DRUG INTERACTIONS

What if these drugs fight with each other in my stomach!

Learning Objectives

•         Determining the interactive potential of an increasingly large number of possible drug combinations

•         This course has been designed to make pharmacist able to identify the potential

•         Drug-drug

•         Drug-food

•         Drug-herbal

•         Drug-lab test interactions

•         General

•         Drug-drug interactions

•         Drug-food interactions

•         Drug-herbal product interactions

•         Drugs interacting with lab tests

•         General definition of drug interaction

•         Incidence / epidemiology

•         Significance levels / significance rating

ONSET

–        Rapid

–        Delayed

SEVERITY

•         Major

•         Moderate

•         Minor

          DOCUMENTATION (evidence based)

•         Established

•         Probable

•         Suspected

•         Possible

•         Unlikely

•         Effects

•         Mechanism (based on the pharmacology & mechanism of action)

•         Management (some interactions on the basis of the severity needs management)

•         TYPES

–        Pharmacokinetic (mechanism in detail)

–        Pharmacodynamic (mechanism in detail)

DRUG INTERACTIONS

Background

•         Drug interactions—First recognized in 1895

–        It was found that Adrenal extract could induced arrhythmias in dogs anaesthetized by Chloroform (Oliver & Schaefer)

•         Drug interaction is enormous today because of

–        Complexity of the therapeutic agents

–        Widespread polypharmacy / irrational use

–        There are however many drug interactions but only few are significant

Importance

•         For a Clinical Pharmacist drug interaction knowledge primarily involves

–        To know or predict the occasion when the potential drug interaction is likely to have clinically significant consequences.

–        Therefore it is essential for a pharmacist to have a practical knowledge of pharmacological mechanisms involved

Definitions

•         The phenomenon that occurs when the effects or pharmacokinetics of a drug are altered by prior administration or co-administration of a second drug.

                                                OR

•         The modification of a drug’s effect by prior or concomitant administration of another drug.

                                               

General

•         A drug interaction may occur when the pharmacological effect of two or more drugs given together is not just a direct function of their individual effects.

•         Sometimes the drug-drug interactions are considered to be adverse drug reactions and do include the beneficial aspect of the interactions (e.g. Ampicillin & Probenecid).

•         However on the other hand the drug interactions may result in adverse drug reactions.

The effect of the drug may be modified by food, smoking, alcohol or environmental pollutants.

•         The drug interaction with the food: (e.g. fatty meals & Griseofulvin).

•         Endogenous substances (e.g. Sulfonamides & Bilirubin in neonates)

•         Herbal (e.g. Ginseng)

•         Environmental and industrial chemicals (e.g. Organophosphorus insecticides & Succinylcholine) 

•         Laboratory tests (e.g. Penicillin & Clinitest)

•         Interactions of a pharmaceutical or physicochemical nature may occur when two or more drugs are mixed prior to administration, these interactions are generally said to be incompatibilities.

Nomenclature

Drug interaction pair typically consists of

An Object drug & a Precipitant drug

•         The activity of the ‘object drug’ is altered and the drug causing this change is termed as the ‘precipitant drug’

•         A drug may be an object drug in one interaction (e.g. Phenytoin—Cimetidine) and precipitant drug in another interaction (e.g. Doxycycline—Phenytoin) à in multi-drug regimen

•         With most pharmacologic interactions, there may be no object or precipitant drug, but simply a synergistic or antagonistic effect with both drugs (e.g. concurrent use of several drugs with CNS depressant actions may result in excessive CNS depression)

Other terms generally used:

•         Index drug

•         Interacting drug

SOME IMPORTANT EXAMPLES

CARBAMAZEPINE èç MACROLIDES

•         Significance   = 1

•         Onset           = Rapid

•         Severity                  = Major

•         Effect           = CBZ concentration                                                         increased (toxicity)

•         Mechanism    =       inhibition of CBZ                                            hepatic metabolism (CYP3A4) &                                    consequently decreased clearance of                                   CBZ 

•          Management          = use other alternatives like                                                         Azithromycin

CARBAMAZEPINE èç MAOIs

•         Significance   = 1

•         Onset           = Delayed

•         Severity                  = Major

•         Effect           = Theoretical risk of severe side                                         effects                                                                              (hyperexcitability,                                                    muscle rigidity, seizures)

•         Mechanism    =       Unknown  

•          Management          = co-administration of both is                                            contraindicated, discontinue                                MAOIs 14 days prior to administration of CBZ

CARBAMAZEPINE èç METRONIDAZOLE

•         Significance   = 4

•         Onset           = Delayed

•         Severity                  = Moderate

•         Effect           = CBZ concentration                                                         increased (toxicity)

•         Mechanism    =       inhibition of CBZ                                            hepatic metabolism (CYP3A4) &                                    consequently decreased clearance of                                   CBZ 

•          Management          = Monitor CBZ levels, adjust dose 

CARBAMAZEPINE èç TCAs (Tricyclic Antidepressants)

•         Significance   = 2

•         Onset           = Rapid

•         Severity                  = Major

•         Effect           = CBZ concentration                                                         increased (toxicity)

•         Mechanism    =       inhibition of CBZ                                                     hepatic metabolism (CYP3A4)                                            decreased clearance of                                                       CBZ  (competition for same enzyme system)

•          Management          =       remove TCAs from therapy or adjust the dose

DRUGS MOST COMMONLY INVOLVED IN THE ADVERSE INTERACTIONS

•         Potent therapeutic agents

•         Narrow therapeutic index (small increase in plasma concentration may produce toxicity)

•         Drugs with which a small decrease in plasma concentration may result in the loss of therapeutic effect.

DRUGS WITH HIGH RISK OF INTERACTION

•         Conc. Dependent Toxicity

•         Digoxin

•         Lithium

•         Aminoglycosides

•         Cytotoxic agents

•         Warfarin

•         Steep dose-response curve (narrow therapeutic index)

•         Verapamil

•         Sulphonylureas

•         Levodopa

•         Patient dependent on therapeutic effect

•         Immunosuppressive e.g. cyclosporine, tacrolimus

•         Glucocorticoids

•         Oral contraceptives

•         Antiepileptic

•         Antiarrhythmics

•         Saturable hepatic metabolism

•         Phenytoin

•         Theophylline

SUSCEPTIBLE PATIENTS

•         Elderly (greatest risk of interaction)

•         Critically ill

•         Undergoing complicated surgical procedures

•         Children (greatest risk of interaction)

•         Pregnant women (greatest risk of interaction)

These patients often have impaired organ function which may affect the

•         Elimination of drug from the body

•         Patients with chronic conditions as:

•         Diabetes

•         HIV infections

•         Asthma

•         Epilepsy

•         High blood pressure

TYPES OF DRUG INTERACTIONS

•         PHARMACOKINETIC

•         PHARMACODYNAMIC

PHARMACOKINETIC INTERACTIONS

•         One drug alters the rate or extent of absorption, distribution or elimination (metabolism or excretion) of another drug

•         Marked inter-individual variability è extent cannot easily be predicted

•         May result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy.

Kinetic Parameters

PARAMETERS HELPFUL IN THE MEASUREMENT OF KINETIC INTERACTIONS

•         Maximum serum concentration

•         Area under the concentration-time curve

•         Half life

•         Total amount of drug excreted in urine

PHARMACODYNAMIC INTERACTIONS

•         One drug induces a change in a patient’s response to a drug without altering the object drug’s pharmacokinetics.

•         The change in drug action is seen without altered plasma concentration.

e.g. the increase in the toxicity of Digoxin produced by potassium-wasting diuretics.

•         Pharmacodynamic interactions generally involve additive, synergistic or antagonistic effects of drugs acting on the same receptor site or physiological system.

•         Pharmacological interactions—concurrent use of two or more drugs with similar or opposing pharmacological actions (e.g. use of alcohol with an anti-anxiety drug and a hypnotic or antihistamine).

PHARMACOKINETIC MECHANISM OF INTERACTION

•         The extent of pharmacokinetic interactions may result in a change drug concentration at the site of action with subsequent toxicity or decreased efficacy.

1.0. ABOSRPTION

•         The oral route è most common and preferable route of administration.

•         Majority of the drugs are given by this route

•          It renders the drugs to be absorbed through the mucous membranes of the gastrointestinal tract.

•         Most of the interactions which occur in the gut result in the reduced rather than increased absorption.

•         For drugs that are given chronically on a multiple dose regimen the rate of absorption is usually unimportant provided the total amount of drug absorbed is not markedly altered e.g. oral anticoagulants

1.1. Delayed absorption is clinically significant where affected drug has short half-life or where it is intended to achieve high plasma levels e.g. analgesics or hypnotics.

Management Altered absorption interactions can be avoided if an interval of 2—3hrs is allowed between the administrations of the interacting drugs.

•         There are many mechanisms by which drugs theoretically alter the absorption of another drug, these include altered splanchnic blood flow, gut motility, gut pH, drug solubility, gut metabolism, gut flora or gut mucosa.

1.1.1. Role of P-glycoprotein

•         The drugs may be excreted back into the GIT lumen by P-glycoprotein,

•          Multi-drug resistant gene that lowers intracellular drug concentration by acting as an energy dependent drug efflux pump (ATP)

•         Numerous drugs are potential substrate for P-glycoprotein transporter.

•         P-glycoprotein is found in normal tissues, including small and large intestine, kidneys, liver (billiary, hepatocytes and endothelial cells at the blood-brain barrier)

•         Herbal products or drugs that may inhibit or induce P-gp may increase or decrease the plasma concentration of P-gp substrate (i.e. drugs)

•         P-gp may be involved in many drug interactions occurring in the GIT, liver and kidney.

•         Orally administered drug that is substrate for P-gp may be secreted back into the GIT lumen by P-gp

•         If a drug is a substrate of a P-glycoprotein in the GIT, uptake from the intestine will be incomplete à Decreasing drug levels

•         For example: co-administration of Digoxin and Rifampicin à Rifampicin result in decreased Digoxin level

          Mechanism    = unknown

          Management = an increase in the Digoxin dosage may be required

1.2. Changes in GI pH

•         The absorption of drug across mucous membranes depends on

                   à extent to which it exists in the non-ionized

                   à lipid-soluble form

•          The ionization depends on the

                   à pH, pKa of drug and the

                   à formulation factors.

•         Weakly acidic drugs à best absorbed at low pH (salicylates) as non-ionized form predominates.

•         Alteration of pH by antacids, proton pump inhibitors or H2 antagonists potentially affect the absorption of other drugs.

For Example: Antacids, H2 antagonists (Cimetidine) and proton pump inhibitors (Omeprazole) can significantly decrease the bioavailability of Ketoconazole and Itraconazole (both requiring gastric acidity for optimal absorption)

•         The alkalizing effects of antacids are transient and potential for drug interaction

•         Can be minimized by leaving an interval of 2—3hrs between the antacid and potentially interacting drugs

For Example: Quinolones / Tetracycline & Antacids (containing Di- & Tri-valent ions)

1.2.1. Absorption, Chelation & other Complexation Mechanisms

•         It’s a physical phenomenon

•         Drugs directly interact with other drugs to form insoluble complexes or chelates resulting in impaired abs or complete inhibition 

•         Drugs most commonly involved: Tetracyclines and Quinolone antibiotics—complex with iron and antacids containing calcium, magnesium and aluminum.(also with dietary constituents of food containing Di- or Tri-valent minerals)

•         They form insoluble complexes

•         Reducing the serum concentration of either object or precipitant drug

•         Adsorbents like activated charcoal may also reduce the absorption of concomitantly administered drugs

•         For Example: Colestyramine—reduces the absorption of Digoxin, Propranolol, Warfarin, TCAs, Cyclosporine and Thyroxin.  

•         Management: separating doses of the interacting drugs by a period of several hours.

1.3. Drug Effects on GI Flora

•         Bacterial flora predominates in the large intestine and is present in much smaller number in small intestine and stomach

•         drugs absorbed from the small intestine, intestinal bacteria inactivate the drug

For Example: 10% of Digoxin is inactivated by the gut bacteria, and introduction of broad spectrum antibiotics result in substantial increase in the levels of Digoxin.

•         Gut bacteria also prevent the bacterial hydrolysis of drug conjugates secreted into bile thus reduce the re-absorption of the active parent drug.

•         Antibiotics reduce the enterohepatic circulation of ethinylestradiol (oral contraceptive) à Reduced circulating estrogen levels è Therapeutic failure.

1.4. Effects on Gastric Motility

•         Drugs that alter the rate at which the stomach empties its contents can affect the absorption

For Example. Anticholinergic, TCAs, Phenothiazines, Antihistamines, Opiates (morphine, Pethidine & codeine) etc.

          Metoclopramide increases the gastric emptying and increases the absorption of Paracetamol (therapeutic advantage in migraine).

2.0. DISTRIBUTION 

•         The main mechanism è Displacement of one drug from the protein binding sites

•         Drug displacement interaction may be defined as a reduction in the extent of plasma protein binding of one drug caused by the presence of another drug è Increased free or unbound fraction of the displaced drug

•         Albumen is the main protein to which the acidic drugs are bound e.g. Warfarin.

•         Basic drugs bind to α1 –acid glycoprotein e.g. TCAs, Lidocaine, Disopyramide, Propranolol.

•         If displacement occurs, then the concentration of free drug rises temporarily, but metabolism & distribution returns free concentration to its previous level è time taken in this depends on the half life of the displaced drug.

•         This short-term rise in free concentration is generally of minor importance in therapeutic drug monitoring

•         For example:

          Patient taking Phenytoin, is given another drug that displaces it from its binding sites è Total plasma Phenytoin concentration will fall even though the free (active) concentration remains the same

Concentration & relative affinities

•         One drug compete with other drug and displace it from the binding site

•         The displaced drug molecule (now active) passes into the plasma à rise in conc.

For exampleè a drug which reduces the binding from (say) 99 to 95% would thereby increase the unbound concentration of free and active drug from 1 to 4% (a fourfold increase). 

•         This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues, so that only drugs with a low apparent volume of distribution (Vd) will be affected

•         Such drugs include the sulphonylureas such as tolbutamide (96% bound, Vd 10 l), oral anticoagulants such as Warfarin (99% bound, Vd 9 l) and Phenytoin (90% bound, Vd 35 l).

•         Other highly bound drugs include diazoxide, etacrynic acid, methotrexate, nalidixic acid, phenylbutazone and the sulphonamides.

Receptor Binding:

•         Binding sites are also significant in drug interaction e.g. Quinidine displaces Digoxin from binding sites in skeletal muscle; increasing the serum concentration of Digoxin (Quinidine also alters the renal excretion of Digoxin).

“This is a pharmacological type of interaction than              typical drug interaction”

•         A beta blocker as Propranolol may displace beta agonist such as Terbutaline è Increasing the likelihood of precipitating an asthmatic attack.

3.0. ALTERED METABOLISM

•         Metabolism is to convert lipid-soluble active compounds to water-soluble inactive substances that can be efficiently excreted

•         Hepatic microsomal enzymes cause the metabolism of many drugs (Phase-I & Phase-II)

•         Mixed Function Oxidases, Characterized by the Cytochrome P-450 isozymes à responsible for the oxidation of many drugs.

•         Derived from the expression of an individual gene

3.1. Effects:

•         The effects of CYP isoenzyme on a particular substrate can be altered by interaction with other drugs.

•         Drugs may be substrate for a isoenzyme and/or may inhibit or induce

•         Induction or inhibition of a single isoenzyme would have little effects on plasma levels of the drug.

•         If a drug is metabolized by a single isoenzyme, induction or inhibition of this enzyme would have a major effect on the plasma concentration of a drug.

For example:

Erythromycin (inhibitor of CYP3A4) is taken by patient given carbamazipine (extensively metabolized by CYP3A4), this may lead to toxicity due to higher concentrations of carbamazipine.

3.2. Enzyme Induction

•         Stimulated increase in enzyme activity.

•         Caused by an increase in the amount of enzyme present.

•         Enzyme induction is a delayed process because it requires the synthesis of enzyme (requiring some time).

•         Approximately 400 drugs and chemicals (e.g. insecticides, chemicals in cigarette smoke or certain vegetables) are enzyme inducers in animals.

•         Phenobarbital, Phenytoin, Carbamazepine and Rifampicin are enzyme inducers of clinical significance.

•         Drug actions altered by inducers  Warfarin, oral contraceptives, chloramphenicol, cyclosporine, disopyramide, doxycycline, griseofulvin, metronidazole, mexiletine, Quinidine, Theophylline, and Verapamil.

3.3. Enzyme Inhibition

•         Enzyme inhibition of drug-metabolizing enzymes generally decreases the rate of metabolism of the object drug.

•         This is likely to result in increased serum concentrations of the object drug and if the drug has narrow therapeutic index, potential drug toxicity.

•         Drug metabolizing enzymes may become saturated when at least 2 drugs using the same metabolic pathway are administered, resulting in a decrease in the rate of metabolism of 1 or both drugs (e.g. Fluoxetine - Imipramine ).

•         Certain drugs may bind to an enzyme system and inhibit enzyme function (e.g. Cimetidine & erythromycin).

•         Other enzyme inhibitors include: Isoniazid, Verapamil, chloramphenicol, Ketoconazole, amiodarone, disulfiram & monoamine oxidase inhibitors.

4.0. ELIMINATION INTERACTIONS

•         Some drugs are excreted either in the bile or in the urine. (Small molecules can easily pass across the membranes of the glomerulus while macromolecules as plasma proteins and blood cells are retained).

•         Blood flow è removes drugs and their metabolites

•         Interactions can occur when drugs interfere with the kidney tubule pH, active transport systems, or blood flow to the kidney thereby altering the excretion of other drugs.

4.1. Changes in Urinary pH

•         Passive reabsorption of drugs depends on the extent to which the drug exists in the non-ionized or lipid soluble form.  

•         At alkaline pH weakly acidic drugs (pKa 3.0—7.5) largely exists as unionized lipid insoluble molecules, which are unable to diffuse into the tubule cells and will therefore be lost in the urine.

•         The renal clearance of such drugs can be increased if the urine is made more alkaline. 

•         The clearance of weak bases (pKa 7.5—10) is higher in acidic urine

•         Strong acids and bases are virtually completely ionized over physiological range of urine pH and their clearance is unaffected by the pH changes

•         These interactions are of minor clinical significance as most of the drugs (weak acids & weak bases) are metabolized by hepatic metabolism rather than renal excretion.

•         Drugs producing large changes in the pH are rarely used clinically.

•         Urine alkalinization* or acidification has been used as a means of increasing the elimination of drug in the poisoning with salicylates* and amphetamines* respectively.

4.2. Changes in Active Renal Tubule Excretion

•         Drugs which use the same active transport system in the kidney tubules can compete with one another for excretion. Such competition between the drugs can be used to therapeutic advantage e.g. Probenecid & penicillin.

•         Methotrexate toxicity (life threatening) is seen in some patients concurrently treated with salicylates and other NSAIDs. The development of toxicity is believed to be due to increased dose of methotrexate (competitive inhibition of renal tubular secretion) or impaired renal function

•         4.3. Changes in renal blood flow 

•         The blood flow through the kidneys is partially controlled by the production of renal vasodilatory prostaglandins.

•         If the production of these prostaglandins is inhibited (e.g. indomethacin) the renal excretion of lithium is reduced with a subsequent rise in serum levels

II-PHARMACODYNAMIC MECHANISM

Generally involve the effects of drugs acting on the same receptors or physiological system as

Additive

Synergistic

Antagonistic

These interactions are much less easy to classify

ANTAGONISM

Drug with agonist actions at a particular type of receptor interacts with antagonist at the same receptor.

For example: Bronchodilator action of a selective β2 adrenoreceptor agonist such as Salbutamol or Terbutaline will be antagonized by β adrenoreceptor antagonists.

Many of the antagonistic interactions occurring at receptor sites are used for therapeutic advantage è Specific antagonists may be used to reverse the effect of another drug at the receptor sites.

For example: Opioid antagonist à Naloxone, benzodiazepine à Flumazenil.

Additive or Synergistic Interactions

•         Two drugs with similar pharmacological effects are given together the effects can be additive.

•         It is not a typical interaction but it in most cases contributes to the adverse drug reactions

•         For example: concurrent use of drugs with CNS depressant effects such as hypnotics, antidepressants, antiepileptics and antihistamines may lead to excessive drowsiness.

•         Combinations with such as Antiarrhythmics, Neuroleptics, TCAs and those producing electrolyte imbalances (diuretics) may lead to ventricular arrhythmias and should be avoided.

•         Some combinations induce ventricular tachycardia with a potential of prolonging QT intervals in ECG.