PH 1.8 Identify and Describe The Management of Drug Interactions

1. PH 1.8 Identify and Describe The
Management of Drug Interactions
Dr Pankaj Kumar Gupta,
Assistant Professor,
Department of Pharmacology,
ESIC Medical College & Hospital, Faridabad

2. Learning Objectives
• What is Drug Interaction?
• Why drug interaction is important?
• Types of Drug Interactions
• Factors Contributing to Drug Interactions
• Mechanism of Drug Interaction
• Pharmaceutical Interactions
• Pharmacokinetic Drug Interactions
• Pharmacodynamic Drug Interactions
• Consequences of Drug Interactions
• Influence of Smoking & Alcohol on Drug Interactions
• Drug-Food/herbal/chemical/disease/laboratory Interactions

3. What is Drug Interaction?
• Pharmacological activity of one drug is
altered by the concomitant use of
another drug or by the presence of some
other substance.

4. Why Does Drug Interaction Important?

5. Why Drug Interaction is Important?
• Drug interactions could account for 1% of
hospitalizations in the general population and 2–
5% of hospital admissions in the elderly.
• Approximately 3–26% of all adverse drug
reactions that require hospital admission are
caused by drug–drug interactions.
https://www.frontiersin.org/articles/10.3389/fphar.2019.00265/full
https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-018-3342-
5#:~:text=Approximately%203%E2%80%9326%25%20of%20all,%25%20%5B4%2C%205%5D.

6. Types of Drug Interactions
1. Drug-drug interactions.
2. Drug-food interactions.
3. Chemical-drug interactions.
4. Drug-laboratory test interactions.
5. Drug-disease interactions.
6. Drug-herbal drug interactions.

7. Result of a Drug Interaction
1. Quantitative i.e. increased or decreased effect (Commonly)
2. Qualitative i.e. rapid or slower effect. (Infrequently)
3. Adverse effect.

8. Factors Contributing to Drug
Interactions
1. Multiple drug therapy.
2. Multiple prescribers.
3. Multiple pharmacological effects of drug.
4. Multiple diseases/predisposing illness.
5. Poor patient compliance.
6. Advancing age of patient.
7. Drug-related factors.

9. Mechanism of Drug Interaction
Pharmaceutical interactions
Pharmacokinetic interactions
– Absorption
– Distribution
– Biotransformation
– Excretion
Pharmacodynamic interactions
– Receptor interaction
– Receptor sensitivity
– Neurotransmitter release/Drug transportation
– Electrolyte balance
Physiological interactions

10. Pharmaceutical Interactions
• Also called as “incompatibility”.
• It is a physicochemical interaction that occurs
when drug is mixed in IV Infusion causing
precipitation or inactivation of active principles.

11. Pharmaceutical Interactions-2
• Example:- Ampicillin, chlorpromazine &
barbiturates interact with dextran in solutions
and are broken down or form chemical
compounds.
• Phenytoin precipitates in dextrose saline.
• Amphotericin precipitates in saline.
• Gentamicin is physically/chemically incompatible
with most beta-lactams, resulting in loss of
antibiotic effect.

12. Pharmacokinetic Drug Interactions
• One drug alters the rate or extent of absorption,
distribution, metabolism or excretion of another
drug. (ADME Interactions)
• A change in blood concentration causes a change
in the drug’s effect.
• Pharmacokinetic drug interactions are classified
as:
• Absorption interactions
• Distribution interactions
• Metabolism interactions
• Excrétion interactions.

13. Absorption Interactions
• The absorption of the one drug is altered.
• The net effect of such an interaction is:
• Faster or slower drug absorption.
• More, or, less complete drug absorption.

14. Mechanism of Absorption
Interactions
• Complexation and adsorption.
• Alteration in GI pH.
• Alteration in gut motility.
• Inhibition of GI enzymes.
• Alteration of GI micro flora.
• Mal-absorption syndrome.

15. Mechanism Displaced Drug Displacer Clinical Effect
1 Complexation &
adsorption
•Ciprofloxacin,
•Pencillamine
•Antacids
•Food & minerals
Supplements
containing Al, Mg,
Fe, Zn & Ca IONS
•Formation of poorly
soluble and
unabsorbable
complex with such
heavy metal ions.
2 Alteration of GI
PH
•Sulphonamides,
•Aspirin
•Ferrous sulphate
•Antacids (Sodium
bicarbonate, Calcium
carbonate)
•Decreased
dissolution and
hence absorption.

16. Mechanism Displaced Drug Displacer Clinical Effect
3
Alteration of gut
motility
Aspirin,
Diazepam,
Levodopa,
Mexiletine
Metoclopramide
(prokinetic)
•Rapid gastric emptying
•Increased rate of
absorption (in intestine)
Levodopa,
Lithium carbonate,
Mexiletine
Anti-cholinergics •Delayed gastric emptying
•Decreased rate of
absorption
4 Alteration of GI
microflora
Digoxin Antibiotics •Increased bioavailability
due to destruction of
bacterial flora that
inactivates digoxin in
lower intestine.
5 Mal-absorption
syndrome
Vitamin A,
Vitamin B12,
Digoxin
Neomycin (induces
structural changes
in intestine)
•Inhibition of absorption
due to mal-absorption

17. Distribution Interactions
• Distribution pattern of the drug is altered.
• The major mechanism for distribution
interaction is alteration in protein-drug
binding.

18. Displaced drug Displacer Clinical Effect Mechanism
Anti-coagulants Phenylbutazone,
chloral hydrate
•Increased clotting time.
•Increased risk of
hemorrhage.
•Competitive
displacement
interactions
Tolbutamide Sulphonamides •Increased hypoglycemic
effect.
•Competitive
displacement
interactions
Phenytoin Sodium valproate •Phenytoin toxicity •It displaces phenytoin
from its binding site on
plasma albumin and
inhibits its metabolism.
Methotrexate Aspirin and
Probenecid
•Methotrexate toxicity •Displace methotrexate
from its protein-binding
site and reduce its rate
of active secretion by
the renal tubules

19. Metabolism Interactions
• Metabolism of the one drug is altered.
• Mechanisms of metabolism interactions include:
• Enzyme induction: Increased rate of metabolism.
• Enzyme inhibition: Decreased rate of metabolism.
• It is the most significant interaction in comparison to
other interactions and can be fatal.

20. Cytochrome P450
• A group of heme-containing enzymes embedded
primarily in the lipid bilayer of the endoplasmic
reticulum of hepatocytes.
• It takes part in the metabolism of many drugs, steroids
and carcinogens.
• Nomenclature
• Arabic number (CYP2) represents the family.
• Capital letter (CYP2D) represents the subfamily.
• Arabic number (CYP2D6) represents the individual enzyme
in the subfamily.

21. • The enzymes transforming drugs in humans belong to
the CYP families 1–4 and more than 30 human CYP
isozymes have been identified to date.
• Of all the different CYP proteins that are present in
the human body, six of them are involved in the
metabolism of 90% of drugs.
• These proteins are CYP1A2, CYP2C9, CYP2D6,
CYP3A4, and CYP3A5.
• The most important are CYP2D6 and CYP3A4.

22. Mechanism Displaced drug Displacer Clinical Effect
CYP450
Enzyme induction
•Corticosteroids,
•Oral contraceptives,
•Coumarins,
•Phenytoin
•Barbiturates •Decreased plasma levels
•Decreased efficacy of
object drugs
•Oral contraceptives
•Oral hypoglycaemics
•Rifampicin •Decreased plasma levels
CYP450
Enzyme inhibition
•Tyramine rich food •MAO Inhibitors •Enhanced absorption of
un-metabolised tyramine.
•Coumarins •Metronidazole
•Phenylbutazone
•Increased anti-coagulant
activity
•Alcohol •Disulphiram,
•Metronidazole
•Increased in plasma
acetaldehyde levels

23. Enzyme Inducers and
Inhibitors : Mnemonic
Cytochrome P450 Inducers Cytochrome P450 Inhibitors
Mnemonic : SCRAP GP Mnemonic
1: VIDEOCASE
Mnemonic
2: SICKFACES.COM
Sulfonylureas, Smoking
Carbamazepine, Corticosteroids
Rifamycins (Rifampicin, Rifabutin)
Alcohol (Chronic)
Phenytoin
Griseofulvin
Phenobarbital
Valproate
Isoniazid
Disulfiram
Erythromycin,
Clarithromycin (not
Azithromycin)
Omeprazole
Cimetidine
Allopurinol
Sulfonamides
Ethanol (Acute)
Sodium valproate
Isoniazid
Cimetidine
Ketoconazole
Fluconazole
Alcohol (Acute)
Chloramphenicol
Erythromycin
Sulphonamides
Ciprofloxacin
Omeprazole
Metronidazole

24. Excretion Interactions
• Excretion pattern of the drug is altered.
• Major mechanisms of excretion interactions
are-
• Alteration in renal blood flow
• Alteration of urine PH
• Competition for active secretions
• Forced diuresis

25. Mechanism Displaced drug Displacer Clinical Effect
1 Changes in active
tubular secretion
•Pencillin
•Cephalosporins,
•Nalidixic acid
•Probenecid •Elevated plasma levels
of acidic drugs
2 Changes in urine
pH
•Amphetamine •Antacids,
•Thiazides,
•Acetazolamide
•Increased passive re-
absorption of basic drugs.
•Increased risk of toxicity
3 Changes in renal
blood flow
•Lithium
bicarbonate
•NSAIDs •Decreased renal
clearance of lithium.
•Risk of toxicity

26. Pharmacodynamic Drug
Interactions
• Pharmacodynamic interactions are those
where the effects of one drug is changed by
the presence of another drug at its site of
action.
• These are of two types
• Direct pharmacodynamic interactions.
• Indirect pharmacodynamic interactions.

27. Direct Pharmacodynamic
Interactions
• In which drugs having similar or opposing
pharmacological effects are used concurrently.
• The three consequences of direct interactions
are:
• Antagonism.
• Addition or summation.
• Synergism or potentiation.

28. 1 Antagonism: •The interacting drugs have
opposing actions
•Acetylcholine and
nor-adrenaline have
opposing effects on
heart rate.
2 Addition or summation: •The interacting drugs have
similar actions and the resultant
effect is the some of individual
drug responses
•CNS depressants like
sedatives and
hypnotics,
3 Synergism or
potentiation:
•It is an enhancement of action
of one drug by another
•Alcohol enhances the
analgesics activity of
aspirin.

29. Indirect Pharmacodynamic
Interactions
• In which both the object and the precipitant
drugs have unrelated effects. but latter in some
way alerts the effects of the former.
• Example: salicylates decrease the ability of the
platelets to aggregate thus impairing the
Homeostasis if warfarin induced bleeding
occurs.

30. Consequences of Drug
Interactions
• The consequences of drug interactions may be:
• Major: Life threatening.
• Moderate: Deterioration of patients status.
• Minor: Little effect.

31. Influence of Smoking &
Alcohol on Drug Interactions
Substance Mechanism Impact
1 Smoking Increases the activity of drug
metabolizing enzymes in the
liver (Metabolic Inducer)
Therapeutic agents like Diazepam,
propoxyphene, theophylline,
olanzapine are metabolized more
rapidly, and their effect is
decreased.
2 Chronic use of
alcohol
Increases the activity of drug
metabolizing enzymes in the
liver (Metabolic Inducer)
The rate of metabolism of drugs
such as warfarin and phenytoin is
increased, probably by increasing
the activity of hepatic enzymes.
3 Acute use of alcohol
by non alcoholic
individuals
Inhibition of hepatic enzymes
(Metabolic Inhibitor)
4 Use of alcoholic
beverages with
sedatives and other
depressants drugs
Additive effect An excessive depressant response.

32. Influence of Food on Drug
Interaction
• Food affects the rate and extent of absorption of
drugs from the GI tract.
• Ex: Many antibiotics should be given at least 1hr before or
2hr after meals to achieve optimal absorption.
• The type of food may be important with regard to
the absorption of concurrently administered drugs.
• Ex: Milk and other dairy products that contain calcium may
decrease the absorption of tetracycline and flouroquinolone
derivatives.
• Diet may also influence urinary pH values.

33. Drug-Food Interactions
Grapefruit juice
Metabolic Inhibitor
• Inhibits intestinal
CYP3A4, and only
slightly affects
hepatic CYP3A4.
• These interactions
result in increased
drug levels.

34. Drug-Herbal Interactions
St. John’s wort
Metabolic Inducer
Induces the cytochrome
P450 isoenzyme CYP3A4.
Decreases plasma
concentration of- Digoxin,
Cyclosporine, Warfarin

35. Drug-Laboratory Interactions
• Some medications can interfere with specific
laboratory tests. This can result in inaccurate
test results.
• Example: tricyclic antidepressants have been
shown to interfere with skin prick tests used to
determine whether someone has certain
allergies.
https://www.healthline.com/health/drug-interactions#other-factors

36. Drug-Disease Interactions
• When use of a drug alters or worsens a
condition or disease or a medical conditions
increases the risk of side effects from specific
drug.
• Pseudoephedrine (a decongestant) can raise blood pressure.
• Metformin (a diabetes drug) and kidney disease: people with
kidney disease should use a lower dosage of metformin.
Metformin can accumulate in the kidneys of people with this
disease, increasing the risk of severe side effects.
https://www.healthline.com/health/drug-interactions#other-factors

37. Drug-Chemical Interactions
• Some drugs produce effects without altering cellular function
and without binding to a receptor.
• For example, most antacids decrease gastric acidity through
simple chemical reactions; antacids are bases that chemically
interact with acids to produce neutral salts.
• The primary action of cholestyramine, a bile acid sequestrant, is
to bind bile acids in the gastrointestinal tract.
https://www.msdmanuals.com/en-in/professional/clinical-pharmacology/pharmacodynamics/chemical-
interactions#:~:text=Some%20drugs%20produce%20effects%20without,acids%20to%20produce%20neutral%20salts.

38. Management of Drug Interactions

39. Reducing the risk of Drug
Interactions
• Identify the patients risk factors.
• Take thorough drug history.
• Be knowledge about the actions of the drugs being used.
• Consider therapeutic alternatives.
• Avoid complex therapeutic regiments when possible.
• Educate the patient.
• Monitor therapy.

40. Drug Interaction Checker
https://reference.medscape.com/drug-interactionchecker
https://www.drugs.com/drug_interactions.html

42. References
https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/1743-7075-5-27
https://www.news-medical.net/life-sciences/What-are-Cytochrome-P450-
Enzymes.aspx
https://www.msdmanuals.com/en-in/professional/clinical-
pharmacology/pharmacodynamics/chemical-
interactions#:~:text=Some%20drugs%20produce%20effects%20without,acids%20to
%20produce%20neutral%20salts
https://epomedicine.com/medical-students/enzyme-inducers-inhibitors-mnemonic/
https://www.medscape.org/viewarticle/418376?icd=login_success_email_match_nor
m
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444856/
https://www.frontiersin.org/articles/10.3389/fphar.2019.00265/full
https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-018-3342-
5#:~:text=Approximately%203%E2%80%9326%25%20of%20all,%25%20%5B4%2
C%205%5D.

43. Thanks