PHCP: Monitoring Drug Interactions

Monitoring Drug Interactions

The concept of drug interaction often is extended to include situations in which

1. Food or certain dietary items influence the activity of a drug (ie, drug-food interactions)

2. Herbs or other natural products influence the activity of a drug

3. Environmental chemicals or smoking influences the activity of a drug

4. A drug causes alterations of laboratory test results (ie, drug laboratory test interactions) 5. A drug causes undesired effects in patients with certain disease states (ie, drug-disease interactions).

MULTIPLE PHARMACOLOGICAL EFFECTS

When considering the potential for interactions between drugs there often is a tendency only to be concerned with the primary effects of the drugs involved and to overlook the secondary activities they possess.

MULTIPLE PHARMACOLOGICAL EFFECTS

MULTIPLE PRESCRIBERS

USE OF NONPRESCRIPTION PRODUCTS

PATIENT NONCOMPLIANCE

DRUG ABUSE

Factors affecting drug interactions

Age

Genetic Factors

Disease state

Renal function

Hepatic function

Alcohol consumption

Individual variation

Patient variables

Pharmacokinetic

Alteration of GI absorption

Alteration of pH

Complexation and Adsorption

Alteration of motility/ Gastric emptying time

Effect of food

Alteration of metabolism in the GI tract

Alteration of the GI flora

Stimulation of metabolism

Inhibition of metabolism

Alteration of Excretion

Alteration of Urinary pH

Alteration of Drug transport

Alteration of Active transport

Pharmacodynamic interaction

Drugs having opposing pharmacologic effects

Drugs having similar pharmacologic effects

Alteration of electrolyte concentration

Interaction at the reception site

Object

The drug affected by the interaction

Precipitant

The drug causing the interaction

delay in absorption

may be undesirable when a rapid effect is needed to relieve acute symptoms such as pain.

residual sedation or hangover in the morning

If the effects of the hypnotic agents are prolonged, the patient may experience excessive

GI absorption

It is the drugs that are not absorbed completely under optimum circumstances that are most susceptible to alteration of

pH

The __ of the GI contents may influence the extent of absorption.

ionized form

Non-ionized form of drugs will be absorbed more readily than the

upper region of the GIT ( having lower pH)

Acidic drugs exist primarily in the non-ionized form in the

Antacids

will raise the pH of the GI content. Absorption will be delayed.

acid

Ketoconazole requires what medium for absorption

antacid

Administer ____ atleast 2 hours after ketoconazole. Avoid concominant use of ketoconazole and H2 blockers and PPI’s

Bisacodyl

is enteric coated because it is extremely irritating

Antacid

may increase pH of the GIT causing disintegration of the enteric coat in the stomach, resulting in vomiting and irritation.

Tetracycline + Metals

Forms complex causing decreased absorption.

Avoid administration with milk, antacids and iron preparation.

Doxycycline and Minocycline

is affected to the lesser extent. in tetracycline and metals

Tetracycline + Metals

Interval of administration should be as long as possible with a minimum time of 1 hour.

Doxycycline + Ferrous preparations

Must consider a 3- hour interval or longer.

Doxycycline + Ferrous preparations

Significant amount of doxycycline is transported back to the GI tract via enterohepatic circulation and the unabsorbed iron still present in the GI tract will prevent reabsorption of the antibiotic.

Fluoroquinolones + Metals

Aluminum and magnesium containing antacids, mild and yogurt reduce the absorption of fluoroquinolones via Metal ion complexation.

Very long drug interval is necessary

Moxifloxacin

should be taken atleast 4 hours before or 8 hours after antacid containing magnesium, aluminum and sucralfate.

Cholestyramine and colestipol

May reduce absorption of

▪ Thyroid hormone

▪ Digoxin

▪ Thiazide

Cholestyramine and colestipol

Prolong administration may decrease absorption of Vitamin K which can cause bleeding

Colesevelam

preferred bile acid sequestrant for situations with potential interaction

Aluminum and iron salts

have been reported to reduce absorption of penicillamine.

2 hours

Penicillamine and metals hour interval

food

also decreases absorption of penicillamine.

Cathartics

Increases GI motility

Decreases absorption of other drugs with special considerations such as enteric coated and sustained release.

Anticholinergic

Decreased GI peristalsis decreases absorption by decreased dissolution

least one hour before meal or 2 hours

Penicillin and tetracycline (except Pen V, Amoxicillin, Doxycycline and Minocycline) must be given at _________ hours after meal

Erythromycin stearate

should follow the same instruction while other erythromycin bases may be given without regard to meal.

30-40 %

Presence of food may reduce the absorption of captopril by

Captopril and food

Administer 1 hour before meal.

Food does not seem to affect other ACEI (enalapril, lisinopril)

Alendronate and Residronate + Food

Food and beverages ( orange juice, coffee and mineral water) may reduce bioavailability

Administer soon after arising at least30 minutes before any food, beverage or medication with

Acarbose and Miglitol

Maximum effectiveness is achieved when administered with the first bite of meal.

GI tract

The absorption of certain agents is influenced by the extent to which they are metabolized in the

MAOI’s + Tyramine

Results in severe hypertensive crisis.

MAO

Tyramine is metabolized by

norepinephrine from the adrenergic neurons.

Unmetabolized tyramine accumulation may act to release

Tyramine

Cheese, wine, pickled fish, concentrated yeast extracts, broad bean pods or fava beans are rich sources of

Grape fruit juice

May increase concentration of:

▪ certain calcium channel blockers. (amlodipne, felodipine, nisoldipine)

▪ HMG CoA reductase inhibitor ( lovastatin)

▪ Cyclosporine

Grapefruit juice

reduce the activity of the CYP450 via CYP3A4 resulting in large amounts of unmetabolized drug that is absorbed which increases serum concentration.

vitamin K

Antibiotics kills natural flora that produces ___. usually, broad spectrum antibiotics like tetracycline causes the interaction.

Sulfonamides

increases the anticoagulant effect due to the displacement of the anticoagluant in the binding site and may inhibit hepatic metabolism

Digoxin and Antibiotic

The bacterial flora contributes in the conversion of the parent compound to the inactive metabolites in the GIT

Reducing bacterial flora decreases ____ metabolism, resulting in high concentration

Estrogen + antibiotic

Bacteria in the intestine hydrolyzes estrogen into its conjugated form that permits the drug to be reabsorbed and contribute to the serum concentration of ____.

Alteration of distribution

Competitive displacement

The drug with the greater affinity for the binding site will displace the other from plasma or tissue protein.

Acidic- albumin

Basic- alpha-1 glycoprotein

Salicylates + Methotrexate

Methotrexate are highly bound to plasma protein.

Salicilates may be capable of displacing it from the binding site.

It may increase the action of methotrexate by inhibiting renal excretion

valproic acid

displaces phenytoin from plasma protein binding.

Enzyme induction

Increased enzyme synthesis resulting in increased amount of drug metabolizing enzymes

E.g. barbiturates, carbamazepine, phenytoin, rifampin, St. john’s worth.

Phenobarbital

increases metabolism of warfarin

Benzodiazepines

will not likely react with warfarin.

hepatic enzyme activity

Heavy smokers has increased ______ due to the polycyclic hydrocarbons that are present in the cigarette

smoking

Diazepam, propoxyphene, theophylline, pentazocin and olanzapine are affected by

Pyridoxine

reduces action of levodopa by accelerating decarboxylation to dopamine in the peripheral tissues.

Disulferam

inhibits the activity of aldehyde dehydrogenaswe ths inhibiting oxidation of acetaldehyde which results in accumulation of excess aldehyde and development of unpleasant characteristics of disulferam reaction.

may inhibit the metabolism of warfarin and phenytoin

Cimetidine

Known to inhibit hepatic oxidative enzyme system

Carbamazepine, diazepam, phenytoin, theophylline, warfarin are some of the drugs that can interact with ____

Famotidine and nizatidine

are less likely to inhibit oxidative metabolic pathway

Salicylates

acidifying and alkalinizing agents

When a drug is in its non ionized form, it will diffuse more readily in the urine and back into the blood.

Acidic drugs

there will be a larger portion of drug in the nonionized form in an acidic urine than in an alkaline urine, producing a more intensified activity

amphetamine

Alkaline urine will diffuse more____ decreasing its urinary excretion.

Probenecid

can increase serum concentrations and prolong activity of penicillin derivatives by blocking their tubular secretion.

Ketoprofen

inhibits the active renal tubular secretion of methotrexate

Diuretics

may cause hyperuricemia

Hyperuricemic action of a diuretic

may necessitate an adjustment in dosage of the agent being used in the treatment of gout

Drugd having similar pharmacological effects

CNS depressants + Alcohol

Increased CNS depressant effect

CHRONIC ALCOHOL USE: Inducer effect

ACUTE ACLOHOL USE: Inhibitor

Excessive potassium loss

Digoxin + Diuretic

Potassium depletion

Cathartics + corticosteroids

May cause elevation of Potassium

ACEI+ K Sparing diuretics

Sodium depletion increases Lithium toxicity

Lithium + Diuretics

MAO

functions to break down catecholamines. Inhibition would cause increased concentration and bring exaggerated response causing hypertensive crisis.

1. Identify patient risk factors

2. Take a thorough drug history

3. Be knowledgeable about the drugs being used

4. Consider therapeutic alternatives

5. Avoid complex therapeutic regimens when possible

6. Monitor therapy

7. Individualize therapy

Reducing the risk of drug interaction

Adverse drug reaction (ADR)

Any response to a drug, which is noxious and unintended which occurs at doses, used in man for prophylaxis, diagnosis or therapy.

This may result from effects of the drug, of the illness, and their interaction with each other.

Drug interaction

It may occur whenever the action of a drug is modified in or on the body by another pharmacologically acting chemical substance.

Pharmaceutical causes of ADR

by altering the quantity of drug available for systemic absorption (e.g. decreasing particle size or changing excepients)

by influencing release rates (e.g. manufacturing factors as tablet hardness)

Pharmacodynamic causes of ADR

increased sensitivity of target organs in the body to drugs.

Pharmacokinetic causes of ADR

the way a drug is handled by the body during absorption, distribution, metabolism and excretion may affect humans in an adverse manner

e.g. diazepam used in patients with liver failure produced prolong coma

e.g. ototoxicity with aminoglycosides when used in patients with renal failure

presence of renal, hepatic and cardiac disease

age ¡ previous adverse drug reaction or drug allergy

gender

Genetic influence

Miscellaneous (diet, smoking, alcohol, environmental exposures, individual variations)

Predisposing factors to Adverse drug reactions

Patient-related factors":

Pharmaceutical properties

Pharmacokinetics properties

Pharmacodynamic properties

Predisposing factors to Adverse drug reactions

Drug-related factors

Adverse effects

predictable, dose-dependent reactions unrelated to the goal of therapy

Adverse effects

often produced by the same drug-receptor interaction responsible for the therapeutic effect, differing only in the tissue/s or organ/s affected.

dryness

Atropine A/E

cough

captopril A/E

constipation

codeine A/E

myopathy

fluvastatin A/E

headache

nitroglycerin A/E

Extrapyramidal symptoms

phenothiazines A/E

bronchial asthma

propanolol A/E

ototoxicity

streptomycin A/E

hypoplasia of the teeth

tetracycline A/E

Type A(Augmented)

refers to actions related to the pharmacological activity of a drug

Extension effects type A

predictable, dose-related responses arising from an extension of therapeutic effect

prevention is made simply by adjustment of dosage regimen

sedation and falls/trauma

benzodiazepines (anxiety neurosis) extension effects

water and electrolyte imbalance

furosemide (diuresis) extension effects

spontaneous bleeding

heparin (thromboembolic disorders) extension effects