Drug-Drug interactions are defined as the change in efficacy or toxicity of one drug by prior or concomitant administration of a second drug.

Drug interactions always involve

• Pharmacokinetics
• Pharmacodynamics

In pharmacodynamic interactions, one drug alters the sensitivity or responsiveness of tissues to another drug by having the same (agonistic) or a blocking (antagonistic) effect. These effects usually occur at the receptor level but may occur intracellularly.

In pharmacokinetic interactions, a drug usually alters absorption, distribution, protein binding, metabolism, or excretion of another drug. Thus, the amount and persistence of available drugs at receptor sites change. Pharmacokinetic interactions alter magnitude and duration, not type, of effect. They are often predicted based on knowledge of individual drugs or detected by monitoring drug concentrations or clinical signs.

11 Drug Interactions

Following below are the clinically important drug interactions a pharmacist should know.

1. Fluoxetine and Phenelzine

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Fluoxetine	Phenelzine	Central serotonin syndrome	Inhibit serotonin metabolism, monoamine oxidase inhibitors (MAOIs) may potentiate the pharmacologic activity of selective serotonin reuptake inhibitors (SSRIs)	Dextromethorphan, Meperidine, and other selective serotonin reuptake inhibitors (SSRIs)	You should wait at least 14 days after stopping Phenelzine before you start treatment with Fluoxetine.

2. Digoxin and Quinidine

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Digoxin	Quinidine	Interaction range from nausea and vomiting to death	A marked increase in plasma concentration levels of digoxin	–	Pharmacists should anticipate the need to reduce the digoxin dose by one half

3. Sildenafil and Isosorbide Mononitrate

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Sildenafil	Isosorbide mononitrate	Sildenafil may markedly increase the hypotensive effects of isosorbide mononitrate	In the presence of PDE5 inhibitors, nitrates can cause intense increases in cyclic guanosine monophosphate and dramatic drops in blood pressure	Nitroglycerin	Pharmacists should advise patients not to take sildenafil with isosorbide mononitrate and nitroglycerin

4. Potassium Chloride and Spironolactone

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Potassium Chloride	Spironolactone	Hyperkalemia which will lead to cardiac failure and death	Excretion of sodium ions while saving potassium ions	Amiloride or triamterene absorbable forms of potassium bicarbonate, citrate, acetate, glauconite, and iodide salts	Patients who are prescribed spironolactone must undergo an evaluation of serum potassium levels

5. Clonidine and Propranolol

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Clonidine	Propranolol	Mysterious hypertension	Clonidine is a central alpha-2 adrenergic agonist that suppresses the sympathetic nervous system from the brain. This activity leads to a decrease in the norepinephrine amounts available in the synaptic cleft of the adrenergic neuron. Alpha-1 receptors then become sensitized because of less norepinephrine available in the cleft. When clonidine is suddenly withdrawn, the result is a large increase in norepinephrine in the synaptic cleft of the adrenergic neuron. The sensitized alpha-1 receptors are stimulated, leading to an exaggerated vasoconstriction.	—	Avoid taking these two drugs simultaneously

6. Warfarin and Diflunisal

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Warfarin	Diflunisal	G.I Bleeding	·Antiplatelet effects and GI erosion associated with NSAIDs and the anticoagulant effect of warfarin. ·Some individual NSAIDs may also alter the pharmacokinetics of warfarin	Keto-profen, piroxicam, sulindac, diclofenac, and ketorolac	A non-NSAID alternative such as acetaminophen or opioid analgesics is preferred. To be cautious, limit the acetaminophen dose to 2 g/day for no more than 7 days.  INR should be monitored closely when acetaminophen exceeds 2 g/day or chronic use >7 days occurs.

7. Theophylline and Ciprofloxacin

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Theophylline	Ciprofloxacin	Toxic increases in theophylline	Hepatic metabolism of theophylline is inhibited by ciprofloxacin via the cytochrome P-450 enzyme system	Clarithromycin, erythromycin, fluvoxamine, and cimetidine	Levofloxacin or ofloxacin should be considered as an alternative to ciprofloxacin

8. Pimozide and Ketoconazole

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Pimozide	Ketoconazole	Prolong the QT interval, Ventricular arrhythmias	Pimozide is a CYP3A4 enzyme substrate, and ketoconazole is a potent inhibitor of CYP3A4. This leads to marked increases in pimozide serum levels	Itraconazole, clarithromycin, erythromycin, diltiazem, and nefazodone	Terbinafine should be considered as an alternative to Ketoconazole

9. Methotrexate and Probenecid

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Methotrexate	Probenecid	Increase in methotrexate levels	Probenecid acts as an active tubular secretion inhibitor and prevents methotrexate from being excreted, thus potentially causing toxicity.	Penicillin’s and Salicylates	Use Acetaminophen alternative to Salicylates or NSAID’s

10. Bromocriptine and Pseudoephedrine

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Bromocriptine	Pseudoephedrine	Severe peripheral vasoconstriction, ventricular tachycardia, seizures, and possibly death	The mechanism may be due to the synergistic effects of both drugs on the dopaminergic system.	—	If these two drugs must be taken concurrently, the patient’s cardiovascular and mental status should be closely monitored.

11. Simvastatin and Amiodarone

Object drug	Precipitant Drug	Effect	Mechanism	Related Drugs	Options
Simvastatin	Amiodarone	Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis	Inhibition of the metabolism of simvastatin/ lovastatin by CYP3A4	—	Preferable statin alternatives include fluvastatin, rosuvastatin, or pravastatin. Predisposing risk factors for rhabdomyolysis include advanced age (>65 years), uncontrolled hypothyroidism, and renal impairment.