General Pharmacology. Case-Study with Solutions

Exam Revision 2017 108 Pages



Chapter 1: General Pharmacological principles

A) Introduction , Routes of drug administration

1. A 4 year old child is brought to the hospital with the complaint of fever, cough, difficulty in breathing and chest pain. On examination he is found to be dull, but irritable with fast pulse (118/min), rapid breathing (RR 55/min ) and indrawing of lower chest during inspiration, wheezing, crepitations and mild dehydration. Body temperature is 40 0C(1040F). The physician makes a provisional diagnosis of acute pneumonia and orders relevant haematological as well as bacteriological investigations. He decides to introduce antibiotic therapy.

a) In case he selects an antibiotic which can be given orally as well as by i.m or i.v injection, which route of administration will be most appropriate in this case?

b) Should the paediatrician administer the antibiotic straight away or should he wait for the laboratory reports?



a) Since the child is seriously ill, a fast and more predictable action of the antibiotic is needed; a parenteral route of administration is right. Moreover oral dosing may be difficult in this case as the child is dull and irritable. Entering a vein for i.v. injection is relatively difficult in children, particularly in the presence of dehydration. Therefore, the antibiotic may be injected i.m. however, if an i.v. line is set up for rehydration, the antibiotic may be administered through the i.v line.

b) In this case the provisionally selected antibiotic may be amoxicillin , which should be started as early as possible, because the child is seriously ill. Waiting for the lab reports to confirm the diagnosis/ select the definitive antibiotic may compromise the prognosis.

B) Dose calculations

2. A 49 year old male patient, 83.3 kg in weight, is to receive immediate release carbamazepine regimen.

a) Compute the daily dose required to achieve a steady state plasma concentration of 7.5 mg/L, assuming monotherapy.

b) If the patient receives phenobarbital medication of 2.0 mg/kg Q12h for the past 3 months and the doctor decides to include a concomitant therapy of carbamazepine in order to better control his seizure, compute the daily maintenance dose required to attain a target steady state concentration of 7 mg/L carbamazepine, using an immediate release formulation. Later on, over the course of treatment, blood samples were evaluated for carbamazepine and were reported to be 12.5 mg/L. How should his daily dose be adjusted to get to the desired concentration?

3. Mala a 49-year-old, 55kg female, had been taking 250mg/day of sodium phenytoin; however, her dose had been increased to 300mg/day because her seizures were poorly controlled and because her phenytoin plasma concentration was only 3mg/L. Now she complains about minor CNS side effects and her measured plasma phenytoin concentration is 26mg/L. This level was decided to be too high for this patient, so the maintenance dose was discontinued. How long would it take for the phenytoin concentration to drop to 15 mg/L after discontinuation of dose?

The following equation may be helpful to solve this problem:

4. Aszad a 75-year-old, 65-kg man (non-obese), was admitted with complaints of increased shortness of breath and yellow sputum production. He has a medical history of congestive heart failure. During his hospital stay, he developed atrial fibrillation and was given digoxin to slow his ventricular rate. He received 3 doses 0.25-mg digoxin IV every 3 hours (starting at 9pm on day 1) and was given a maintenance dose of 0.25-mg tablets each morning (starting at 9am on day 2). His serum creatinine is stable at 1.3 mg/dL.

Calculate his expected digoxin plasma concentration at 9am on day 4. (Hint: A graph of the expected concentration time profile might be helpful to answer this problem)

5. Which combination of the following pharmacokinetic changes is the best one to describe the elderly and neonates? (These groups share similar PK characteristics.)

1) Low renal clearance
2) Relatively less body water
3) Low metabolic clearance
4) Decreased protein binding
5) Longer half-lives

A) 1 & 4
B) 1, 3, & 4
C) 1, 4, &5
D)1, 3, 4 &5 all of the above

6. A clinical study was conducted to assess the effect of carbamazepine on the pharmacokinetics of drug X after a single oral dose. The mean drug X concentration-time profile is shown in the Figure. It is known that drug X is metabolized mainly by CYP3A4. Describe the graph and make a conclusion. Close circles: Drug X alone Open circles: Drug X with carbamazepine.

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Fig-1: Mean plasma concentration Vs time in hr

7. Vertilmicin is an investigational aminoglycoside being evaluated for its antimicrobial effect. The route of administration for this drug is via intravenous bolus. Approximately 99.9% of this drug is eliminated by the kidney. Tubular secretion and reabsorption do not play a role in its elimination. Vertilmicin has no significant plasma protein binding. Assuming ideal body weight for this individual (male, 47 years of age, 70 Kg with serum creatinine of 2.1 mg/dL), compute the following pharmacokinetic parameters:

(a) Clearance

(b) Half-life, assuming that volume of distribution was related to body weight at 0.35 l/kg

8. Drug X is administered as 250 mg IV bolus dose. Two hours after administration, the concentration in the plasma was 5 mg/L and 10 hours after administration the plasma concentration was 1 mg/L. The drug is a lipophilic compound and is cleared by the liver. This patient has a liver blood flow of 90 L/h. The fraction of drug bound to tissue is 0.6.

a) Time required to reach C0.

b) Compute Vd

c) Comment whether this drug is a high extraction or low extraction drug. Assuming that hepatic clearance is 80% of total body clearance, compute the extraction ratio for this drug.

d) If Drug Y induces the enzymes responsible for Drug X metabolism, would you expect to see a change in clearance?



a) Note : Carbamazepine has a clearance of 0.064 L/h/kg for monotherapy. For immediate release carbamazepine, the oral bioavailbility is 0.8

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b) Carbamazepine has a clearance of 0.1 L/h/kg for polytherapy

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5. So the answer is D

It means Low renal clearance and , Low metabolic clearance with Decreased protein binding and Longer half-lives.


a) The peak plasma concentrations and AUC of Drug X administered alone are higher than that with carbamazepine co-administration.

b)Carbamazepine is a potent inducer of CYP3A4 which influenced the concentrations of Drug X significantly.


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a) Assuming no loading dose and a constant dosing interval, it takes less time to reach steady state for a drug with higher degree of accumulation.

b) A multicompartmental body model only has one volume of distribution.So it is 0.6 only.

c) Induction of hepatic biotransformation enzymes will affect the clearance of low extraction drugs.

d) Assuming that the volume of distribution stays constant, when clearance decreases, it will take a longer time to steady state and result in an increased half-life. . Bioequivalence is assessed as the absence of a statistically significant difference in the rate and extent which the active pharmaceutical ingredient becomes available. Bioequivalent products are therapeutically interchangeable.

C) Pharmacokinetics of drugs

9. A 60 year lady complained of weakness, lethargy and easy fatigability. Investigation showed that she had iron deficiency anaemia (Hb. 8g/dl). She was prescribed cap. Ferrous fumarate 300 mg twice daily. She returned after one month with no improvement in symptoms. Her Hb. Level was unchanged. On enquiry she revealed that she felt epigastric distress after vtaking the level was unchanged. On enquiry she revealed that she felt epigastric distress after taking the iron capsules, and had started taking antacid tablets along with the capsules.

What could be the possible reason for her failure to respond to the oral iron medication?

10. A 50 year old man with type 2 diabetes was maintained on tab. Glibenclamide 5 mg twice daily. He developed toothache for which he took tab. Aspirin 650 mg 6 hrly. After taking aspirin he experienced anxiety, sweating, palpitation, weakness, ataxia, and was behaving abnormally. These symptoms subsided when he was given a glass of glucose solution.

a) What could be the explanation for his symptoms?

b) Which alternative analgesic should have been taken?

Solved answers

9. Gastric acid is required for the absorption of oral iron salts. Concurrent ingestion of antacid tablets could have interfered with iron absorption. Hence, the anaemia failed to improve.

10. a) Aspirin displaces sulfonylureas from plasma protein binding sites. Therefore, plasma concentration of unbound (and active) glibenclamide would have risen after aspirin ingestion causing hypoglycemia which produced the symptoms. As such, glucose ingestion relieved the symptoms.

b) Paracetamol and ibuprofen are analgesics equally effective in toothache as aspirin, and do not displace or otherwise interact with sulfonylureas. As such, these analgesics are more suitable for the given patient.

D) Elimination of Drugs

11. A 30 year old mother of 2 children weighing 60 kg was taking combined oral contraceptive pill containing levonorgestrel 0.15 mg+ ethinylestradiol 30 µg for day cyclically (3 weeks treatment-1week gap). She developed fever with cough and was diagnosed as a case of pulmonary tuberculosis after sputum smear examination. She was put on isoniazid (300 mg)+ rifampin (600mg)+ pyrazinamide(1.5g)+ ethambutol (1g) daily for 2 months, followed by isoniazid (600mg)+ rifampin (600mg thrice weekly). In the 3rd month she failed to have the usual withdrawal bleeding during the gap period of contraceptive cycle. After 10 days her urinary pregnancy test was found to be positive.

a) What could be the reason for failure of the oral contraceptive?

b) What precaution could have prevented the unwanted pregnancy?

12. A 20 year old paytient weighing 60 kg has to be prescribed an antiepileptic drug (available as 200 & 400mg tablets) for generalized tonic-clonic seizures. The pharmacokinetic parameters and therapeutic plasma concentration of the selected drug are :


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What should be the loading dose and the daily maintenance dose of the drug for this patient ?



a) Rifampin is known to induce the metabolism of contraceptive steroids, thus after regular intake of rifampin for more than 2 weks (needed for enzyme induction) the steady state blood level of levonorgestrel & ethinylestradiol could have fallen below the threshold for inhibition of ovulation/ contraception. As such, fertility was restored and the women conceived.

b) In view of the essentiality of rifampin (other antitubercular drugs) in this patient and the likelihood of failure of the oral contraceptive, the couple should have been advised to take additional/alternative contraceptive measure such as condom or intrauterine device.

12..The total volume of distribution (Vd) should be calculated first.

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For this patient : loading dose 720 mg initially; or practically 3 ½ tablets of 200 mg each. Maintenance dose : 984 mg/day.

The maintenance dose may be one 400 mg tab. In the morning and 1 ½ tab. (600 mg) in the evening.

Chapter 2: Pharmacodynamics &Pharmacotherapy & Drug development

1. A patient being treated with methotrexate developed oral ulceration, megaloblastic anaemia and other toxic symptoms. Given that 1) Mtx acts by inhibiting the enzyme dihydrofolate reductase (DHFRase) which generates the essential coenzyme tetrhydrofolic acid (THFA) from dihydrofolic acid (DHFA) needed for one carbon transfer reactions, ii) Mtx binds to the catalytic site of DHFRase with an affinity 50,000 times greater than the natural substrate DHFA, and that iii) two forms of folate viz. folic acid and folinic acid (N5 formyl THFA) are available for therapeutic use:

a) Which type of enzyme inhibition will be produced by Mtx?
b) Which form of folate should be used to treat Mtx toxicity ?

2. A 65 year old male hepatic cirrhosis patient was admitted to the hospital for treatment of gross ascetic fluid. He responded with brisk dieresis, but on the 3rd day he was found to be talking irrelevant, was weak and partly disoriented. He had a fainting episode on getting up from the bed. His serum K+ was 2.8 mEq/L (low) and blood pH was 7.8 (raised).

a) What is the likely cause of his condition on the 3rd da?
b) What should be the principles of management of this complication?



a) Since Mtx. Binds to the same site of DHFRse as the endogenous metabolite DHFA, it will act as a competitive inhibitor. However, because the binding affinity of Mtx for the enzyme is 50,000 times greater, even excess DHFA will not be able to displace it from the enzyme and non equilibrium type of inhibition will be produced.

b) Folic acid administered as a drug will not be able to counteract Mtx toxicity because it will not be converted to the active coenzyme form THFA. On the other hand, folinic acid will supply readymade active coenzyme THFA and will be able to overcome Mtx toxicity.


a) The most likely pathogenesis of the symptoms on the 3 rd day of diuretic therapy in the patient is occurrence of hypokalaemic alkalosis, which precipitated hepatic encephalopathy. In cirrhotics with moderate to severe hepatic dysfunction, ammonia (NH3) produced by gut bacteria is not completely detoxified by conversion to urea in liver.. blood NH3 tends to rise. This ionizes partly to NH4+ and is excreted in urine as NH4Cl. The NH4+ do not cross the BBB. During alkalosis, NH3 ionizes to a lesser extent, raising blood NH3 level, which enters brain tlo cause encephalopathy. Weakness and postural hypotension are the other manifestations of hypokalaemic alkalosis.

b) The diuretic should be withheld till the fluid electrolyte and acid base balance is restored. Intravenous infusion of KCl along with normal saline can hasten recovery from hypokalemia and alkalosis. Oral lactulose (a non absorbable disaccharide) helps in reducing blood NH3 into poorly absorbed NH4+ . lowering of stool pH by lactulose has a suppressant effect on NH3 producing gut bacteria.


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general pharmacology case-study solutions




Title: General Pharmacology. Case-Study with Solutions