Question-4: 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 per day cyclically (3 weeks treatment—
1 week 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 (600 mg) +
pyrazinamide (1.5 g) + ethambutol (1.0 g) daily for 2 months, followed by isoniazid (600 mg)
+ rifampin (600 mg) 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?
Solution:(a) Rifampin is known to induce the metabolism of contraceptive steroids. Thus, after regular intake of rifampin for more than 2 weeks (needed for enzyme induction) the steady-state blood level of levonorgestrel and ethinylestradiol could have fallen below the threshold for inhibition of ovulation/contraception. As such, fertility was restored and the woman conceived. (b) In view of the essentiality of rifampin (and 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 contraceptive device.
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Question-5:A 20-year-old patient weighing 60 kg has to be prescribed an antiepileptic drug (available as 200 and 400 mg tablets) for generalized tonic-clonic seizures. The pharmacokinetic parameters and therapeutic plasma concentration of the selected drug are: Target steady-state plasma concentration (Cpss) – 6 mg/L Oral bioavailability (F) – 70% Volume of distribution (V) – 1.4 L/kg Clearance (CL) – 80 ml/hr/kg Plasma half life (t½) – 15 hours What should be the loading dose and the daily maintenance dose of the drug for this patient?
Solution: The total volume of distribution and total body clearance for this patients has to be calculated first. Total V = 1.4 L/kg × 60 kg = 84 L
Total body clearance (CL) = 80 ml/hr/kg × 60 kg
= 4.8 L/hr
Fractional bioavailability (F) = 70/100
= 0.7
Applying the formula: Loading dose = (target cp x V)/F Or
= (6mg/L x 84 L)/0.7 Or
= 720 mg
Maintenance dose rate = (Cpss x CL)/F Or
= (6 mg/L x 4.8 L/hr)/0.7 Or
=41 mg/hr Or
=41 mg/hr x 24 hr
= 984 mg/day
For this patient: Loading dose 720 mg initially; or practically 3½ tablets of 200 mg each. Maintenance dose: 984 mg/day. To be practical, the maintenance dose could be one 400 mg tab. in the morning and 1½ tab. (600 mg) in the evening.
Question-6:A patient being treated with methotrexate (Mtx) developed oral ulceration, megaloblastic anaemia and other toxic symptoms. Given that (i) Mtx acts by inhibiting the enzyme dihydrofolate reductase (DHFRase) which generates the essential coenzyme tetrahydrofolic 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?
Solution:(a) Since Mtx binds to the same site of DHFRase 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 nonequilibrium 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.
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(a) What could be the reason for failure of the oral contraceptive?
(b) What precaution could have prevented the unwanted pregnancy?
Solution:(a) Rifampin is known to induce the metabolism of contraceptive steroids. Thus, after regular intake of rifampin for more than 2 weeks (needed for enzyme induction) the steady-state blood level of levonorgestrel and ethinylestradiol could have fallen below the threshold for inhibition of ovulation/contraception. As such, fertility was restored and the woman conceived. (b) In view of the essentiality of rifampin (and 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 contraceptive device.
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Question-5:A 20-year-old patient weighing 60 kg has to be prescribed an antiepileptic drug (available as 200 and 400 mg tablets) for generalized tonic-clonic seizures. The pharmacokinetic parameters and therapeutic plasma concentration of the selected drug are: Target steady-state plasma concentration (Cpss) – 6 mg/L Oral bioavailability (F) – 70% Volume of distribution (V) – 1.4 L/kg Clearance (CL) – 80 ml/hr/kg Plasma half life (t½) – 15 hours What should be the loading dose and the daily maintenance dose of the drug for this patient?
Solution: The total volume of distribution and total body clearance for this patients has to be calculated first. Total V = 1.4 L/kg × 60 kg = 84 L
Total body clearance (CL) = 80 ml/hr/kg × 60 kg
= 4.8 L/hr
Fractional bioavailability (F) = 70/100
= 0.7
Applying the formula: Loading dose = (target cp x V)/F Or
= (6mg/L x 84 L)/0.7 Or
= 720 mg
Maintenance dose rate = (Cpss x CL)/F Or
= (6 mg/L x 4.8 L/hr)/0.7 Or
=41 mg/hr Or
=41 mg/hr x 24 hr
= 984 mg/day
For this patient: Loading dose 720 mg initially; or practically 3½ tablets of 200 mg each. Maintenance dose: 984 mg/day. To be practical, the maintenance dose could be one 400 mg tab. in the morning and 1½ tab. (600 mg) in the evening.
Question-6:A patient being treated with methotrexate (Mtx) developed oral ulceration, megaloblastic anaemia and other toxic symptoms. Given that (i) Mtx acts by inhibiting the enzyme dihydrofolate reductase (DHFRase) which generates the essential coenzyme tetrahydrofolic 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?
Solution:(a) Since Mtx binds to the same site of DHFRase 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 nonequilibrium 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.
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