Bostentan

Question.

218. Bostentan is a:

1. Serotonin uptake injibitor.

2. Endothelin receptor antagonist.

3. Leukotriene modifier.

4. Calciuim sensitizer.

Answer

2. Endothelin receptor antagonist.

Reference

CMDT 2002 Page 450

http://www.pharmacist.com/new_drug/tracleer.cfm

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Discussion

• It is endothelin receptor antagosnist
• Generic name: Bosentan
• Manufacturer: Actelion
• Drug Class:
• PROSTACYCLIN
• Dual endothelin receptor antagonist
• Indications: Treatment of pulmonary arterial hypertension.
• Dosage: Initiate treatment at an oral dosage of 62.5 mg twice daily for 4 weeks and then increase to a maintenance dosage of 125 mg twice daily.
• Evidence of liver damage present in 14% of patients in Bosentan: Randomized Trial of Endothelin Receptor Antagonist Therapy trial, but no evidence suggests agent can cause irreversible liver damage.
• It has been made available to patients at the University of Pittsburgh Medical Center as part of a clinical trial. Bosentan works by blocking the action of a hormone called endothelin. Endothelin exists in higher levels in people with PH is a hormone that is harmful to the lung and pulmonary arteries. The damaged lung and pulmonary arteries create the blood flow resistance that results in hypertension. Bosentan was designed to offset endothelin, lowers the endothelin levels, reversing its effects, resulting in lower artery pressure.
• Tracleer blocks the action of endothelin, a substance made by the body. Endothelin narrows blood vessels and elevates blood pressure. Although endothelin is present in healthy people, high concentrations of the hormone have been found in the plasma and lungs of patients with PAH suggesting it is capable of causing the disease.
• Liver function tests are needed
• Because of its potential to cause birth defects, Tracleer must not be prescribed to pregnant women. Female patients of childbearing potential must therefore take measures to prevent pregnancy, and monthly pregnancy testing will be required.

Explanation

1. Serotonin uptake injibitors are Fluoxetine, Fluvoxamine, Paroxetine.

2. Endothelin receptor antagonist.

3. Leukotriene modifiers are Montelukast and Zafirlukast.

4. Calcium sensitizer is Levosimendan.

Comments

Myocardial stunning refers to the phenomenon of transient myocardial dysfunction after brief periods of coronary ischaemia and reperfusion. During stunning there is less myocardial fibre shortening and myocardial oxygen consumption is near normal, indicating a low efficiency of the contractile apparatus. Depressed responsiveness of the myofilaments to Ca ions is regarded as an important factor in the process of stunning. Levosimendan (Levo) increases the sensitivity of troponin C in a Ca-dependent way.

STRUCTURE AND DYNAMICS OF CARDIAC TROPONIN C

Cardiac Troponin C (cTnC) plays a pivotal role in the function of heart. The heart contraction is induced by a conformational change of cTnC triggered by the binding of calcium ions which are released from the sarcoplasmic reticulum. The conformational change of cTnC allows myosin to interact with actin filaments. Subsequently, the heart contracts as the filaments glide past each other. Knowledge of the three-dimensional structure of cTnC and its induced conformational changes at atomic resolution provide new means for understanding the basic events in the heart contraction. This knowledge is also of applied importance. In a number of cases impaired heart functions can be alleviated by drug molecules designed to make troponin C more prone to a conformational change. These drugs which increase the calcium sensitivity are designated calcium sensitizers. It would be most useful for further development of these pharmaceuticals to be able to demonstrate the drug binding and its consequences to the conformation and dynamics of cTnC.

Considering the fundamental role of cardiac troponin C in the heart function and the possibilities to modulate the function by pharmaceuticals a study of cTnC by methods of structural biology is most interesting and useful. The three-dimensional structure of cTnC should be determined in complex with relevant motifs of TnI. In addition deeper insight into the structure-function relationship should be gained by a molecular dynamics study.

A new calcium sensitizer drug levosimendan was discovered by calcium dependent affinity chromatography on a troponin complex column (Haikala et al., 1992). The screening was based on a hypothesis that calcium sensitizers bind in the hydrophobic patch formed in the regulatory domain of TnC following a calcium induced conformational change (Ovaska and Taskinen, 1991). It was recently shown that the new calcium sensitizer drug levosimendan binds to human cardiac troponin C (Pollesello et al., 1994).

Tips

Newer drugs are being asked with increased frequency these days. Go through the last few pages of Sure Success in PG (big book) by Ram Gopal and also the web site given above

Lignocaine toxicity

Question.

217. Cardiac or central nervous system toxicity may result when standard lidocaine doses are administered to patients with circulatory failure. This may be due to the following reason:

1. Lidocaine concentration are initially higher in relatively well perfused tisseues such as brain and heart.

2. Histamine receptors in brain and heart gets suddenly activated in circulatory failure.

3. There is a sudden out-burst of release of adreneline, noradreneline and dopamine in brain and heart.

4. Lidocaine is converted into a toxic metabolite due to its longer stay in liver.

Answer

1. Lidocaine concentration is initially higher in relatively well perfused tisseues such as brain and heart.

Reference

Harrison 15^th Page 425 and Figure 70.1

Satoskar 17^th Edition Page 384

Goodman Gillman 10^th Edition

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Discussion

Lidocaine is a rapidly active drug. In circulatory failure, due to decreased hepatic flow, the metabolism of lidocaine is hampered and this leads to high levels in blood and obviously the high levels affect the well perfused tissues

Explanation

Lidocaine concentration are initially higher in relatively well perfused tisseues such as brain and heart. And this is the reason for Cardiac or Central nervous system toxicity when Standard Lignocaine is given to this patients

Comments

Question for Anaesthetists

Tips

A word about Ester and Amide Local Anaesthetics.

If the Name of the Anaesthetic agent has two times the alphabet “i” it is an amide eg Prilocaine, Lignocaine, Dibucaine.

If the Name of the Anaesthetic agent has the alphabet “i” only once it is an ester eg Cocaine, Tetracaine, Benzocaine.

Gastric Obstruction

Question.

214. Presence of food might be expected to interfere with drug absorption by slowing gastric emptying, or by altering the degree of ionisation of the drug in the stomach. Which of the following statements is not correct example:

1. Absorption of digoxin is delayed by the presence of food.

2. Concurrent food intake may severely reduce the rate of absorption of phenytoin.

3. Presence of food enhances the absorption of hydrochlorthiazide.

4. Anitimalarial drug halofantrine is more extensively absorbed if taken with food.

Answer

3. Presence of food enhances the absorption of hydrochlorthiazide.

Reference

KDT 5^th Edition Pages 372(Phenytoin), 748 (Halofantriene) and 4^th Edition Pages 492(digoxin), 384(Phenytoin), 565(Thiazides),

Halofantriene – Park, Katsung ,Harrison 15^th Edition Table 414-4

Goodman Gilman 9^th Edition Page 957

CMDT 2003 Page 441

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Discussion

Presence of Food generally dilutes the drug and retards absorption. Certain drugs form complexes with certain constituents of the food. For example Tetracycline complexes with Calcium and more over food delays Gastric emptying. Thus most drugs are better absorbed if taken in empty stomach. But few drugs which are irritant are better given with food.

Explanation

1. Absorption of digoxin as well as digitoxin is delayed by the presence of food.

2. Concurrent food intake may severely reduce the rate of absorption of phenytoin.

3. Presence of food has no effect on the absorption of hydrochlorthiazide.

4. Anitimalarial drug halofantrine is more extensively absorbed if taken with fatty food (Katsung).

Comments

A question for which one needs knowledge of Pharmacokinetics (often ignored)

Tips

Make a note of drugs that are increased with food (other than Halofantriene)

ICU Infection

Question.

215. In post-operative intensive care unit, five patients developed post-operative wound infection on the same day. The best method to prevent cross infection occurring in other patients in the same ward is to:

1. Give antibiotics to all other patients in the ward.

2. Fumigate the ward.

3. Disinfect the ward with sodium hypo chlorite.

4. Practice proper hand washing.

Answer

4. Practice proper hand washing.

Reference

Katzung 7^th Edition Pg-805,

Nelson Chapter-174

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Discussion

Strict attention to hand washing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another

Transmission of S. aureus generally occurs by direct contact or by spread of heavy particles over a distance of 6 ft or less. Spread by fomites is rare. Heavily colonized individuals and perianal carriers are particularly effective disseminators. Neonates are extremely susceptible to staphylococci; the nasopharynx, skin, perineum, and umbilical stump are the most common sites of colonization. Autoinfection is common, and minor infection (e.g., styes, pustules, paronychia) may be the source of disseminations. Handwashing between contacts with patients decreases the spread of staphylococci from patient to patient. Older children and adults are more resistant than the neonate to colonization.

PREVENTION. Staphylococcal infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another . Use of a detergent containing an iodophor, chlorhexidine, or hexachlorophene is recommended. In hospitals or other institutional settings, all persons with acute staphylococcal infections should be isolated until they have been treated adequately. There should be constant surveillance for nosocomial staphylococcal infections within hospitals. Infectious disease control measures may reduce the spread of infection

Explanation

1. Give antibiotics to all other patients in the ward is not the best method.

2. Fumigate the ward is a far fetched option.

3. Disinfect the ward with sodium hypochlorite – Asking for too much.

4. Practice proper hand washing is the best option.

Comments

A Micro Question from Pharmac / Nelson as well as many surgery books

Tips

Phenytoin Toxicity

Question.

216. Granulocytopenia, gingival hyperplasia and facila hirsutism are all possible side effects of one of the following anticonvulsant drugs.

1. Phenytoin.

2. Valproate.

3. Carbamazepine.

4. Phenobarbitone.

Answer

1. Phenytoin.

Reference

Katzung, 7^th Edition Pages 391

KDT 5^th Edition Page 372 & 4^th Edition Page 385

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Discussion

The adverse effects of Phenytoin are

1. Gum Hyperplasia

2. Hirsutism, acne

3. Hypersensiticity reactions – rashes, DLE, Lymphadenopathy, neutropaenia which requires discontinuation of therapy

4. Megaloblastic Anemia due to Decreased Absorbtion and Increased Excretion of Folic Acid

5. Granulocytopaenia and even Pancytopaenia

6. Osteomalacia

7. Hyperglycaemia due to inhibition of Insulin release

8. Foetal Hydantoin Syndrome

a. Hypoplastic Phalanges

b. Cleft Palate

c. Hare Lip

d. Microcephaly

Explanation

1. Phenytoin causes all the fetures given above.

2. Valproate causes Fulminant hepatitis and during pregnancy Neural Tube defects in Off Spring.

3. Carbamazepine produces dose related neurotoxicity and hepatitis, lupus like syndrome, rarely agranulocytosis and aplastic anaemia.

4. Phenobarbitone causes rashes, megaloblastic anaemia and osteomalacia.

Comments

Side effects of the drugs are best read from the Table in Harrison

Tips

Note the 5 H in the adverse effects

н Hyperplasia of Gums,

н Hirsutism,

н Hypersensiticity reactions

н Hyperglycaemia

н Hydantoin Syndrome

pKa of a drug

Question.

213. The extent to which ionisation of a drug takes place is dependent upon pKa of the drug and the pH of the solution in which the drug is dissolved. which of the following statements is not correct.

1.pKa of a drug is the pH at which the drug is 50% ionized.

2.Small changes of pH near the pKa of a weak acidic drug will not affect its degree of ionisation.

3.Knowledge of pKa of a drug is useful in predicting its behaviour in various body fluids.

4.Phenobarbitone with a pKa of 7.2 is largely ionized at acid pH and will be about 40% non-ionised in plasma.

Answer

4.Phenobarbitonewith a pKa of 7.2 is largely ionized at acid pH and will be about 40% non-ionised in plasma.

Reference

KDT 5^th Edition Page 12 Figure 2.3 & 4^th Edition Chapter 2 Pages 11,12 Fig 2.3

Harper 25^th Edition Page 23 Figures 3.6, 3.7

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Discussion

pKa of a substance is the pH at which it is 50 % ionized. And small changes of pH near its pKa will not affect the ionization of Acidic as well as Basic Drugs. And of course the knowledge of pKa is needed in predicting the behaviour of various drugs in body fluids. Just because we know the pKa of Aspirin we are able to understand why it is selectively concentrated in the gastric mucosa at concentration much higher than that of the gastric lumen. Because we know the pKa of Phenobarbitone, we are able to Use Forced Alkaline diuresis for its excretion

Explanation

1.pKa of a drug is the pH at which the drug is 50% ionized.

2.Small changes of pH near the pKa of a weak acidic drug will not affect its degree of ionisation.

3.Knowledge of pKa of a drug is useful in predicting its behaviour in various body fluids.

4.Phenobarbitone with a pKa of 7.2 is largely unionized at acid pH and is more ionised in Alkaline pH. Remember Forced Alkaline Diuresis for Phenobarbituric ACID !!!!)

Comments

This question can be solved easily if one knows the basic concepts of Acid, Base and pH

Tips

· As already told, if one has strong correct concepts in Acid Base and Electrolyte Balance, about 5% of Questions can be attended with minimum fuss

· This question carries a chance of being wrongly interpreted and considering Answer 4 as correct. Be careful !!! Phenobarbitone is Phenobarbituic ACID and is not a Basic Drug !!!

HLA Class 3

Question.

209. The HLA class 3 rejection genes are important elements in

1. Transplant rejection phenomenon.

2. Governing susceptibility of autoimmune diseases.

3. Immune surveillance.

4. Antigen presentaion and elimination.

Answer

2. Governing susceptibility of autoimmune diseases.

Reference

Harrison's15^th Edition,Pg-1832 Chapter 306 Chapter 308 Table 308-3

Ananthanarayanan 5^th Edition Page 118

Ananthanarayanan 6^th Edition Page 120,121

Nelson Table 117 -1

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Discussion

Harrison and Nelson says that the Diseases Common Variable Immunodeficiency and IgA deficiency are mostly due to defects in MHC III. A polymorphism in the promoter of the TNF-a (TNF-alpha) gene in the HLA class III region, which is associated with quantitative variation in the production of TNF, has recently been shown to have an association with the manifestations of a number of infectious diseases, including cerebral malaria, mucocutaneous leishmaniasis, lepromatous leprosy, scarring trachoma, persistent hepatitis B infection, and fatal meningicoccal meningitis

And we can see that derangement in the metabolism of Complement C2 and C4 leads to SLE and other diseases

Explanation

1. Transplant rejection phenomenon involves MHC I and MHC II.

2. Autoimmune diseases like SLE are due to derangement in C2 and C4.

3. Immune surveillance is by MHC I and MHC II.

4. Antigen presentaion and elimination is by MHC II.

Comments

Theme Couple from HLA III

Tips

Theme couples from Immunology are the best and worst that can happen in a competitive exam. Best for those who know the answer and worst for those who don’t know it. Because Immunology is a “decider” cause there will be a few who will have a strong grasp of the subject and they will surge forward

NK Cells

Question.

210. All of the following statements about NK cells are true. except:

1. They are derived from large granular cells.

2. They comprise about 5% of human peripheral lymphoid cells.

3. They are MHC restricted cytotoxic cells

4. They express lgG Fc receptors.

Answer

3. They are MHC restricted cytotoxic cells

Reference

Nelson 15^th Edition Chapter 116

Ananthanarayanan 5^th Edition Page 116

Harrison 15^th Edition Page 1810

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Discussion

Natural Killer Cells

· These are large, granular lymphocytes, not classical T or B cells

· They belong to the group of Null Cells

· They account for 5 to 10 % of Lymphocytes

· Lyse cultured tumour cells and virus-infected cells very efficiently in vitro.

· Interferon is a potent activator of natural killer cells.

· IL 2 activates them to LAK cells

· They express

o CD 16 –FcR for IgG

o CD 56 – Mediates NK Homotypic Adhesion

Explanation

1. They are derived from large granular cells.

2. They comprise about 5% of human peripheral lymphoid cells.

3. They are defined by their functional capacity to mediate non-MHC-restricted cytotoxicity.are not MHC restricted cytotoxic cells

4. They express lgG Fc receptors.

Comments

NK-cell activity has been found in human fetal liver cells at 8{endash}–11 wk of gestation. NK lymphocytes are also derived from bone marrow precursors. Thymic processing is not necessary for NK-cell development, although NK cells have been found in the thymus.

Tips

The names and other details of various Cluster of Differentiation are to be studied from Nelson, Harrison and Robbins. Table 305-1 from Harrison is to be read (that’s easy J!!) and to be remembered (how L??)

Bioavailability

Question.

212. All of the following statements regarding bioavailability of a drug are true except:

1. It is the proportion (fraction) of unchanged drug that reaches the systemic circulation.

2. Bioavailability of an orally administered drug can be calculated by comparing the Area Under Curve (0- ) after oral and intravenous (iv) administration.

3.Low oral bioavailability always and necessarily mean poor absorption.

4.Bioavailability can be determined from plasma concentration or urinary excretion data.

Answer

3.Low oral bioavailability always and necessarily mean poor absorption.

Reference:

Katzung,7^th Edition Page 40

KDT 5^th Edition Page 15 & 4^th Edition Page 15 Figure 2.4

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Discussion

Bioavailability of a drug is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.

Following intravenous route the bioavailablilty is 100 %.

Oral Route is associated with low bioavailability due to the following reasons

1. The drug may be incompletely absorbed

2. The absorbed drug may under go first pass metabolism in intestinal wall/liver or may be excreted in bile

IM/SC Route may be associated with a low bioavailability and that is due to

1. Local Binding

Bio availability is determined by the Area under the Plasma Concentration-time Curve.

Explanation

1. It is the proportion (fraction) of unchanged drug that reaches the systemic circulation.

2. Bioavailability of an orally administered drug can be calculated by comparing the Area Under Curve (0- ) after oral and intravenous (iv) administration.

3.Low oral bioavailability always and necessarily does not mean poor absorption. It could be also due to first pass metabolism

4.Bioavailability can be determined from plasma concentration or urinary excretion data.

Comments

A drug with low bioavailability will have a very high Oral Dose compared to its parenteral dose (eg Propanolol)

Tips

This is an area from which few problems may be asked

Memory T Cells

Question.

207. Memory T cells can be identified by using the following marker:

1. CD45 RA.

2. CD45 RB.

3. CD45RC.

4. CD45RO.

Answer

4. CD45RO.

Reference

Harrison's15^th Edition,Pg-1808 Table 305 -1

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Discussion

T lymphocytes require the thymus for their development and show a set of characteristic surface glycoproteins and their own form of receptor, as described above. They can be divided into types: cytotoxic T lymphocytes that carry the CD8 glycoprotein and helper T cells that carry CD4 in mice. The latter can be divided according to the cytokines they release on antigen contact into Th1 (IL-2 and interferon-gamma;) and Th2 (IL-4, -5, and -10).

T cells may also be divided into those in an inactive state (virgin T cells) and preactive state (memory T cells) by the CD45 glycoprotein isotype on the cell surface. Thus, there is a very high proportion of CD45RA positive (virgin) in cord blood, and CD45RO (memory) T cells appear during early life. In vitro, T-cell proliferation to recall antigens (e.g. tetanus toxoid) involves CD45RO T cells, whereas T-cell proliferation to alloantigens involves both CD45RA and -RO populations.

Explanation

1. CD45 RA.
1. Subset T cells,
2. Medullary thymocytes,
3. "Naive" Tcells
2. CD45 RB.
1. All leukocytes
3. CD45RC.
1. Subset T cells,
2. Medullary thymocytes,
3. "naive" T cells
4. CD45RO.
1. Subset T cells,
2. Cortical thymocytes,
3. "Memory" T cells

Comments

A new Question from Harrison !!

Tips

The development of monoclonal antibody technology led to the discovery of a large number of new leukocyte surface molecules. In 1982, the First International Workshop on Leukocyte Differentiation Antigens was held to establish a nomenclature for cell-surface molecules of human leukocytes. From this and subsequent leukocyte differentiation workshops has come the cluster of differentiation (CD) classification of leukocyte antigen

MHC Class 3

Question.

208. MHC class 3 Genes Encode;

1. Complement Component C3

2. Tumor necrosis factor.

3. Interleukin 2.

4. Beta 2 microglobulin.

Answer

2. Tumor necrosis factor.

Reference

Harrison's15^th Edition,Pg-1832 Chapter 306

Ananthanarayanan 5^th Edition Page 118

Ananthanarayanan 6^th Edition Page 120,121

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Ananthanarayanan

Discussion

Please note that Human MHC antigens are synonymous with Human Leucocyte Antigen(HLA) and MHC Complex of genes with HLA Complex

The HLA class III region is a name given to a

• cluster of genes between the class I and class II complexes,
• which includes genes
• for the two closely related cytokines
• tumor necrosis factor (TNF-alpha) and
• lymphotoxin (TNF-beta);
• the complement components
• C2,
• C4, and
• Bf;
• heat shock protein (HSP)70; and
• the enzyme 21-hydroxylase

Explanation

1. Complement Component C3 is not coded by HLA III. Instead only C2 and C4 are coded by HLA III

2. Tumor necrosis factor, is coded by HLA III.

3. Interleukin 2 is not coded by HLA III.

4. Beta 2 microglobulin is not coded by HLA III.

Comments

A question directly from Ananthanarayanan, yet could be easily missed

Tips

Immunology from Ananthanarayanan may look simple and nominal, but most questions can be answered from Ananthanarayan alone

Cell Cycle

Question.

199. The correct sequence of cell cycle is:

1. G0-G1-S-G2-M.

2 .G0-G1-G2-S-M.

3 .G0-M-G2-S-G1.

4 .G0-G1-S-M-G2.

Answer

1. G0-G1-S-G2-M.

Reference

Robbins 6^th Edition Page 50

KDT 4^th Edition Page 836

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Robbins

Discussion

The normal cell cycle proceeds as G1 à S à G2 à M à G1

Some times after M the cels go into a state of rest called G0. Then they come back to G1 ie G0 à G1 à S à G2 à M à G1

And certain drugs act over certain phase

Phase	Drugs
G1	Vinblastine
S	Methotrexate, Cytarabine, 6-TG,6-MP, Hydroxyurea Mitomycin C, Doxorubicin, Daunorubicin
G2	Daunorubicin, Bleomycin, Etoposide
M	Vincristine, Vinblastine, Paclitaxel

Explanation

1. G0-G1-S-G2-M. is the correct sequence

2 .G0-G1-G2-S-M is an incorrect sequence

3 .G0-M-G2-S-G1 is an incorrect sequence

4 .G0-G1-S-M-G2 is an incorrect sequence

Comments

Cell cycle is gaining importance as our understanding of the cyclins and other molecules increase !!

Tips

If you feel that your memory is failing you often remember that the most sensitive phase to Radiotherapy is G2M That means G2 is followed by M. We know that two G won’t come next to each other. Hence only S can come before G2 and…. so on ……