Introduction to Pharmacotherapy:

Drug interactions
BY
Getu Bayisa
Assistant Professor of Clinical
Pharmacy, B.Pharm.
RVU|Hachalu Hundessa Campus,
Pharmacy Department
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 Introduction
• A drug interaction results when the effects of a drug
are altered in some way by the presence of another
drug, by food, or by environmental exposure.

• The frequency and significance of drug interactions

vary considerably among different patient
populations.

• Drug interactions are regarded as clinically

meaningful when they have the potential to produce
excessive toxicity or reduce therapeutic activity.

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 Introduction#2
• Some interactions can be exploited for their potential
clinical benefit. E.g., The protease inhibitor ritonavir

• Geriatric patients, polypharmacy and taking drugs

with narrow therapeutics window are risk factors for
drug interactions.

• The clinical severity of the effect of interaction can be

classified as minor, moderate, and
severe(micromedex health series) or as
A,B,C,D,X(lexi-comp).
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Introduction#3
 Minor drug interactions usually have limited clinical
consequences and require no change in therapy.

 Moderate interactions often require an alteration in

dosage or increased monitoring.

 Severe interactions should generally be avoided

whenever possible, as they result in potentially serious
toxicity.

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 MECHANISMS OF DRUG INTERACTIONS
 A pharmacodynamic interaction results when a drug
interferes with a second drug at its target site, or
changes in some way its anticipated pharmacologic
response.
• Pharmacodynamic interactions do not involve changes
in the concentration of drug in plasma.
 Antagonist
• Drugs with opposing pharmacological actions acting
on the same receptor. E.g., salbutamol (a beta-2
agonist) with metoprolol (a beta-2 antagonist)

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MECHANISMS OF PD DRUG
INTERACTIONS#2
 Additive:1+1=2
 Drugs with a similar mechanism of action may have
an additive effect. E.g., Fluoxetine (an SSRI) with
clomipramine (a tricyclic antidepressant with
serotonergic activity) can cause serotonin syndrome
in some patients.
 Synergistic:1+1>2
 E.g., Using a combination of antibiotics in treatment
of resistant pathogen.

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MECHANISMS OF PD DRUG
INTERACTIONS#3
 Fluid/electrolyte imbalance :
E.g., diuretics that cause hypokalaemia can increase
the toxicity of digoxin.

 Indirect interactions:
NSAID’s can reduce the effectiveness of
antihypertensive by causing salt and water
retention.

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 PK interactions
Interactions affecting drug absorption
• Interactions affecting drug absorption may result in
changes in the rate of absorption, the extent of
absorption, or a combination of both
• Interactions resulting in a reduced rate of absorption
are not typically clinically important for maintenance
medications
• For acutely administered medications, such as
sedative-hypnotics or analgesics, a reduction in the
rate of absorption may cause an unacceptable delay
in the onset of the drug’s pharmacologic effect.
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 Interactions affecting drug absorption#2

 A change in the extent of drug absorption that

exceeds 20% is generally considered to be
clinically significant

 The extent of absorption can be affected by

changes in gastrointestinal motility,
gastrointestinal pH, intestinal cytochrome P450
(CYP) enzyme and transport protein activity,
and drug chelation in the gut.

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 Interactions affecting drug absorption#3

 Change in gastrointestinal PH (ketoconazole and H2

- antagonists
 Chelation in the gut (calcium and TTC)

 Change in gastrointestinal motility (Metoclopramide

increases gut motility and prevents complete
absorption of slow dissolving digoxin preparations )
 Change in gastrointestinal flora: digoxin/macrolide,
antibiotics and Oral contraceptives

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 Interactions affecting drug distribution

 Theoretically, drugs that are highly protein bound

(>90%) may displace other highly protein-bound
drugs from binding sites, thereby increasing drug
distribution.
 The transient increase in unbound concentration may
be clinically important for drugs with a limited
distribution, a narrow therapeutic index, or a long
elimination half-life

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 Interactions affecting drug distribution#2
 No examples of clinically significant plasma
protein displacement interactions involving
nonrestrictively metabolized drugs have been
identified

 In general, due to a compensatory increase in

elimination, protein binding displacement
interactions are not usually significant and other
mechanisms are responsible

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 Examples
• Sucralfate, some milk  Block absorption
products, antacids, and of quinolones, tetracycline,
oral iron preparations and azithromycin
• Omeprazole, lansoprazole,  Reduce absorption
H2-antagonists of ketoconazole,
delavirdine
• Didanosine (given
as a buffered tablet)  Reduces ketoconazole
absorption
• Cholestyramine
 Binds raloxifene,
thyroid hormone, and
digoxin

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 Interactions affecting drug metabolism
 Consequences of drug metabolism
 Inactive products
 Active metabolites
 Similar to parent drug
 More active than parent
 New action
 Toxic metabolites

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 Phases of Drug metabolism

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 Interactions affecting drug metabolism#3

 drug metabolism is composed of 2 distinct pathways

of biochemical processing, Phase I and Phase II.
 Phase I: is a chemical modification (typically
oxidation, hydrolysis, or reduction reactions)
performed primarily by members of the CYP enzyme
family
 Phase II metabolism consists of the
biotransformation of endogenous compounds by
reactions such as glucuronidation, sulfation,
methylation, acetylation, and glycine conjugation.

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 Interactions affecting drug metabolism#4

 Modulation of CYP-mediated metabolism is the

primary mechanism by which one drug interacts
with another

 Most clinically significant metabolic interactions

involve either inhibition or induction of
cytochrome P-450 enzymes in the liver .

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 Cytochrome P450 Isoforms
 CYP1A2
 CYP3A
 CYP2C9
 CYP2C19
 CYP2D6

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 Interactions affecting drug metabolism#6
 An inducer is a drug that causes increased activity
of a CYP isoenzyme by causing increased
synthesis.

 Enzyme inhibition occurs when the inhibitor drug

binds to the CYP isoenzyme and prevents binding
(and therefore metabolism) of the substrate drug.

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 Cytochrome P450 3A
• Responsible for metabolism of:
– Most calcium channel blockers
– Most benzodiazepines
– Most HIV protease inhibitors
– Most HMG-CoA-reductase inhibitors
– Cyclosporine
– Most non-sedating antihistamines
– Cisapride
• Present in GI tract and liver

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 CYP3A Inhibitors
• Ketoconazole
• Itraconazole
• Fluconazole
• Cimetidine
• Clarithromycin
• Erythromycin
• Grapefruit juice

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 CYP3A Inducers
 Carbamazepine
 Rifampin
 Rifabutin
 Ritonavir
 St. John’s wort

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 Cytochrome P450 2D6
 Absent in 7% of Caucasians,
1–2% non-Caucasians
 Hyperactive in up to 30% of East Africans
 Catalyzes primary metabolism of:
 Codeine
 Many -blockers
 Many tricyclic antidepressants
 Inhibited by:
 Fluoxetine
 Haloperidol
 Paroxetine
 Quinidine

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 Cytochrome P450 2C9
 Absent in 1% Caucasians and
African-Americans
 Primary metabolism of:
 Most NSAIDs (including COX-2)
 S-warfarin (the active form)
 Phenytoin
 Inhibited by:
 Fluconazole

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 Cytochrome P450 2C19
• Absent in 20–30% of Asians,
3–5% Caucasians
• Primary metabolism of:
– Diazepam
– Phenytoin
– Omeprazole
• Inhibited by:
– Omeprazole
– Isoniazid
– Ketoconazole

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 Cytochrome P450 1A2
• Induced by smoking tobacco
• Catalyzes primary metabolism of:
– Theophylline
– Imipramine
– Propranolol
– Clozapine
• Inhibited by:
– Many fluoroquinolone antibiotics
– Fluvoxamine
– Cimetidine

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 Interactions Affecting Renal Excretion
 The pharmacokinetic properties of drugs that are
primarily renally excreted may be altered by changes
to active transport systems, urinary pH, and renal
blood flow.
 The acidic compounds phenobarbital, aspirin, and
other salicylates, with concurrent antacid or sodium
bicarbonate administration
 Probenecid use with penicillin or cephalosporins
 Methotrexate with NSAIDs.
 Lithium with NSAIDs
The end!!
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