Drug Interaction

Dr. Hesham Aly Salem 2008 Cairo University Faculty of Pharmacy Dept. of Pharmacology & Toxicology

when Drug +

• Another drug • Herbal medicine • Food • Drink • Environmental chemical agent.

Changed Effect

OR

Outcome of drug interaction may be HARMFUL or BENEFICIAL

Harmful Interaction

↑ the effect of the drug

Toxicity

↓ the effect of the drug.

Combined Toxicity

No therapeutic effect

Harmful Interaction Combined Toxicity

1

The use of more than one drug, each of which has toxic effects on the same organ Æ ↑ Organ damage even though the therapeutic dose of either drug alone may be insufficient to produce toxicity

Harmful Interaction Combined Toxicity

2

The use of two drugs, one of them has toxic effects on certain organ, while the other has no intrinsic toxic effect on this organ Æ ↑ Organ damage even though the therapeutic dose of the toxic drug alone may be insufficient to produce toxicity

Harmful Interaction

Acute & potential life-threatening hypertensive crisis

TOXICITY

e.g.: MAOIs + Tyramine-rich foods

Harmful Interaction

Additive CNS depression

TOXICITY

e.g.: Two or more CNS depressants

Reduction of Therapeutic Effect

Harmful Interaction e.g.: Tetracyclines or Quinolones + Antacids or Milky foods

↓ or even abolish effects of these antibacterials

Beneficial Interaction e.g.: Antihypertensive + Diuretics

Additive therapeutic effect (Antihypertensive effects possibly not obtainable with either drug alone)

Patient Variability • You can predict the mechanism of drug interaction ………….BUT • In practice, it is very difficult to predict what will happen when an individual patient is given two potentially interacting drugs

Patient Variability • Many drugs may interact in some patients and may not in others. • Some patients apparently can tolerate the adverse outcome of interactions, while others cannot tolerate.

Also, do not uncritically extrapolate the interactions seen with one drug to all members of the same group: e.g.: Erythromycin + Lovastatin ↑ levels of lovastatin (erythromycin inhibits lovastatin metabolism but not affect pravastatin)

SOOOOO Choose a non-interacting alternative If this is not available You can give interacting drugs together but with appropriate precautions

Pharmacokinetic Interaction

Pharmacodynamic Interaction

Results in change of the delivery of the drug to its site of action

Results in change of the response of the drug at its site of action

BOTH

Mechanisms Through Affecting 1. ABSORPTION 2. DISTRIBUTION 3. METABOLISM

(BIOTRANSFORMATION)

4. EXCRETION

Drug absorption interactions

The interaction may affect: • The EXTENT of absorption (total amount absorbed) •The RATE of absorption

Affecting the EXTENT of drug absorption

1. Changes in GIT pH 2. Changes in drug free from 3. Changes in drug transport proteins

Affecting the EXTENT of drug absorption

1. Changes in GIT pH

May affect the extent to which the drug exist in the non-ionized lipid-soluble (absorbable form) Affect the passage of drugs through mucous membranes by simple PASSIVE diffusion

Affecting the EXTENT of drug absorption

1. Changes in GIT pH

PPI, H2RA, antacids Æ × pH ÆØ the absorption drugs that require acid medium for absorption (e.g. ketoconazole)

Affecting the EXTENT of drug absorption

2. Changes in drug free form

Adsorption - Chelation - Complexation

Reduce the EXTENT of drug absorption

Affecting the EXTENT of drug absorption

2. Changes in drug free form

• Activated charcoal • Antacids Æ ADSORB a large number of drugs given Æ Reduce the amount absorbed of drugs.

Affecting the EXTENT of drug absorption

2. Changes in drug free form • Metallic ions (found in antacids & diary products) Æ CHELATE with certain drugs. e.g.: Tetracycline can chelate with Ca, Al, Bi, Fe Æ complexes Æ poorly absorbed Æ Reduce the amount absorbed of drugs Æ Reduced antibacterial effects.

Affecting the EXTENT of drug absorption

2. Changes in drug free form

• Cholestyramine (Resin intended to bind bile acids and cholesterol metabolites in the gut) Æ BINDS to several drugs (e.g. digoxin, warfarin, lthyroxine), Æ reduce the amount absorbed of drugs.

Affecting the EXTENT of drug absorption

2. Changes in drug free form

Separating the administration of the interacting drugs by 2 to 3 hours may reduce the effects of this type of interaction.

Affecting the EXTENT of drug absorption

3. Changes in drug transport proteins

Drugs & endogenous substances cross biological membranes by: 1. Passive diffusion 2. Carrier (transporter)-mediated process The most well known is P-glycoprotein. glycoprotein

P-glycoprotein Efflux pump found in the membranes of certain cells Æ Push drugs & metabolites out of these cells Was , where Was first first identified identified in in some some cancer cancer cells cells, where itit actively actively transported transported multiple multiple chemotherapeutic chemotherapeutic drugs drugs out out of of cancer cancer cells, cells,thereby therebyrendering renderingthem themresistant resistantto todrug drugaction. action. The -glycoprotein inhibitors The development development of of specific specific PP-glycoprotein inhibitors ((valspodar) valspodar) Æ Æ improve improve the the penetration penetration of of cytotoxic cytotoxic drugs drugs into intothe thecancer cancercells. cells.

P-glycoprotein Have an impact on: 1. The extent of drug absorption (via intestine) 2. The drug distribution (to brain, testis, placenta) 3. The drug elimination (in urine, bile).

P-glycoprotein Affecting the EXTENT of drug absorption P-glycoprotein in cells of the gut lining Ejects some already-absorbed drug molecules back into the intestine Ø total amount of drug absorbed

P-glycoprotein Effect Effect on on the the drug drug distribution distribution P-glycoprotein in endothelial cells of BBB Ejects certain drugs from the brain

& Limiting CNS penetration & effects

P-glycoprotein Effect Effect on on the the drug drug elimination elimination P-glycoprotein in tubular cells of kidney Ejects certain drugs into the urine (Active tubular excretion) Elimination of these drugs

P-glycoprotein The actions of P-glycoprotein can be:

induced or inhibited by some drugs Æ Affect the pharmacokinetic of drugs that depend on this protein on their absorption, distribution & elimination.

P-glycoprotein Inducers of P-glycoprotein: Rifampin Inhibitors of P-glycoprotein: Verapamil – Ketoconazole Example: Digoxin affected by P-glycoprotein Æ ↓ plasma digoxin levels ?? Rifampin Verapamil Æ ↑ plasma digoxin levels. Example: Ritonavir affected by P-glycoprotein Ketoconazole Æ ↑ CSF levels of ritonavir

Affecting the RATE of drug absorption

Changing the GIT motility & gastric emptying are the main factors affecting the rate of drug absorption

Affecting the RATE of drug absorption

Changes in GIT motility Decrease the rate of

Increase the rate of

stomach emptying

stomach emptying

Delay the drug delivery to

Hasten the drug delivery

the site of absorption

to the site of absorption

Ø Rate of absorption

× Rate of absorption

For drugs that absorbed in ileum (Most of drugs)

Affecting the RATE of drug absorption

However,... The changing in the RATE of drug absorption is seldom clinically important BUT in certain cases it may be important ...When?

Affecting the RATE of drug absorption 1. If the drug is administered as single dose regimen and intended to give rapid effect (e.g. hypnotics, analgesics) Reduction in the rate of absorption may lead to failure to achieve the adequate effect “providing that no change in the total amount of drug absorbed”. N.B.: The rate of absorption is usually not important for chronically-given multiple dose drug regimen

Affecting the RATE of drug absorption 2. If the change in the RATE of absorption results in change in the EXTENT of absorption. FOR 1. Poorly absorbed drugs 2. Drugs subjected to intestinal mucosal metabolism

Affecting the RATE of drug absorption

1. For poorly absorbed drugs Changes in gut motility Æ Affect the time available for drug dissolution & absorption

Affect the total AMOUNT absorbed

Affecting the RATE of drug absorption

Changes in GIT motility Decrease the gut motility (e.g.: Anticholinergic drugs)

Increase the gut motility (e.g.: Prokinetic drugs)

× time available for drug

Ø time available for drug

dissolution & absorption

dissolution & absorption

× amount absorbed

Ø amount absorbed

Affecting the RATE of drug absorption

2. For drugs subjected to intestinal mucosal metabolism Changes in gut motility Æ Affect the contact time between the drug & the intestinal mucosa Æ Affect the amount metabolized before absorption

Affect the total AMOUNT absorbed

Affecting the RATE of drug absorption

Changes in GIT motility Decrease the gut motility

Increase the gut motility

( e.g.: Anticholinergic drugs)

(e.g.: Prokinetic drugs)

× time available for drug

Ø time available for drug

metabolism by mucosa

metabolism by mucosa

Ø amount absorbed

× amount absorbed

Affecting the RATE of drug absorption

Changes in GIT motility e.g.: Anticholinergic drugs /Levodopa Anticholinergic effects Æ may reduce the amount absorbed of levodopa, possibly because the exposure time to intestinal mucosal metabolism is increased.

Drug absorption interactions Malabsorption caused by certain drugs

Neomycin Malabsorption syndrome ↓ absorption of certain drugs (digoxin & methotrexate)

Drug distribution interactions

HOW HOW 1. Changes in drug transport proteins 2. Changes in drug-plasma protein binding

Drug distribution interactions

1. Changes in drug transport proteins

Inhibitors of P-glycoprotein Æ ↑ uptake of drug into the brain Æ ↑ CNS effects OR adverse effects (may be beneficial or harmful).

Drug distribution interactions 2. Changes in drug-plasma protein binding

Many drugs are transported with some proportion of their molecules in solution (free, unbound) and the rest bound to plasma proteins (particularly albumin).

Drug distribution interactions 2. Changes in drug-plasma protein binding

Drug + PP ↔ Drug-PP Free

Bound

Free ¾ Pharmacologically active ¾ Subjected to metabolism & excretion. Bound ¾ Pharmacologically inactive ¾ Reservoir which is temporarily protected from metabolism & excretion.

Drug distribution interactions 2. Changes in drug-plasma protein binding

Drug + PP ↔ Drug-PP Free

Bound

As the free molecules become metabolized, some of the bound molecules become unbound and pass into solution to exert their normal pharmacological action.

Drug distribution interactions 2. Changes in drug-plasma protein binding ¾ One drug may compete with another on PP Æ Displacing it (Depending on their concentrations and relative affinities for PP) Æ ↑ number of free and active molecules ¾ Such increase in the free concentration (and thus the effect) of the displaced drug in plasma will be transient owing to Compensatory increase in drug disposition

Drug distribution interactions 2. Changes in drug-plasma protein binding SO…Clinically, such interactions are unlikely to result in adverse effects …UNLESS…??????. For: • Drugs given IV Or having very low Vd and have • Narrow therapeutic index Æ Toxicity OR • High extraction ratio - Short t1/2 Æ Reduced effect

Drug distribution interactions 2. Changes in drug-plasma protein binding This interaction is important in therapeutic drug monitoring.

As the drug is displaced from PP Æ ↑free drug Æ Quickly eliminated by metabolism and excretion Æ The amount of free active drug returns to normal. However, the total amount of drug would now be reduced. Therefore if the total drug was monitored Æ ??? if the free drug was monitored Æ ???☻