1 ) A hypertensive patient has been using nifedipine for some time

without untoward effects. If he experiences a rapidly developing

enhancement of the antihypertensive effect of the drug, it is most likely
due to which of the following?

(A) Concomitant use of antacids

(B) Foods containing tyramine
(C) Furanocoumarins in grapefruit juice
(D) Induction of drug metabolism
(E) Over-the-counter decongestants
•Compounds in grapefruit juice can increase the rate and extent of
bioavailability of several dihydropyridine calcium channel
blockers, including felodipine and nifedipine. This interaction may
be due to inhibition of the metabolism of the dihydropyridines by
intestinal wall CYP3A4 or inhibition of the P-glycoprotein
transporter in the same location. The answer is C.
• 2 ) A 55-year-old patient currently receiving a drug for a
psychiatric condition is to be started on diuretic therapy for
mild heart failure. Consideration should be given to the fact
that thiazides are known to reduce the excretion of which of
the following?

(A) Diazepam
(B) Fluoxetine
(C) Imipramine
(D) Lithium
(E) Trifluoperazine
•Thiazides reduce the clearance of lithium by about 25%.
They do not alter the clearance of the other agents listed.
The answer is D.
• 3 ) A 43-year-old woman with type 2 diabetes and hypertension visits
your clinic. Her current blood pressure (measured 3 times) is not at
target: 155/98 mm Hg, despite the fact that she is taking
hydrochlorothiazide and captopril. The antihypertensive effects of
captopril can be antagonized (reduced) by which of the following?

(A) Angiotensin II receptor blockers

(B) Loop diuretics
(C) NSAIDs
(D) Sulfonylurea hypoglycemic
(E) Pioglitazone
•NSAIDs interfere with the antihypertensive action of angiotensin-
converting enzyme inhibitors; the other drugs listed enhance the blood
pressure-lowering effects of captopril and other members of the “pril”
drug family. Pioglitazone is a hypo glycemic drug used in patients with
type 2 diabetes mellitus and has no significant effect on blood
pressure. The answer is C.
• Case Study 4
•An elderly patient comes to the pharmacy with a prescription for the
following medications:
• salbutamol inhaler 200 µcg as required,
• beclometasone inhaler 200 µcg twice daily,
• bendroflumethiazide 2.5mg daily,
• modified release diltiazem 180mg once daily and
• atenolol 50mg daily.
The atenolol was being started by the patient's primary care doctor,
apparently because of inadequate blood pressure control

• Question What action should the pharmacist take?

•There are two reasons to be concerned about the addition of atenolol
to this patient's drug regimen. First, there is a potentially hazardous
interaction with diltiazem which may result in severe bradycardia or
heart block.

• Second, the patient is receiving treatment for obstructive airways

disease and this may be worsened by the atenolol.

•The prescription should be discussed with the prescriber.

•Case Study 5
•A 42-year-old woman is on long-term treatment with
azathioprine 100 mg daily and bendroflumethiazide 2.5 mg
daily. The latter was discontinued after an episode of gout
but she had three further episodes over the following year.
Her doctor considers prescribing allopurinol as prophylaxis.

Question
•Is this likely to cause a clinically significant interaction?
• Answer:
• Azathioprine is metabolised in the liver to mercaptopurine and then
converted to an inactive metabolite by the enzyme xanthine oxidase.
Allopurinol is an inhibitor of xanthine oxidase and will lead to the
accumulation of mercaptopurine which can cause bone marrow
suppression and haematological abnormalities such as neutropenia and
thrombocytopenia.

• The dose of azathioprine should be reduced by at least 50% and close

haematological monitoring is required if allopurinol is used
concomitantly.
• Case Study 6
A 75-year-old man presented to the hospital with symptoms of muscle
weakness, stiffness, and dark urine. A diagnosis of rhabdomyolysis and acute
renal failure was made.
The patient’s medical history included hypocholesteremia for which he took
atorvastatin for approximately 2 years. Verapamil treatment had recently been
initiated for hypertension. Upon admission, all medications were discontinued and
the patient was treated with intermittent hemodialysis.
Genotyping results showed that the patient had a single-nucleotide polymorphism
(SNP) within genes encoding the organic anion-transporting polypeptide (OATP)
1B1. He was also found to be a poor metabolizer of CYP2C19.

• 1. Discuss the causes of the patient’s symptoms, including the interactions

between atorvastatin and verapamil and the effect of the SNP.
• 1. Discuss the causes of the patient’s symptoms, including the interactions
between atorvastatin and verapamil and the effect of the SNP
• Atorvastatin is metabolized extensively by CYP3A4 in the liver, and verapamil is a
moderate inhibitor of CYP3A4.
• Initiation of verapamil therapy led to inhibition of CYP3A4 metabolism, which is
believed to have contributed to atorvastatin overexposure, thus increasing the risk
of rhabdomyolysis.
• Atorvastatin is also a substrate for OATP1B1 hepatic uptake transporter. Therefore,
the patient’s SNP in OATP1B1 may have contributed to the adverse event by
decreasing the hepatic uptake of atorvastatin, thereby increasing the circulating
levels of atorvastatin.
• This case illustrates the clinical relevance and relationship between
pharmacogenetics and drug-drug interactions in the development of statin-induced
myopathy.
• 1 ) A patient suffering from a depressive disorder is being treated with
imipramine. If he uses diphenhydramine for allergic rhinitis, a drug interaction is
likely to occur because :

(A) Both drugs block muscarinic receptors

(B) Both drugs block reuptake of norepinephrine released from sympathetic
nerve endings
(C) Diphenhydramine inhibits imipramine metabolism
(D) Imipramine inhibits the metabolism of diphenhydramine
(E) The drugs compete with each other for renal elimination
• This is a good example of an additive drug interaction resulting
from 2 drugs acting on the same type of receptor. Most tricyclic
antidepressants, phenothiazines, and older antihistaminic drugs
(those available without prescription) are blockers of muscarinic
receptors. Used concomitantly, any pair of these agents will
demonstrate a predictable increase in atropine-like adverse
effects.
The answer is A.
• 2 ) If phenelzine is administered to a patient taking fluoxetine, which of
the following is most likely to occur?

(A) A decrease in the plasma levels of fluoxetine

(B) Antagonism of the antidepressant action of fluoxetine
(C) Agitation, muscle rigidity, hyperthermia, seizures
(D) Decreased metabolism of fluoxetine
• The drug interaction between the inhibitors of monoamine oxidase
used for depression and the drugs that selectively block serotonin
reuptake (SSRIs) is called the serotonin syndrome.
• In the case of phenelzine and fluoxetine, the interaction has
resulted in a fatal outcome. Key interventions include control of
hyperthermia and seizures. The answer is C.
• 3 ) AJ is a 45-year-old homeless man participating in a drug rehabilitation
program that supplies daily methadone. AJ reports that he needs more
methadone to avoid with drawal, since he started treatment for his
tuberculosis. Which of the following drugs might have caused this
scenario?

(A) Ciprofloxacin
(B) Cyclosporine
(C) Erythromycin
(D) Rifampin
(E) Tetracycline
• Rifampin is an effective inducer of hepatic P450 isozymes.
Cyclosporine and tetracycline have no significant effects on
drug metabolism. Ciprofloxacin and erythromycin are inhibitors
of drug metabolism. The answer is D.
• Case Study 4
A 78-year-old man visited a hospital for cough and increased sputum, for which he
was prescribed clarithromycin, a macrolide antibiotic.
• The following day he was admitted to another hospital for loss of consciousness. His
medical history included hypertension, atrial fibrillation and chronic kidney disease.
He reportedly took two calcium-channel blockers, nifedipine and diltiazem, as well as
carvedilol (a beta-blocker), irbesartan (angiotensin receptor blocker), isosorbide
dinitrate, and dypiridamole. At admission his blood pressure was 96/38 mm Hg,
relative to a historical baseline value of 140/70 mm Hg. His pulse rate was 44 bpm.
Physical examination showed no abnormal findings and his peripheries were warm. A
12-lead ECG revealed atrial fibrillation.
• The differential diagnoses considered were septic shock, cardiogenic shock and
hypovolaemic shock. However, the patient’s respiratory symptoms were mild, and he
required no supplemental oxygen. Cardiogenic shock was ruled out by transthoracic
echocardiogram. Even after his heart rate increased to 70 bpm after atropine
administration, his blood pressure showed no improvement. He showed no signs of
fluid loss to suggest hypovolemic shock.
1. Discuss the complex drug interactions that contributed to hypotension in this
• 1. Discuss the complex drug interactions that contributed to hypotension in this
patient

• Calcium-channel blockers, including nifedipine and diltiazem, are metabolized extensively

by CYP3A4.
• Clarithromycin is a strong inhibitor of CYP3A4, and diltiazem and its metabolites are also
CYP3A4 inhibitors. Inhibition of CYP3A4 metabolism can cause excessive exposure of
calcium-channel blockers, which can result in vasodilatory hypotension.

• In addition, the combination of two calcium-channel blockers and a beta-blocker can lower
cardiac output due to bradycardia and thus worsen hypotension.
• In this case, the hypotension presented one day after the patient began using a combination
of calcium-channel blockers and clarithromycin. Typically inhibition of CYP3A4 by
clarithromycin and erythromycin does not occur immediately, as these agents are
mechanism-based inhibitors. In this case, however, the patient was taking two calcium-
channel blockers and carvedilol, which may have contributed to the onset of symptoms.
• Since carvedilol is also metabolized by CYP3A4, its plasma concentrations may
also have been increased by clarithromycin. Finally, the patient’s age might be
expected to contribute to the severity of the adverse outcome that resulted from
this complex drug interaction.
• Benzothiazepine calcium-channel blockers have negative inotropic and
chronotropic effects and, in excess, can disturb the cardiac conduction system.
β-Blockers prevent the compensating increase in heart rate. Consequently, these
medications would effectively worsen hypotension. Since carvedilol is also
metabolized by CYP3A4, its plasma concentrations may also have been
increased by clarithromycin. Finally, the patient’s age might be expected to
contribute to the severity of the adverse outcome that resulted from this complex
drug interaction.
• 5 ) Lois is a 77-year old woman who has been your patient for a number of years. Over the
last two years, she has had a gradual decline in her cognitive function, primarily manifesting
as difficulty with names and memory impairment. Two months ago, she started risperidone
0.5 mg twice daily because of increased agitation and nocturnal wandering. Lois is cared for
by her daughter, Anne
• Lois had a pre-syncopal episode at home and sustained a fracture in the fall. This was
treated conservatively and she was discharged from the department with analgesia (tramadol
50 mg four times daily, as needed). Lois’other medical problems are insomnia, hypertension
and depression. Her current medications are: aspirin 150 mg in the morning, risperidone
(Risperdal) 0.5 mg twice daily, diltiazem CR (Cardizem CD) 180 mg at night, metoprolol
(Betaloc) 50 mg twice daily, paroxetine (Aropax) 20 mg in the morning recently ,
temazepam 20 mg at night, tramadol (Tramal) 50 mg four times daily as needed.
• On examination, Lois is alert and interactive. She is afebrile. Her BP is 110 / 70 mmHg and
her pulse rate is 60 . Her MMSE score is 22/30 (changed from previous visit). The remainder
of the physical examination is normal.
• 2- Possible drug interactions and potential effects • Respondents reported
• − diltiazem and metoprolol 74%. Potential effects include bradycardia 29%, heart
block/arrhythmia 17%
• − paroxetine and tramadol 64%. Potential effects include serotonin syndrome
58%
• − temazepam and risperidone 33%. Potential effects include enhanced sedative
effect/drowsiness 22%
• paroxetine and metoprolol : inhibit the metabolism of the beta-blocker metoprolol
and can thus cause lowering of blood pressure, bradycardia, and other undesired
effects.
 2. What specific advic e would you offer Anne
about non-drug measures to help with Lois’
agitation?

•− increased supervision/carer 28%

•− maintaining a well-defined routine 23%
• − adequate lighting and use of a night-light 18%
 3. List any changes you would consider making to
Lois’ medication regimen.

• − cease tramadol 75%

• − substitute paracetamol for pain relief 58%
• − cease temazepam 57% − review the use of temazepam or reduce the dose 13%
• − review antihypertensive regimen 64%
• − decreased renal function 87%
• − decreased liver function 68% −
• - polypharmacy 56%
• − poor compliance 32%
• − increased sensitivity to drugs 26%
•Case 1

• Mrs C is a 62-year-old woman with a history of hypertension, atrial

fibrillation and type 2 diabetes. She is a non-smoker and obese. Her current
medication comprises flecainide 100 mg twice a day, aspirin 75 mg daily,
simvastatin 40 mg and diltiazem 180 mg daily. Mrs C is suffering from a
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?
• Answers
• 1. There is potential for interaction between simvastatin and diltiazem and between
simvastatin and clarithromycin. Some statins, particularly simvastatin and atorvastatin, are
metabolised by cytochrome P450 (CYP3A4) and co-administration of potent inhibitors of
this enzyme may particularly increase plasma levels of these statins and so increase the risk
of dose-related side effects, including rhabdomyolysis. Clarithromycin is a potent inhibitor
of CYP3A4 and diltiazem is a less potent inhibitor.

• 2. Current advice is that diltiazem and simvastatin may be given together provided the
simvastatin dose does not exceed 40 mg daily, so it is reasonable for this therapy to be
continued. However, clarithromycin should not be given together with simvastatin.
Myopathy and rhabdomyolysis have been reported in patients taking the combination. Mrs
C should be advised not to take her simvastatin while she is taking clarithromycin and to
start taking it again after she has completed the course of antibiotic
•Case 2 :

• A 48-year-old man with a history of epilepsy is admitted to hospital with tremor,

ataxia, headache, abnormal thinking and increased partial seizure activity. His
prescribed medicines are phenytoin 300 mg daily, clonazepam 6 mg daily and
fluoxetine 20 mg daily. It transpires that fluoxetine therapy had been initiated 2
weeks previously. The patient's phenytoin level is found to be 35 mg/L; at the last
outpatient clinic visit 4 months ago, it was 18 mg/L.

• Question What is the proposed mechanism of interaction between

fluoxetine and phenytoin and how should it be managed?
• Fluoxetine is believed to inhibit the metabolism of phenytoin by the cytochrome
P450 isoenzyme CYP2C9, potentially leading to increased plasma phenytoin
levels. There are a number of published case reports and anecdotal
observations of phenytoin toxicity occurring with the combination, but the
available evidence is conflicting.

• A review by the U.S. Food and Drug Administration suggested that a marked
increase in plasma phenytoin levels, with accompanying toxicity, can occur within
1–42 days (mean onset time of 2 weeks) after starting fluoxetine. If fluoxetine is
added to treatment with phenytoin, the patient should be closely monitored.
Ideally the phenytoin plasma levels should be monitored and there may be a
need to reduce the phenytoin dosage.
 •Case 3
• A 79-year-old man presented to hospital with a 3-day history of increasing confusion and
collapse. He had a history of chronic lumbosacral pain, treated with oxycodone 10 mg
twice daily and amitriptyline 75 mg daily. Five days before hospital admission he had
been prescribed tramadol 100 mg four times daily for worsening sciatica. On admission
the patient had a Glasgow Coma Scale of 11 and he was delirious and hallucinating.
There were no focal neurological signs. Over the next 2 days he became increasingly
unwell, confused and sweaty with pyrexia and muscular rigidity. Biochemical tests
showed a metabolic acidosis (base deficit of 10.7) and an elevated creatine kinase level
of 380 IU/L. There was no evidence of infection. At this stage a diagnosis of probable
serotonin syndrome was made.

• Questions
• 1. What is serotonin syndrome and what drugs are most commonly
associated with it?
• 2. How is serotonin syndrome managed?
• Answers 1.
• Serotonin syndrome is often described as a clinical triad of mental status changes,
autonomic hyperactivity and neuromuscular abnormalities. However, not all these features
are consistently present in all patients with the disorder.
Symptoms arising from a serotonin excess range from diarrhoea and tremor in mild cases to
delirium, neuromuscular rigidity, rhabdomyolysis and hyperthermia in life- threatening cases.
Disturbance of electrolytes, transaminases and creatine kinase may occur. Clonus is the most
important finding in establishing the diagnosis of the serotonin syndrome.
A wide range of drugs and drug combinations has been associated with the serotonin
syndrome, including MAOIs, tricyclic antidepressants, SSRIs, opioids, linezolid and 5HT1-
agonists. Tramadol is an atypical opioid analgesic with partial µ antagonism and central
reuptake inhibition of serotonin (5HT) and noradrenaline. At high doses it may also induce
serotonin release. Tramadol is reported as causing serotonin syndrome alone (in a few case
reports) and in combination with SSRIs, venlafaxine and atypical antipsychotics.
• 2- Management of the serotonin syndrome involves removal of the precipitating
drugs and supportive care. Many cases typically resolve within 24 h after
serotonergic drugs are stopped but symptoms may persist in patients taking
medicines with long half-lives or active metabolites.

• The 5HT2A-antagonist cyproheptadine and atypical antipsychotic agents with

5HT2A-antagonist activity, such as olanzapine, have been used to treat serotonin
syndrome, although their efficacy has not been conclusively established.
 •Case 4
• A 23 year-old female kidney transplant recipient (3 months post-transplant) presented with
cutaneous nodules with fever and pulmonary nodules on CT. The patient was maintained
on cyclosporine (300 mg/day), mycophenolate mofetil, and prednisone (5 mg/day) for
immunosuppression.
• At this dose, the cyclosporine plasma trough (i.e. pre-dose) level was approximately
150 ng/mL, which is within the therapeutic target range. Cyclosporine levels are
monitored to ensure an appropriate level of immunosuppression, while avoiding
exposure-related nephrotoxicity and acute renal failure post-transplant
• A work-up resulted in diagnoses of infection with Apergillus and cytomegalovirus (CMV).
Treatment was initiated with IV ganciclovir for CMV and voriconazole for Apergillus. At
the same time, the dose of cyclosporine was decreased to 50 mg/day.

• 1. Explain the drug interaction that required the reduction in dose of cyclosporine.
•Explain the drug interaction that required the reduction in dose of
cyclosporine.

• Cyclosporine is a substrate for CYP3A4, while voriconazole is an inhibitor. Therefore, an

increase in exposure of cyclosporine is anticipated because of CYP3A4 inhibition by
voriconazole. In addition, the reduction in cyclosporine dose was intended to minimize
immunosuppression in the face of a growing infection.

• Furthermore, it has been demonstrated that voriconazole increases

cyclosporine serum levels in kidney transplant recipients, including
approximate 2.5-fold increases in trough concentrations.