level by increase its first pass metabolism.

16. Renal excretion Active tubular secretion
It occurs in the proximal tubules.
The drug combines with a specific protein to pass through the proximal tubules.
When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug, this will reduce such a drug excretion increasing its con. and hence its toxicity.
E.g. Probenecid Decreases tubular secretion of Methotrexate

17. Passive Tubular Reabsorption
Excretion and reabsorption of drugs occur in the tubules by passive diffusion which is regulated by concentration and lipid solubility.
Ionized drugs are reabsorbed lower than non-ionized ones
E.g. Sodium bicarbonate increases lithium clearance and decreases its action
Antacids Increases Salicylates clearance and decreases its action.

18. Managing drug interaction
Monitoring therapy and making adjustments
Monitoring blood level of some drugs with narrow therapeutic index e.g. Digoxin, anticancer agents…etc
Monitoring some parameters that may help to characterize the early events of interaction or toxicity e.g., with warfarin administration, it is recommended to monitor the prothrombin time / INR to detect any change in the drug activity
Increase the interest of case report studies to report different possibilities of drug interaction