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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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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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 ……