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Monday, August 07, 2017

Drug Interactions: Implications, Mechanisms and Effects

The following are the presentation outlines 
Definition
Introduction
Patients at risk
Implications of drug interaction
Mechanism of drug interaction
Forms of drug interaction
Possible interventions/ preventions
Case study
Conclusion

Definition of Drug Interactions



An interaction is said to occur when the effects of a drug are altered by the co-administration of another drug, herbal medicine, food, drink or other environmental chemical agents (Baxter, 2010).

Today with increasing availability of complex therapeutic agents and widespread polypharmacy, the potential for drug interaction is enormous and they have become an increasingly important cause of adverse drug reactions (ADR).


Drug interactions can be useful, of no consequence, or harmful.

PATIENTS  AT RISK

Patients on many drugs
Patients with hepatic or renal disease
Patients on long term therapy of chronic disease
Patients with more than one 'prescriber'
The elderly 

IMPLICATIONS

Therapeutic failure
Adverse drug reactions
Morbidity and mortality

MECHANISMS OF DRUG INTERACTIONS

The mechanisms of drug interaction can be conveniently divided into those with a pharmacokinetic basis and those with pharmacodynamic basis.

Pharmacokinetic interactions

Interactions that affect the processes by which drugs are absorbed, distributed, metabolised or excreted.
Such interactions may result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy.

    Absorption

A number of factors can affect the rate of absorption or the extent of absorption (i.e. the total amount of drugs absorbed)
Change in G.I PH
The absorption of a drug across mucous membranes depends on the extent to which it exist in the non-ionised, lipid-soluble form.
The ionisation state depends on the PH of its milieu.

Weakly acidic drugs such as salicylates (e.g aspirin) are better absorbed at low PH
An alteration in gastric PH due to basic drugs such as antacids, histamine H2 antagonists (e.g cimetidine) or proton pump inhibitors (e.g omeprazole) therefore has the potential to affect the absorption of acidic drugs e.g. ketoconazole, itraconazole, aspirin, ibuprofen.

The alkalinizing effects of antacids on the GIT are transient and the potential for interaction may be minimized by leaving an interval of 2-3hrs between the antacid and the potentially interacting drug.

ii. Chelation and Complex Formations
Certain drugs react directly within the GIT to form chelates and complexes which are not absorbed.
Examples: tetracyclines and quinolones (e.g ciprofloxacin) antibiotics can form complex with iron and antacids containing calcium, aluminium, and magnesium
Bisphosphates (e.g alendronate) are often co-prescribed with calcium supplements in the treatment of osteoporosis. If these are taken concomitantly , however, the bioavailability of both is significantly reduced, with the possibility of therapeutic failure.


Most chelation and adsorption interactions can be avoided if an interval of 2-3hrs is allowed between doses of the interacting drugs.

iii. Malabsorption
Example: Orlistat is a specific long-acting inhibitor of gastric and pancreatic lipases, thereby preventing the hydrolysis of dietary fat to free fatty acids and triglycerides.
This can theoretically lead to reduced absorption of fat soluble drugs co-administered with orlistat.

Drug distribution

Following absorption, a drug undergoes distribution to various tissues including to its site of action.
Albumin is the main plasma protein to which acidic drugs such as warfarin are bound while basic drugs such as tricyclic antidepressants (e.g amitryptillin), propranolol e.t.c are generally bound to alpha-acid glycoprotein.

A drug displacement interaction is defined as a reduction in the extent of plasma protein binding of one drug cause by the presence of another drug resulting in an increased free or unbound fraction of the displaced drug e.g. if sulphonamide (cotrimoxazole) is administered, it displaces warfarin from albumin leading to a rapid increase in the concentration of free warfarin in the plasma.

Drug metabolism

Metabolism refers to the process by which drugs and other compounds are biochemically modified to facilitate their degradation and subsequent removal from the body (excretion)
The liver is the principal site of drug metabolism
Phase 1metabolism generally involves the cytochrome P450 enzymes found in the liver.

Examples of some inducers and inhibitors of the major cytochrome450 isoenzymes.


Interaction due to enzyme induction

PRIMARY DRUG                     INDUCING AGENT                     EFFECT OF INTERACTION

1. Wafarin                               Barbiturates e.g. phenytoin                     Decreased anticoagulation

2. Prednisolone/ciclosporin     Anticonvulsants e.g. carbamazepin        Reduced immunosuppression 

3. Oral contraceptives                   Rifampicin                                                 Pregnancy
    (e.g. levonorgestrel)



Interaction due to enzyme inhibition

PRIMARY DRUG                     INHIBITING DRUG                 EFFECT OF INTERACTION

1. Phenytoin                                    Cimetidine                                         Phenytoin intoxication


2. Warfarin                                Allopurinol, metronidazole,                    Haemorrhage
                                                   Co-trimoxazole


3. Simvastatin                               Clarithromycin                                      myopathy


Elimination Interaction

Most drugs are excreted in either the bile or urine.
Drugs that use the same active transport system in the kidney tubules can compete with one another for excretion
E.g. Probenecid may be given to increase the plasma concentration of penicillins.

Pharmacodynamic Interactions
Occurs when the effects of the drugs are changed by the presence of another drug at its site of action.
It sometimes involves competition for specific receptor sites.
Their effects can often be predicted when the pharmacology of co-administered drugs is known.

Antagonistic Interactions

A drug with an agonist action at a particular receptor type will interact with antagonists at that receptor e.g. the bronchodilator action of a selective B2-adrenoceptor agonist such as salbutamol will be antagonist by beta-adrenoceptor antagonist such as carvedilol.
Specific antagonists may be used to reverse the effect of another drug at the receptor sites; examples include the opoid antagonist Naloxone and the benzodiazepine antagonist flumazenil.

Some examples of drugs that have opposing pharmacological action include;
Anticoagulants and vitamin k
Levodopa and antipsychotics (e.g chlorpromazine are dopamine antagonist).

Additive or Synergistic Interactions

If two drugs with similar pharmacologic effects are given together, the effects can be additive.
This interaction can contribute to ADR.
Example: concurrent administration of antidepressants (e.g amitryptillin) with antihistamines (e.g piriton) may lead to excessive drowsiness.
NSAIDs ( e.g Ibuprofen, ASA) with clopidegrol can increase the risk of bleeding.

ACE inhibitors (e.g. lisinopril) with K-sparing duiretics (e.g spironolactone) can increase the risk of hyperkalemia.

FORMS OF DRUG INTERACTION.

I. Drug-drug interaction.

Occur when two or more drugs react with each other 
It’s the most common type of drug interaction.

II. Drug-Food interactions
It is well established that food can cause clinically important changes in the drug absorption.

Hence the advice that certain drugs should not be taken with food for e.g. iron tablets (e.g fersolate) and antibiotics (e.g ciprofloxacin, erythromycin,  amoxycillin).

III. Drug-Herbs Interaction
There has been a marked increase in the availability and use of herbal products
Such products often contain pharmacologically active ingredients which can give rise to clinically significant interactions when used concurrently with other conventional drugs.

Examples
Asian ginseng enhance hypoglycaemic effect
Hawthorn berries enhance hypotensive effect
potent anti-oxidants like Vit. C and bioeffective can affect the potency of ACT anti malarial drugs when use concurrently.

POSSIBLE INTERVENTIONS

Switching one of the potential interacting drugs 
Allowing an interval of 2-3hrs between administration of the interacting drugs
Altering the dose of one of the interacting drugs
Advising patients to seek guidance about their medication if they plan to start a herbal remedy as they may need close monitoring. 

CASE STUDY

Mrs C is a 62 year old woman with a history of hypertension, atrial fibrilation and type 2 diabetes. She is a non-smoker and obese. His current medication comprises Flecainide 100mg twice a day, aspirin 75mg daily, simvastatin 40mg and diltiazem 180mg daily. Mrs C is suffering from respiratory tract infection and her primary care doctor has prescribed a 5-day course of clarithromycin.

Questions

1.Are there likely to be any clinically significant drug interactions?

2.What advice do you give?



Conclusion


Problems associated with drug interaction and declining physiological function are very real. 
Therefore, health care workers need to be alert to the possibility of drug interactions and take appropriate steps to minimize their occurrence.

Compiled and Written by Pharmacist Kokari Salihu

References


Baxter, k. (Ed.), 2010. Stockley’s Drug Interactions, ninth ed. Pharmaceutical Press, London

Boyer, E.W., Shannon, M., 2005. Current Concepts: the serotonin syndrome. N. Engl. J. Med. 352, 1112-1120

Lee, w., Kim, R. B., 2004. Transporters and renal drug elimination. Ann. Rev. Pharmacol. Toxicol. 44, 137-166



Clinical Pharmacy and therapeutics, fifth edition
A textbook of clinical pharmacology and therapeutics. Fifth edition.

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