Indian Society for Rational Pharmacotherapeutics

It gives me immense pain to inform all that Dr K K Sharma, former Professor & Head Pharmacology and Principal UCMS New Delhi, Author and Editor of very popular Text book of Pharmacology Sharma and sharma, Founder President ISRPT, author of many books and research papers convener of M**S, eminent Pharmacologist of the country, a popular teacher among undergraduate and postgraduates across the country and par excellence teacher and over all a excellent human being and Nobel soul left for heavenly abode today morning at 7.38 AM. I pray Almighty God to grant the highest place in heaven to his pious soul.
May god give patience and courage to all his creations as pharmacologist
He may have left us physically but he will always remain in our hearts and mind generation of generations to come.
ISRPT

Explain why- Autonomic Nervous System

a) Explain why low dose of dopamine is preferred in hypovolemic shock?
Answer: In hypovolemic shock, due to decreased blood volume, the blood pressure falls. This leads to compensatory increase in vasomotor centre activity i.e. increase in sympathetic discharge/ outflow. This causes vasoconstriction of blood vessels including renal artery through stimulation of α1 adrenoreceptor further leading to renal hypo perfusion hence acute tubular necrosis. Dopamine at low dose (i.e.

General Pharmacology

Q1. Rifampin decreases the bioavailability of digoxin by oral route. Explain why?
Ans. P-glycoprotein is expressed in multiple key organs in drug disposition such as small intestine, blood–brain barrier, kidney, and liver. Therefore, P-glycoprotein mediated drug–drug interactions can occur at various organs and tissues.
P glycoprotein is efflux transporter in gut epithelium involved in efflux of various drugs such as digoxin. Rifampin being an inducer of P glycoprotein, it could reduce digoxin plasma concentrations by limiting its absorption from the GI tract and/or by increasing the elimination of digoxin from kidney.The effect of rifampin on digoxin plasma concentrations is greater following oral digoxin than intravenous digoxin, indicating that the effect of rifampin may be greater on the absorption of digoxin than on its renal elimination.
Like rifampin, St. John's wort has also demonstrated increase P-gp activity in the intestine resulting in lower plasma digoxin concentrations.

Q2. Explain why toxicity of statins such as rosuvastatin and pravastatin is increased in the presence of cyclosporin A?
Ans. Statins are taken up by hepatocytes via OATP1B1 transporters and subsequently metabolized and eliminated. Cyclosporin A inhibits OATP1B1 transporters, hence block the hepatic uptake of these statins leading to their increased plasma concentrations. This may increase the chances of toxicity such as myopathy, sleep disorders etc..

Q3. Drug free period is given for transdermal nitroglycerine patch therapy for patients of angina pectoris. Explain why.
Ans. Transdermal patch of nitroglycerine provides steady delivery of nitroglycerine for 24 hours with 70-90% bioavailability. Continuous exposure to nitroglycerine may lead to marked attenuation of pharmacological effects i.e. development of tolerance to nitroglycerine.
The mechanism of action of nitrates is believed to involve nitrate receptors that are present in vascular smooth muscle. The nitrate receptors possess sulfhydryl groups which reduce nitrates to nitrite and nitric oxide (NO) which causes vascular smooth muscle relaxation to benefit the patients of angina pectoris. Tolerance may result from reduced capacity of vascular smooth muscles to convert nitroglycerine to NO, volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups or generation of free radicals. Therefore, patch should be removed for at least 8 hours every day to provide drug free interval to replenish sulfhydryl groups group in smooth muscle, which prevents development of tolerance.

Q4. Penicillin G is not preferred by oral route. Explain why?
Ans. Since PnG is acid labile majority of it is destroyed in acidic pH in the stomach. Result of this only less than one-third of the orally administered dose is absorbed.

Q5. Anaesthetic action of thiopentone sodium is terminated in few minutes. Explain why?
Ans. Thiopentone sodium is a highly lipid soluble drug. After a single intravenous bolus administration, it preferentially distributes into highly perfused into the organs/tissues rich in lipids like brain and spinal cord. Hence produces anaesthesia within a single brain arm circulation time i.e. 10-30 sec with peak effect in 1 min.
Subsequently blood levels fall due to drug redistribution from the CNS back into the blood and diffuses to less perfused tissues such as muscle, viscera and adipose tissue resulting in rapid termination of its action(5-8min).

Q6. Explain why drug dosages of many drugs varies in elderly age group as compared to adults?
Ans. There is alteration in pharmacological response of drugs in elderly age group due to altered physiology and psychology due to aging process. The absorption of drugs is restricted by diminished secretion from salivary glands and delayed gastric emptying. There is altered first pass metabolism due to diminution in hepatic function. Elimination is altered due to decreased renal function. Pharmacodynamic of the drug is also affected by changes in receptor site response, alteration in homeostatic mechanisms and variation in blood brain barrier pe*******on. Hence alteration in drug dosages is required in elderly.

Q7. Analgesic effect of codeine is lost in the presence of quinidine. Explain why?
Ans. Codeine is metabolism by CYP2D6 to its active form i.e. morphine. Quinidine inhibits CYP 2D6 enzyme to prevent active conversion of codeine to morphine. Hence it diminishes the analgesic effects of morphine.

Q8. Ketoconazole is given with orange juice in a patient with achlorhydria. Explain why?
Ans. Ketoconazole is more soluble in low pH. Hence acidic medium facilitates its absorption. Patient with achlorhydria lacks gastric acid secretion hence orange juice provides the necessary acidic pH needed for Ketoconazole absorption.

Q9. Explain why legislation in some countries provide tax relief and other incentives for the development of orphan drugs?
Ans. Orphan drugs are the drugs meant for the treatment of rare and neglected diseases. These diseases may have large unmet need for the development of drugs for their management. The high cost incurred on orphan drug development but the consumption and sales of such drugs is less. The manufacturer may not be able to recover the costs incurred. Hence, tax benefits/rebates are given to promote the development of such drugs.

Q10. Patients on lithium therapy should be closely monitored if NSAIDS are prescribed. Explain why?
Ans. NSAIDS are cyclo-oxygenase inhibitors and prevent the production of vasodilatory prostaglandins (PGs) i.e. PGE-2 and PGI-2. Hence, renal blood flow is reduced which leads to reduced delivery of sodium. This results in increased reabsorption of lithium as it competes with sodium for reabsorption i.e. urinary clearance of the lithium is reduced. Rising levels of lithium may lead to toxicity. Hence its levels should be monitored in patients who are taking NSAIDs concomitantly.

Q1. Rifampin decreases the bioavailability of digoxin by oral route. Explain why?

Ans. P-glycoprotein is expressed in multiple key organs in drug disposition such as small intestine, blood–brain barrier, kidney, and liver. Therefore, P-glycoprotein mediated drug–drug interactions can occur at various organs and tissues.
P glycoprotein is efflux transporter in gut epithelium involved in efflux of various drugs such as digoxin. Rifampin being an inducer of P glycoprotein, it could reduce digoxin plasma concentrations by limiting its absorption from the GI tract and/or by increasing the elimination of digoxin from kidney.The effect of rifampin on digoxin plasma concentrations is greater following oral digoxin than intravenous digoxin, indicating that the effect of rifampin may be greater on the absorption of digoxin than on its renal elimination.
Like rifampin, St. John's wort has also demonstrated increase P-gp activity in the intestine resulting in lower plasma digoxin concentrations.

Q2. Explain why toxicity of statins such as rosuvastatin and pravastatin is increased in the presence of cyclosporin A?

Ans. Statins are taken up by hepatocytes via OATP1B1 transporters and subsequently metabolized and eliminated. Cyclosporin A inhibits OATP1B1 transporters, hence block the hepatic uptake of these statins leading to their increased plasma concentrations. This may increase the chances of toxicity such as myopathy, sleep disorders etc..

Q3. Drug free period is given for transdermal nitroglycerine patch therapy for patients of angina pectoris. Explain why.

Ans. Transdermal patch of nitroglycerine provides steady delivery of nitroglycerine for 24 hours with 70-90% bioavailability. Continuous exposure to nitroglycerine may lead to marked attenuation of pharmacological effects i.e. development of tolerance to nitroglycerine.
The mechanism of action of nitrates is believed to involve nitrate receptors that are present in vascular smooth muscle. The nitrate receptors possess sulfhydryl groups which reduce nitrates to nitrite and nitric oxide (NO) which causes vascular smooth muscle relaxation to benefit the patients of angina pectoris. Tolerance may result from reduced capacity of vascular smooth muscles to convert nitroglycerine to NO, volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups or generation of free radicals. Therefore, patch should be removed for at least 8 hours every day to provide drug free interval to replenish sulfhydryl groups group in smooth muscle, which prevents development of tolerance.

Q4. Penicillin G is not preferred by oral route. Explain why?

Ans. Since PnG is acid labile majority of it is destroyed in acidic pH in the stomach. Result of this only less than one-third of the orally administered dose is absorbed.

Q5. Anaesthetic action of thiopentone sodium is terminated in few minutes. Explain why?

Ans. Thiopentone sodium is a highly lipid soluble drug. After a single intravenous bolus administration, it preferentially distributes into highly perfused into the organs/tissues rich in lipids like brain and spinal cord. Hence produces anaesthesia within a single brain arm circulation time i.e. 10-30 sec with peak effect in 1 min.
Subsequently blood levels fall due to drug redistribution from the CNS back into the blood and diffuses to less perfused tissues such as muscle, viscera and adipose tissue resulting in rapid termination of its action(5-8min).

Q6. Explain why drug dosages of many drugs varies in elderly age group as compared to adults?

Ans. There is alteration in pharmacological response of drugs in elderly age group due to altered physiology and psychology due to aging process. The absorption of drugs is restricted by diminished secretion from salivary glands and delayed gastric emptying. There is altered first pass metabolism due to diminution in hepatic function. Elimination is altered due to decreased renal function. Pharmacodynamics of the drug are also affected by changes in receptor site response, alteration in homeostatic mechanisms and variation in blood brain barrier pe*******on. Hence alteration in drug dosages is required in elderly.

Q7. Analgesic effect of codeine is lost in the presence of quinidine. Explain why?

Ans. Codeine is metabolism by CYP2D6 to its active form i.e. morphine. Quinidine inhibits CYP 2D6 enzyme to prevent active conversion of codeine to morphine. Hence it diminishes the analgesic effects of morphine.

Q8. Ketoconazole is given with orange juice in a patient with achlorhydria. Explain why?

Ans. Ketoconazole is more soluble in low pH. Hence acidic medium facilitates its absorption. Patient with achlorhydria lacks gastric acid secretion hence orange juice provides the necessary acidic pH needed for Ketoconazole absorption.

Q9. Explain why legislation in some countries provide tax relief and other incentives for the development of orphan drugs?

Ans. Orphan drugs are the drugs meant for the treatment of rare and neglected diseases. These diseases may have large unmet need for the development of drugs for their management. The high cost incurred on orphan drug development but the consumption and sales of such drugs is less. The manufacturer may not be able to recover the costs incurred. Hence, tax benefits/rebates are given to promote the development of such drugs.

Q10. Patients on lithium therapy should be closely monitored if NSAIDS are prescribed. Explain why?

Ans. NSAIDS are cyclo-oxygenase inhibitors and prevent the production of vasodilatory prostaglandins (PGs) i.e. PGE-2 and PGI-2. Hence, renal blood flow is reduced which leads to reduced delivery of sodium. This results in increased re-absorption of lithium as it competes with sodium for reabsorption i.e. urinary clearance of the lithium is reduced. Rising levels of lithium may lead to toxicity. Hence its levels should be monitored in patients who are taking NSAIDs concomitantly.

After a long gap there are some questions pertaining to General Pharmacology. Department of Pharmacology, Lady Hardinge Medical College shall be pleased if UG and PG students respond to these questions. Model answers will be uploaded after 5 days.

Q1. Explain why rifampin decreases the bioavailability of orally administered digoxin?

Q2. Explain why toxicity of statins such as rosuvastatin and pravastatin is increased in the presence of cyclosporin A?

Q3. Explain why drug free period is considered for transdermal nitroglycerine patch therapy?

Q4. Explain why penicillin G is not preferred by oral route?
Q5. Explain why anaesthetic action of thiopentone sodium is terminated in few minutes?

Q6. Explain why drug dosages of many drugs vary in geriatric patients as compared to adults?

Q7. Explain why analgesic effect of codeine is lost in the presence of quinidine?

Q8. Explain why ketoconazole is given with orange juice in a patient with achlorhydria?

Q9. Explain why legislation in some countries provides tax relief and other incentives for the development of orphan drugs?

Q10. Explain why patients on lithium therapy should be closely monitored if NSAIDS are prescribed concomitantly?

Question for undergraduates

1 .Explain the paradoxical effect of beta blockers as antihypertesive agent ?
2. Explain why therapeutic lag is greater with the use of tricyclic antidepressants than for SSRIs ?

ISRPT is pleased to all the members and the viewers
of this page that Faculty members of Department of Pharmacology, JIPMER, Pudducherry have agreed to interact and contribute the teaching learning material for both UG and PG students in Pharmacology. ISRPT acknowledges the kind gesture of Dr. Ravindran HoD, JIPMER

Model answers for the few questions of Class test on Endocrine System at LHMC, ND
Students/respondant may send their suggestions and or queries to the dept of Pharmacology, LHMC or email [email protected]

EXPLAIN WHY
Q1. Octreotide is preferred over somatostatin for treatment of acromegaly?
Ans: Somatostatin has shorter t1/2 (2-3min) as compared to octreotide (t1/2 of 1.5-1.7hrs.). Octreotide is 45 times more potent than somatostatin. In addition, somatostatin is a non- selective inhibitor of GH release whereas octreotide bind preferentially to somatostatin 2 and somatostatin 5 receptors in pituitary to inhibit GH secretion. Further octreotide is associated with lesser chances of glycemic derangement. In pancreas somatostatin, inhibits insulin secretion due to its non-selective action on somatostatin receptors. Hence octreotide is preferred over somatostatin for treatment of acromegaly.

Q2. Propylthiouracil is used in pregnancy for the treatment of hyperthyroidism?
Ans: Propylthiouracil is preferred in pregnancy because it is 75% plasma protein bound and small amount is available for trans-placental transfer. Whereas methimazole is not protein bound. Further, there is known risk of fetal abnormalities associated with methimazole use in pregnancy. Hence propylthiouracil is preferred in pregnancy.

Q3. Insulin detemir is long acting insulin preparation?
Ans: Insulin detemir is an insulin analog modified by the addition of a saturated fatty acid to the amino group of Lys in chain B at 29 position. After subcutaneous administration it is absorbed in the circulation and binds to albumin via its fatty acid chain from which it is released slowly. Due to this it has smoother time–action profile and longer duration of action requiring only twice daily administration.

Q4. Flutamide is co-administered with leuprolide for the treatment of cancer prostate?
Ans: Long-acting GnRH agonists like leuprolide when given continuously inhibits the secretion of gonadotropins due to down regulation of GnRH receptors in pituitary. But increase in hormone levels occurs initially due to GnRH agonism which may flare up cancer prostate. The action of this increased gonadotropin secretion can be blocked by co-administration of flutamide, an androgen receptor blocker. The use of flutamide alone increases LH secretion and in turn testosterone levels through feedback. Androgen is also synthesis from the non-gonadal i.e. peripheral sources which can be blocked by flutamide. Further, co-administration of two have additive efficacy in the treatment of cancer prostate.

Q5. Ergometrine is not used for induction of labour?
Ans. Therapeutic dose of ergometrine causes increase in frequency and force of contraction of both upper and lower segment of uterus leading to difficulty in fetal descent & arrest of labour unlike oxytocin which contracts only upper segment.
Sustained contraction compromises the blood supply to the foetus leading to fetal hypoxia which precludes its use for induction of labour. It is recommended for the prevention and treatment of postpartum hemorrhage.

RATIONALE
1. Metyrapone in cushing’s syndrome
Ans: Metyrapone has a diagnostic and therapeutic role in cushing’s syndrome. It is a relatively selective inhibitor of CYP11B1 (11β-hydroxylase), which converts 11-deoxycortisol to cortisol in the glucocorticoid biosynthetic pathway resulting in decrease synthesis of cortisol and compensatory increase in ACTH.
Diagnostic administration of metyrapone in patients with pituitary-dependent Cushing’s syndrome exhibits an increased ACTH (or 11-deoxycortisol) levels while patients with ectopic secretion of ACTH exhibits no change in ACTH (or 11-deoxycortisol) levels.
Therapeutically, metyrapone is used for short time treatment of cushing’s syndrome as an adjuvant either preoperative or for control of residual disease persisting post operatively.

2. Calcitriol in chronic renal failure.
Ans: Calcitriol (1, 25 dihydroxycholecalciferol) is active form of vitamin D3. Usually vitamin D3 is converted to active form by hydroxylation first in liver from cholecalciferol to 25 hydroxycholecalciferol (by 25 alpha hydroxylase) and then in kidney to 1, 25 dihydroxycholecalciferol (1 alpha hydroxylase).
In chronic renal failure, this rate limiting step of hydroxylation of 25 hydroxycholecalciferol is reduced. Therefore, calcitriol is administered in chronic renal failure to bypass the hydroxylation step that occurs in kidney.
3. Combined oral contraceptive pills (OCP’s)
Ans: Combined oral contraceptive pills contain an estrogen and a progestin. Reasons for this combination are:
i. Progestrin enhances the action of estrogen through its negative feedback to pituitary to inhibit FSH and LH release which ultimately inhibits ovulation.
ii. Progestrin makes the endometrial environment more hostile for the s***m.
iii. Their combination helps in lowering the dose of estrogen required. This minimizes the adverse effects viz irregular bleeding, endometriosis etc without compromising efficacy
iv. Progestrin in OCP ensures prompt withdrawal bleeding at the end of cycle, benefits women psychologically as physiological pattern of menstrual cycle is maintained.
v. Progestrin in OCP reduces the risk of endometrial carcinoma caused by estrogen component.

4. GnRH analogues in female infertility
Ans: GnRH in short and intermittent duration (pulsatile) increases the production of FSH and LH from pituitary whereas continuous GnRH administration reduces the synthesis of gonadotrophins (FSH and LH) by downregulating of GnRH receptors present on pituitary. Long acting GnRH analogues like buserelin, nafarelin cannot be used for stimulation of ovulation.
In female fertility, proper timing of maturation and release of o**m is important which can be predicted precisely with exogenous FSH and LH administration.

We hope that you solved/answered all the questions. The model answers of these questions are given below. We shall be glad if you communicate your queries/clarification in this regard.

1. Dose of warfarin has to be reduced in a patient of chronic liver disease?
In chronic liver disease, the serum albumin levels are reduced. Being an acidic drug warfarin binds to albumin. So in such cases, the free fraction of warfarin will be higher in the blood. This can cause enhanced anticoagulant action of warfarin may leading to potential risk of bleeding.

2. More quantity (Dose) of lidocaine is required to treat ventricular arrhythmia in the patients having Crohn’s disease as co-morbid condition?
In Crohn’s disease (an inflammatory condition) the level of alpha glycoprotein (globulins) is raised. Lidocaine being a basic drug binds to alpha glycoprotein. This may reduce availability of free lidocaine leading to therapeutic failure.

3. Excessive exogenous vitamin K administration is not preferred in preterm neonates?
There is a practice of administration of Vitamin K in neonates to stimulate the synthesis of vitamin K dependent clotting factors (II, VII, IX, X). If excessive Vitamin K is given, it may displace bilirubin bound to albumin to cause jaundice. Since the blood brain barrier is not well developed in premature neonates, displaced bilirubin can enter brain to cause kernicterus.

4. Regular Insulin administered intravenous has 3 liters of volume of distribution?
IV Insulin cannot cross the intact blood vessels owing to its larger size i.e. confined to intravascular compartment. Thus have volume of distribution equal to plasma water i.e. 3L.

5. Haemodialysis is not useful in imipramine toxicity?
Imipramine is a basic drug and 90% is bound to alpha glycoprotein in blood. This bound fraction (90%) cannot be removed by haemodialysis. Moreover, it serves as a reservoir for the free fraction of drug which is responsible for toxicity. So, haemodialysis is not much of use as to eliminate imipramine from blood.

6. Therapeutic dose monitoring of phenytoin is recommended?
Phenytoin is metabolized by cytochrome P450 using 1st order kinetics. When higher theraperutic or toxic dose of phenytoin is given the enzymes metabolizing phenytoin gets saturated and changes its elimination kinetics from first to zero order. This can disproportionately increases serum phenytoin levels to cause toxicity. Hence, therapeutic dose monitoring is recommended.

7. Digoxin is given as loading dose in patient of heart failure with atrial fibrillation?
Or
There is a lag period for the manifestation of pharmacological effect of digoxin?
Apparent volume of distribution of digoxin is large (6-7 L/Kg) as it extensively binds to skeletal and cardiac muscles. Due to which it has long distribution phase resulting in lag time before optimum pharmacological effect is observed. In addition terminal half life of digoxin is 1.5 days would take 3-4 days to attain desired steady state concentration (SSC). Therefore in case of emergency condition a loading dose is required to achieve quick SSC.

8. Chloroquine is given in malaria patient initially as loading dose?
Chloroquine binds to adipose tissue and gets concentrated in extravasular tissues with volume of distribution around 1300 L/Kg. Loading dose of chloroquine fills these extravascular sites quickly to attain required therapeutic concentration in blood.

9. Furosemide should be used with caution in patient having hypersensitivity to sulfonamides?
Both furosemide and sulfonamides are sulphamoyl derivative. Due to similarity in chemical structure, patient hypersensitive to sulfonamides may have cross sensitivity with frurosemide. Caution should be taken whole should be taken while using these drugs.

10. Diuretic action of acetazolamide is self limiting?
Acetazolamide is carbonic anhydrous inhibitor causes loss of excess bicarbonate, sodium, potassium and water in urine, which makes the urine alkaline. Continued use of acetazolamide depletes body bicarbonate leading to mild metabolic acidosis. As a result of compensatory mechanism there is reabsorption of sodium in the terminal part of distal tubule leading to self limiting action of acetazolamide over a couple of days use. Due to which it is rarely used as a diuretic.

11. Vitamin K administration is advised with prolonged cefaperazone therapy?
Cefaperazone can cause hypoprothrombinemia by inhibiting the synthesis of vitamin K dependent clotting factors in liver. Therefore vitamin K administration is advised with prolonged cefaperazone therapy to prevent bleeding disorder.

12. Montelukast in used in bronchial asthma despite it increases absolute eosinophil count?
Montelukast is leukotriene receptor antagonist. Leukotriene, major inflammatory mediators of bronchial asthma is mainly secreted by mast cells. Eosinophil count is already high in patient of bronchial asthma use of monteleukast will further enhance eosinophil counts. Montelukast use is associated with increase in eosinophil count as adverse effects. Since the leukotrienes are released from the mast cells but not the eosinophils will not affect the therapeutic outcomes.

13. Half life of heparin is shorter in patient with pulmonary embolism?
Acute phase proteins like alpha 1 acid glycoprotein, platelet factor 4 etc are raised in pulmonary embolism. Heparin binds to these proteins to reduce the availability of free heparin produce therapeutic effects. Therefore heparin dose has to be increased in pulmonary embolism.

14. Sodium nitroprusside should be used with caution in a patient of liver disease?
Sodium nitroprusside get converted to cyanide ion in RBC. These cyanide ions are metabolized in the liver. Thus in case of liver disease these cyanide ions are not metabolized and can cause cyanide toxicity.

15. Analgesic effect of codeine is reduced in the presence of quinidine?
Quinidine inhibits CYP2D6 enzyme in the liver and prevent conversion of codeine into its active metabolite morphine. This could leads to reduced analgesic effect of codeine.

16. Gastric lavage is indicated in morphine poisoning from intra venous route?
Morphine is a basic and lipophilic drug. Because of that it secretes from blood to stomach and get ionized there in acidic pH. Therefore gastric lavage is indicated to remove this ionized morphine from stomach.

17. Extra pyramidal symptoms (EPS) are rare with aripiprazole use as antipsychotics?
Aripiprazole, third generation antipsychotic, is a partial agonist at D2 receptors which account for the incidence of extrapyramidal side effects equivalent to placebo.

18. Amphotericin B should not be combined with corticosteroid?
Amphotericin B and corticosteroid both decreases blood potassium levels which may lead to fatal hypokalemia when given together. Severe hypokalemia may lead to life threatening arrhythmia.

19. Moxifloxacin is not combined with sotalol?
Sotalol is class III anti arrhythmic drug and can cause QT prolongation. Therefore, it should not be combined with other drugs (moxifloxacin) causing QT interval prolongation. This can leads to torsades de pointes.

20. Caspofungin should not be administered with atorvastatin?
Caspofungin inhibits organic anion transport protein 1B1 in kidney which is responsible for tubular secretion of atorvastatin. This would increase atorvastatin levels in blood leading to higher risk of muscular and hepatic adverse effects.

21. Why loading dose of digoxin is calculated based on lean body weight?
Digoxin extensively binds to skeletal and cardiac muscles and does not distribute substantially to body fat. Hence lean body mass should be considered to calculate its loading dose.