basic principle of chemotherapy by saeid kashefi

SAEID KASHEFI

Pharmacology

II

Chemotherapy

I. General Chemotherapy 1) Basic principle of chemotherapy …………………………………………….……3

2) Sulphonamides, trimethoprim ……………………………………………….……15

3) Quinolones, urinary antiseptics ………………………………………….….……19

4) β-lactam antibiotics…………………………………………………………………23

5) Aminoglycosides……………………………………………………………………30

6) Tetracyclines ……………………………………………………………………….36

7) Chloramphenicol …………………………………………………………….……..41

8) Macrolides …………………………………………………………………….……43

9) Miscellaneous agents ……………………………………………………….……48

II. Specific Chemotherapy 1) TB ……………………………………………………………………………………53

2) Leprosy………………………………………………… …………………………..58

3) Antiviral ……………………………………………………………………………..60

4) Antifungal …………………………………………………………………………...67

5) Antiprotozoal………………………………………………………………………..75

Antiamebic ………………………………………………………………..75

Antimalarial ……………………………………………………………….72

6) Anthelmintics ………………………………………………………………………..82

6) Anticancer ……………………………………………………………………….…86

2012-2013

SAEID KASHEFI

Basic principle of

Chemotherapy

SAEID KASHEFI

1) Classify the antibiotics based on their mechanism of action. Describe the mechanism of action

of each group of drugs? (10)

Different ways of Classification

1. Chemical Structure

2. Mechanism of action

3. Type of organisms

against which it is active

4. Spectrum of activity

5. Type of action

6. Source of the antibiotic

Classification I: Chemical Structure

Sulfonamides Diaminopyridines Quinolones β lactams Tetracycline Imidazoles

Dapsone

Sulfamethoxazole

PAS

Trimethoprim

Pyrimethamine

Nalidixic acid

Ciprofloxacin

Penicillins

Cephalosporins

Monobactams

Doxycycline

Minocycline

Miconazole

Clotrimazole

Aminoglycosides Macrolides Polypeptides Nitrofurans Nitroimidazoles Miscellaneous

Streptomycin

Gentamycin

Paromomycin

Amikacin

Neomycin

Erythromycin

Clarithromycin

Azithromycin

Roxithromycin

Polymyxin-B

colistin

Bacitracin

Nitrofurantoin

Furazolidone

Metronidazole

Tinidazole

Rifampicin

Vancomycin

Griseofulvin

Ethambutol

Clofazimine

Chloramphenicol

Classification II: Mechanism of Action

Inhibits Cell wall

synthesis

Inhibits protein

synthesis

Inhibits DNA

synthesis

Inhibits DNA

gyrase

β lactams

Vancomycin

Bacitracin

Cycloserine

Tetracyclines

Chloramphenicol

Clindamycin

Idoxuridine

Acyclovir

Zidovudine

Metronidazole

Iodoquinol

Quinolones

Inhibits intermediary

metabolism

Interferes with DNA

function

Cause Leakage of Cell

membranes

Misreads m-RNA

sulfonamides

PAS

Trimethoprim

Ethambutol

Rifampicin

Metronidazole

Polymyxins

Colistin

Bacitracin

Amphotericin B

Nystatin

Hamycin

Aminoglycosides

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Classification III: Type of Microbe affected

Antibacterial Antifungal Antiviral Antiprotozoal Anthelmintic

penicillins,

aminoglycosides

Griseofulvin

Amphotericin

Idoxuridine

Acyclovir

Amantadine

Chloroquine

Pyrimethamine

Mebendazole

Pyrantel

DEC

Classification IV: Spectrum of activity

Narrow Spectrum Broad Spectrum

Penicillin G,

Streptomycin,

Erythromycin

Tetracycline,

Chloramphenicol

Classification V: Type of Action

Primarily Bacteriostatic Primarily Bactericidal

Sulfonamides

Macrolides

Erythromycin

Clindamycin

Tetracycline

Chloramphenicol

Ethambutol

Nitrofurantoin

Novobiocin

Trimethoprim

Penicillin

Cephalosporins

Aminoglycosides

Vancomycin

Bacitracin

Metronidazole

Polymixin

Pyrazinamide

Quinolones

Rifampicin

Isoniazid

Co-trimoxazole

Classification VI: Source

Fungal Bacteria Actinomycetes

Penicillin,

Cephalosporin

Griseofulvin

Polymyxin,

Colistin,

Aztreonam

Aminoglycosides,

Tetracyclines,

Chloramphenicol

Macrolides

SAEID KASHEFI

Mechanism of action of certain antibiotics

Agent Example Mechanism of Action / Notes

Aminoglycosides streptomycin neomycin

Inhibit protein synthesis by binding to a portion of the bacterial ribosome. Most of them are bacteriocidal (cause bacterial cell death).

Bacitracin Inhibits cell wall production by blocking a step in the process (recycling of the membrane lipid carrier) which is needed to add on new cell wall subunits.

β-lactam antibiotics

penicillins cephalosporins carbapenems monobactams

Group of antiobiotics which contain a specific chemical structure (a beta-lactam ring)

Cephalosporins Similar to penicillins in their mode of action, but they treat a broader range of bacterial infections. The have structural similarities to penicillins and many people with allergies to penicillins also have allergic reactions to cephalosporins.

Chloramphenicol Inhibits protein synthesis by binding to a subunit of bacterial ribosomes (50S).

Glycopeptides vancomycin Interferes with cell wall development by blocking the attachment of new cell wall subunits (muramyl pentapeptides).

Macrolides erythromycin Inhibit protein synthesis by binding to a subunit of the bacterial ribosome (50S).

Lincosamides clindamycin Inhibit protein synthesis by binding to a subunit of the bacterial ribosome (50S).

Penicillins Inhibit formation of the bacterial cell wall by blocking cross-linking of the cell wall structure. The cell wall is a needed protective casing for the bacterial cell wall.

Quinolones Block DNA synthesis by inhibiting one of the enzymes (DNA gyrase) needed in this process.

Rifampin Inhibits RNA synthesis by inhibiting one of the enzymes (DNA-dependent RNA polymerase) needed in this process. RNA is needed to make proteins.

Tetracyclines Inhibit protein synthesis by binding to the subunit of the bacterial ribosome (30S subunit).

Trimethoprim and Sulfonamides

Blocks cell metabolism by inhibiting enzymes which are needed in the biosynthesis of folic acid which is a necessary cell compound.

SAEID KASHEFI

Buy AT 30 and SELL at 50

30 S 50S

Aminoglycosides

Tetracyclines

Streptogramines

Erythromycin

Lincosamides

Linezolide

SAEID KASHEFI

2) Explain the difference between broad spectrum and narrow spectrum antibiotics. Give

examples? (2)

An antibiotic may be classified as "narrow-spectrum" or "broad-spectrum" depending on the range of bacterial

types that it affects.

1) Narrow-spectrum antibiotics are active against a select group of bacterial types.

A narrow-spectrum antibiotic acts only against specific families of bacteria.

2) Broad-spectrum antibiotics are active against a wider number of bacterial types and, thus, may be used to treat a

variety of infectious diseases.

Broad-spectrum antibiotics are particularly useful when the infecting agent (bacteria) is unknown.

A broad-spectrum antibiotic acts against many different kinds of disease-causing bacteria, including both

gram-positive and gram-negative bacteria.

Narrow Spectrum Broad Spectrum

Penicillin G,

Streptomycin,

Erythromycin

Tetracycline,

Chloramphenicol

SAEID KASHEFI

3) What are the limitations of antimicrobial agents? Explain, giving suitable example, the various

way in which microbes acquire resistance? (4+8)

Problems of Chemotherapy

1) Toxicity : a] Local & b] Systemic

2) Hypersensitivity

3) Nutritional deficiency

4) Masking of Infections

5) Drug Resistance

6) Superinfection

Local irritancy Systemic toxicity

Local: Irritation

At site of administration

Gastric irritation, pain

Pain, abcess at site of im

injection.

Thrombophlebitis

Most antimicrobials are irritant

Especially see:. Erythromycin,

tetracyclines, some cephalosporins,

chloramphenicol

Most AMA have systemic toxicity

Safe

Penicillin, Cephalosporins [some] Erythromycin Safe even at 100 times therapeutic dose

Moderately toxic

Aminoglycosides 8th cranial nerve, Nephrotoxicity Tetracyclines Liver & kidney damage

Chloramphenicol bone marrow depression

Very toxic

Polymyxin B neurological & kidney toxicity Vancomycin hearing loss & Nephrotoxicity Amphotericin kidney, bone marrow, neurological

toxicity

2. Hypersensitivity

Most AMAs cause hypersensitivity

Most frequent penicillins, cephalosporins, sulfonamides

3. Nutritional factors,

Nutritional deficiency

↓B complex group, Vitamin K synthesis by microflora

Neomycin malabsorption syndrome

4. Masking of infection

Eg short course of streptomycin masks tuberculosis

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5. Drug Resistance

Naturally resistant:

gram –ve resistant to penicillin

clinically insignificant

Acquired resistance:

Occurs on prolonged exposure to the AMA

Important Clinical problem

Depends on both AMA & microbe

Some microbes are more prone Eg tubercle bacteria, staphylococci

Some less prone: Strep pyogenes still sensitive to penicillin

Gonococci rapidly developed resistance to sulfonamides but slowly to penicillin

Mechanisms of drug resistance

[1] Mutation (single & multistep) [2] Gene transfer Conjugation

1. Mutation :

spontaneous, heritable genetic change

Resistant mutants proliferate selectively

Single step: a single mutation confers resistance: RAPID

Eg Enterococci to streptomycin

E coli & Staphylococci to rifampicin

Multistep: stepwise graded decrease in sensitivity: Slow

Many organisms develop gradual resistance to erythromycin, tetracycline, chloramphenicol

2. Gene transfer Mechanisms

[1] Conjugation, [2] Transduction, [3] Transformation

Conjugation Transduction Transformation

an important mode of resistance

Transfer of DNA (chromosomal or

plasmid) carrying resistance gene

Occurs through the sex pili during

conjugation

More common among gram –ve

Occurs more in colon, rich in

microflora

Sometimes from nonpathogenic to

pathogenic microbes

Gene transfer through a

bacteriophage

R factor enters virus,

delivered to infected

bacterium

Occurs in penicillin,

erythromycin,

chloramphenicol

R factor from a resistant

bacterium enters the medium

Picked up a nonresistant

bacterium

Rare eg pneumococcal

resistance to penicillin G

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Nature of Resistance

1) Drug tolerant

loss of AMA target

Eg. Staph aureus, E coli with RNA polymerase that does not bind rifampicin

Altered metabolic pathway

Eg. Sulfonamide resistant bacteria switch to using preformed folic acid instead of synthesising it

2) Drug destroying

β lactamase destroyed by Staphylococci, Haemophilus, Gonococci

Aminoglycosides are acetylated, phosphorylated etc.

3) Drug Impermeable

Hydrophilic AMAs enter through porins

Eg. chloroquine resistant falciparum do not take up drug

4) Cross Resistance

Defn: Resistance to one AMA confers resistance to a closely related AMA

Total cross resistance Partial cross

resistance

Two way One way

Sulfonamides &

Tetracyclines : resistance

to one means resistance

to all

Resistance to

gentamycin but not

amikacin

erythromycin

Clindamycin two way

Neomycin resistance

leads to streptomycin

resistance

Not vice versa

6. Super infection

Appearance of a new infection when treating another

Intestinal microflora inhibit pathogens

Microflora compete with pathogens for nutrition

Killing microflora normally nonpathogenic components of microflora Eg Candida proliferate becomes

pathogenic

Prolonged use of broad spectrum kills microflora superinfection

Eg tetracycline, chloramphenicol >> amoxicillin

More when combinations are used

More when host immunity is compromised

Eg. corticosteroids, immunosuppressants, diabetes

Site of superinfections : oropharynx, intestinal, respiratory, genitourinary tracts [ Loci harboring commensals]

Superinfections more difficult to treat

Common superinfections

Candida albicans diarrhoea, thrush, vulvovaginitis

Staphylococci enteritis

Clostridium difficile pseudomembranous enterocolitis

SAEID KASHEFI

4) Outline the important factors that affect the choice of an antimicrobial agent in therapeutics? (7)

Factors influencing the choice of an AMA

1) Patient factors 2) Drug factors 3) Infecting Organism Factors

Patient Factors Drug factors

1) Age

2) Renal/ Hepatic function

3) Drug Allergy

4) Site of infection

5) Pregnancy

6) Genetic factors

7) Impaired host defence

1) Spectrum of activity

2) Type of activity Cidal Vs Static

3) Sensitivity of organism [MIC ; post antibiotic effect]

4) Relative toxicity [Choose less toxic one Eg penicillin]

5) pharmacokinetics

6) route of administration

7) evidence of clinical efficacy

8) cost

A) Patient Factors

1) Age

Conjugation & excretion of chloramphenicol in new born gray baby syndrome [ emesis, hypotonic,

hypothermic, irregular respiration, ashen gray cyanosis, cardiovascular collapse, death]

Sulfonamides displace bilirubin from protein binding sites kernicterus in neonates [ poor BBB]

↑T ½ of aminoglycosides in elderly ↑ VIII cranial nerve toxicity

Tetracycline accumulates in growing teeth discolored teeth in children < 6 yr

2) Impaired Renal function

To be used with caution Aminoglycosides, Cephalosporins, Vancomycin, Ethambutol

To be avoided Cephalothin, nitrofurantoin, nalidixic acid, tetracycline

Impaired Hepatic function

To be used with caution [ reduce doses] Chloramphenicol, INH, Metronidazole, Rifampin

To be avoided Erythromycin, pyrazinamide, tetracyclines, Pefloxacin

3) Drug Allergy

most frequently caused by beta lactams, sulfonamides, fluoroquinolones, nitrofurantoin

4) Pregnancy

Better to avoid because of risk to fetus

Tetracycline, aminoglycosides, fluoroquinolones, chloramphenicol

5) Genetic Factors

Primaquine, nitrofurantoin, sulfonamides, chloramphenicol hemolysis in G6PD deficiency

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6) Site of infection

Pus decreases action of aminoglycosides & sulfonamides Necrotic material delays healing ; nearly impossible

Hematomas

Promote bacterial growth

Penicillin, cephalosporin, tetracyclines bind to degraded hemoglobin

Lowering of pH reduce aminoglycoside & macrolides

Anaerobic environment aminoglycosides don‘t act in the centre of abcess

Barriers: Ophthalmic, prostatic, SABE, etc Some drugs don‘t penetrate barriers

7) Impaired host defense [Neutropenia, AIDS]

Cidal drugs needed

Intensive therapy complete eradication

Reserve drugs

B) Drug factors

1) Spectrum of activity :

Narrow spectrum better [ but limited by diagnostic accuracy! ]

But broad spectrum for empirical therapy

2) Type of activity Cidal Vs. Static

Cidal >>Static especially in immunocompromised, severe cases

Less accessible bec of a barrier --SABE

3) Sensitivity of organism [MIC ; post antibiotic effect]

4) Relative toxicity [Choose less toxic one Eg penicillin]

5) Pharmacokinetics

Most antibiotics given at 2-4 T ½ attain effective conc intermittently

Concentration dependent inhibition Action depends on peak conc Eg aminoglycosides

Single doses better than divided doses

Time dependent inhibition: Penicillins

Action based on time conc is maintained > MIC

Divided doses better

Penetration

Quinolones tissue penetration

Ceftrioxone, Ciprofloxacin CSF penetration

6) Route

Oral for less severe cases Parenteral for severe cases, Eg septicemia, meningitis

7) Evidence of clinical efficacy

Clinical evidence most important! Reliable clinical trial data

8) Cost

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5) Explain with example any 5 indications of chemo-phylaxis? (5)

1. Prophylaxis against specific organisms In general highly satisfactory; the choice of drug is clearcut.

(a) Rheumatic fever: group A Streptococci: long acting penicillin G is the drug of choice for preventing

recurrences.

(b) Tuberculosis: Children, HIV positive and other susceptible contacts of open cases: Isoniazid alone or with

rifampin is recommended.

(c) Mycobacterium avium complex (MAC): HIV/ AIDS patients with low CD4 count may be protected against

MAC infection by azithromycin/ clarithromycin.

(d) HIV infection: Health care workers exposed to blood by needle stick injury: zidovudine + lamivudine +

indinavir. Offspring of HlV positive woman can be protected by zidovudine given to pregnant mother and then to

the newborn for 6 weeks.

(e) Meningococcal meningitis: during an epidemic, especially in contacts; rifampin/ sulfadiazine / ceftriaxone

may be used.

(f) Gonorrhoeae /syphilis: before or immediately after contact: ampicillin/ceftriaxone.

(g) Recurrent genital herpes simplex: Acyclovir prophylaxis may be given when four or more recurrences occur

in a year.

(h) Malaria: for travellers to endemic areas with high transmission rate: chloroquine/mefloquine.

(i) Influenza A2: during an epidemic, especially in contacts: amantadine.

(g) Cholera: tetracycline prophylaxis may be given to close contacts of a case.

(k) Whooping cough: non-immunized child contact during the incubation period: erythromycin can abort clinical

disease.

(1) Plague: contacts curing an epidemic: doxycycline.

2. Prevention of infection in high risk situations it may be valid and satisfactory in certain situations, but

controversial in others.

(a) Dental extraction, tonsillectomy, endoscopies cause damage to mucosa harbouring bacteria bacteremia

occurs. In patients with valvular defects, this can cause endocarditis: appropriate prophylaxis with amoxicillin or

clindamycin may be given few hours before to few hours after the manipulation.

(b) Catheterization or instrumentation of urinary tract: cotrimoxazole or norfloxacin. Patients with valvular

lesions may be protected with ampicillin, gentamicin or vancomycin during catheterization.

(c) To prevent recurrences of urinary tract infection in patients with abnormalities of the tract:

cotrimoxazole or nitrofurantoin may be given on a long-term basis since the organism mostly is E. coll.

(d) Chronic obstructive lung disease, chronic bronchitis: ampicillin /doxycycline/ ciprofloxacin has been used

to prevent acute exacerbations: but are of doubtful value.

(e) Immunocompromised patients (receiving corticosteroids or antineoplastic chemotherapy, neutropenic

patients): penicillin/cephalosporin an aminoglycoside or fluoroquinolone are often used to prevent respiratory

tract infections and septicaemiae, but incidence of superinfections is high.

3. Prevention of infection in general this is highly unsatisfactory in most cases and must be condemned.

(a) Neonates, especially after prolonged or instrumental delivery.

(b) To prevent postpartum infections in the mother after normal delivery.

(c) Viral upper respiratory tract infections: to prevent secondary bacterial invasion.

SAEID KASHEFI

6) Give the advantages of antimicrobial combination with example? (2)

Advantages Disadvantages

1) Synergism

2) Reduce ADR

3) Prevent resistance

4) Broaden spectrum

1) Promote a casual outlook in diagnosis / choice of AMA

2) Increase incidence of ADRs

3) Increase superinfections

4) Emergence of resistant organisms in inadequate doses

5) Increased cost

6) Antagonistic combinations Eg Penicillin + Tetracycline

A. Synergism

1 Additive

A. Bacteriostatic + Bacteriostatic

B. Tetracycline+ Chloramphenicol

2. Supra additive

A. Co-trimoxazole (cidal effect)

B. Bactericidal + Bactericidal

Penicillin + Aminoglycoside

INH+ Rifampin

B. Reduces ADRs

Combinations help reduce dose ↓ ADRs

Eg Streptomycin + Penicillin G in bacterial endocarditis

C. Reduces emergence of resistance

INH + Rifampin + Pyrazinamide in Tuberculosis

D. Broaden spectrum

Useful in severe infections, mixed infections

SAEID KASHEFI

Sulphonamide

SAEID KASHEFI

7) Explain how cotrimoxazole acts as a synergistic combination? (2)

8) Explain the rational of the combination cotrimoxazole in chemotherapy? (4)

9) Explain how cotrimoxazole acts as synergistic combination? (2)

10) Describe the mechanism of sequential blockade in antimicrobial action with subtile

examples? (4)

Individually, both sulfonamide and trimethoprim are bacteriostatic, but the combination becomes cidal against

many organisms.

Maximum synergism is seen when the organism is sensitive to both the components, but even when it is

moderately resistant to one component, the action of the other may be enhanced.

Combination of Sulphonamide with trimethoprim (5:1 gives 20:1 Cp)

Trimethoprim + Sulphamethoxazole PABA

Similar t1/2 (11 and 10h)

Sequential inhibition of enzymatic pathway

Synergistic combination

Sequential Blockade

Pteridine Dihydropteroic acid (Inhibited by

Sulphonamide)

Dihydrofolic acid Tetrahydrofolic acid (Inhibited

by trimethoprim)

Bacteriostatic effect to bactericidal

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Special purpose:

Sulfacetamide Silver Sulfadiazine Sulfasalazine Sulfadoxine

Sulfacetamide (eye) ? As eye drops & ointment

High aqueous solubility

Neutral pH and non-irritant nature of the drug

Good penetrability on topical administration

Low incidence of hypersensitivity reactions

Low cost

Silver Sulfadiazine topical for

preventing infections of burn

wounds. Silver slowly release

silver ions which are toxic to

microorganism, not effective in

the presence of pus and tissue

fluids

Sulfasalazine

colon (ulcerative

colitis)

Sulfadoxine

resistant

falciparum

(with

pyrimetham

ine)

Adverse effect of Sulfonamides

(ABC of Rash)

Pharmacogenetic Variation in Drug

response due to enzyme deficiency

Drug interactions

A- Aplastic anemia

B- Bilirubin displacement

(Kernicterus)

C- Crystalluria

R-Rash

A-Acetylation

S-SLE

H-Hemolysis of G-6-PD

deficiency

Glucose -6-phosphate dehydrogenase deficiency

American Negros, Mediterranes Jews, Middle East and South East races – deficient in G6PD

Responsible for supply of NADP ---acts as cofactor for glutathion reductase

NADP---oxidised glutathion to reduced gutathion-------convertes Fe+++ to Fe++ in hemoglobin---also stability to RBC

Oxidising drugs Primaquine, Sulfone, nitrofurantoin----hemolytic anaemia

Potentiate the action of

Sulphonylureas

Oral anticoagulants

Hydantoins

By inhibition of metabolism

and/OR

Displacement from protein

binding

SAEID KASHEFI

11) Why is sulphacetamide preferred to other sulpha drugs for ophthalmic use? (2)

Sulfacetamide sodium it is a highly soluble compound yielding neutral solution which is only mildly irritating to the

eye in concentrations up to 30%.

It is used topically for ocular infections due to susceptible bacteria

It attains high concentrations in anterior segment and aqueous humour after topical instillation.

The incidence of sensitivity reactions with ocular use of sulfacetamide sodium has been low; but it must be

promptly stopped when they occur.

SAEID KASHEFI

Quinolones

SAEID KASHEFI

12) Classify fluoroquinolones with examples.

Describe their MOA. Compare and contrast norfloxacin with ciprofloxacin.

Why are fluoroquinolones not given to people under the age of 18 years? (2+3+2+1)

13) Describe the antimicrobial spectrum and mechanism of action of fluoro-quinolones.

Enumerate their therapeutic uses and adverse effect? (2+2+2+2)

14) Compare and contrast ciprofloxacin and levofloxacin? (5)

examples Uses Pharmacokinetics

FIRST Gram -ve

Norfloxacin

Ciprofloxacin,

Ofloxacin,

Pefloxacin,

Lomefloxacin

Urinary tract

infections

Gonorrhoea

Chancroid

Gastroenteritis

Typhoid Bone and soft tissue

infections

Respiratory

Tuberculosis

Gram –ve

septicaemias

Meningitis

Oral bioavailability- 80 to 95%

Wide distribution – tissues and

fluids

Half-life: 3 h (Nor- and

Ciprofloxacin)

– 10 h (Pefloxacin), t1/2 >10 h

(Spar- and Levofloxacin)

++ cations interfere with

absorption

Renal elimination (GF and TS)

Adverse effects Drug Interactions

Second Gram +ve

Gram –Ve

Levofloxacin

Prulifloxacin

GIT- nausea,

vomiting, diarrhoea

Headache,

dizziness, insomnia,

rashes

Acute hepatitis,

hepatic failure

(Trovafloxacin)

Photosensitivity-

QTc interval

prolongation

Damage to

growing cartilage

Ciprofloxacin, Grepafloxacin

and Pefloxacin inhibit

Theophylline, warfarin

metabolism

NSAIDs with Fluoroquinolones

CNS stimulation

Seizures

Third Gram +ve Gatifloxacin

Sparfloxacin

Gemifloxacin

Gram +ve

+ Anaerobes

Moxafloxacin

Trovafloxacin

Alatrofloxacin

Finafloxacin

SAEID KASHEFI

Mechanism of action

Inhibition of DNA gyrase

– Prevents relaxation of positively supercoiled DNA

Topoisomerase IV

– Interferes with separation of replicated chromosomal DNA

MOA Kinetics ADR Uses

Pefloxacin Methyl derivative of

norfloxacin

Higher Lipid

solubility

Cumulates in

plasma, Higher

Cp

Dose reduction in

liver disease

Meningeal infections

Ofloxacin More potent than

cipro for G+ve

No interference

from food

Dose reduction in

Renal failure

Urethritis

Cervicitis

Atypical pneumonia,

leprosy

Levofloxacin Higher activity

against G +ve

No drug interactions

with theophylline

100% oral

bioavailability

Very useful in

pneumonia,

bronchitis, sinusitis,

pyelonephritis

Once daily dosing

Sparfloxacin Difluorinated

quinolone

Very effective

against G +ve, B.

fragilis, Mycobacteria

Phototoxicity

Prolongation of QT

interval

Should not be given

along with

o Cisapride

o TCAs

o Phenothiazines

o Class I and III

antiarrhythmics

Pneumonia, chronic

bronchitis, sinusitis,

TB and leprosy

Single dose per day

Gatifloxacin Highly effective

against Strep.

pneumoniae,

anaerobes

Prolongation of QT

interval

Phototoxicity and

CNS effects

Pneumonia, chronic

bronchitis, UTI

gonorrhoea

One dose per day

Moxafloxacin High activity against

beta lactam and

macrolide resistant

streptococci

May precipitate

seizures

Prolongs QT

interval

Useful in pneumonia,

bronchitis, otitis

media, sinusitis

Single daily dose

SAEID KASHEFI

15) Why cisapride avoided in patient taken sparfloxacin? (2)

It has caused a higher incidence of phototoxic reactions: recipients should be cautioned not to go out in the sun.

Slight prolongation of QTc interval has been noted in 3% recipients; should be avoided in patients taking

cisapride, tricyclic antidepressants, phenothiazines, class IA and class III antiarrhythmics, etc.

Sparfloxacin metabolized in liver by glucuronidation and hase longer t1/2 (18-20).

Because of longer t1/2 it is suitable for single daily dosing.

(Cisapride is CYP3AP enzyme inhibitor)

sparfloxacin Should not be given along with

– Cisapride

– TCAs

– Phenothiazines

– Class I and III antiarrhythmics

SAEID KASHEFI

β-lactams

Penicillin

Cephalosporin

SAEID KASHEFI

16) Classify penicillins with examples. Describe their mechanism of action of its two penicillins

used pseudomonas infection? (5+3+2)

Antipseudomonal Penicillin

Carbenicillin

Not active orally

IM or IV

ADRs: Fluid retention, Bleeding

Uses: Burns, UTI, Septicemias

Natural Penicillins Penicillin G

Semi-Synthetic

Acid-resistant phenoxymethyl Penicillin (Penicillin V)

Penicillinase-

resistant

Methicillin, Cloxacillin, Dicloxacillin, Nafcillin, Oxacillin, Flucloxacillin

Amino-penicillins Ampicillin, Amoxacillin ( Broad spectrum drugs, susceptible to

penicillinase, orally effective)

Antipseudomonal

(Carboxypenicillin)

Carbenicillin, Ticarcillin, Azlocillin, Piperacillin

( Broad spectrum drugs, susceptible to penicillinase, Poor oral absorption )

Ureidopenicillins Mezlocillin, Piperacillin

B-lactamase

inhibitors

Clavulanic acid, Sulbactam, Tazobactam

Reverse spectrum Pivmecillinam ( Effective against Gram negative organisms )

SAEID KASHEFI

17) Describe with a neat diagram the biosynthesis of bacterial cell wall. Explain the mechanism of

action of drugs that inhibit the process involved in wall synthesis? (8)

Mechanism of action of Penicillins-

Inhibition of Bacterial Cell Wall Synthesis

- Inhibition of transpeptidation cause:

Cross linking absent

Cell wall deficient forms

burst under osmotic pressure

Peptidoglycan cause mechanical stability

Gram +ve 50-100—thick,

Gram –ve 1-2 thick

Peptidoglycan

Glycon chains-liner stand of two alternative amino

sugar

NAG-N-acetyl glycosamine

NAMA-N-acetyl muramic acid

Cross linked by peptide chains

Involves 30 bacterial enzymes

Peptidoglycan contains 3 stages:

1) Precursor formation

2) Formation building block

3) Completion of cross link

NAG-N-acetyl glycosamine

NAMA-N-acetyl muramic acid

1. NAMA-NAG

2. L-alanine

3. D-GLUTAMINE

4. L-lysine--------------- (glycine) 5

5. D-alanine

6. D-alanine

Uridine diphosphate (UDP)-acetyl muramyl-penta-

peptide

Alanine racemase-racemization of L-alanine

D-alanyl-D-alanine synthetase

Transpeptidase

SAEID KASHEFI

Mechanism of action of penicillins

1. All β-lactams inhibit cell wall synthesis

2. Cell wall is a cross linked peptidoglycan polymer

3. Polysaccharides crosslinked with pentapeptide

4. Polysaccharide alternate N acetyl glucosamine + N acetyl muramic acid

• Penicillin binds to proteins [PBP] that catalyse the transpeptidase reaction which cross links the

Polysaccharide with peptide

• This occurs in dividing cells only

• Faulty cell wall osmotic lysis bactericidal

• Gram +ve cell walls have peptidoglycan but –ve have alternate layers of lipoproteins also present

• More active on gram +ve

SAEID KASHEFI

18) With a diagram describe the mechanisms of action of 3 drugs which inhibit bacterial cell wall

synthesis at different stages? Mention the draw backs of penicillin G? (6+2)

Cycloserine Vancomycin Bacitracin Β-lactam

Is a chemical analogue of

D-alanine

Inhibits bacterial cell wall

synthesis by inactivating

the enzymes which

racemize l-alanine an link

2 D-alanine residue

Binds to terminal

dipeptide sequence

of peptidoglycan unit

prevents its release

from carrier

inhibits cell wall

synthesis,

Bactericidal

It acts by inhibiting cell wall synthesis at a step

earlier than that inhibited by penicillin.

It increases the efflux of ions by binding to cell

membrane.

Bactericidal.

Penicillin binds to proteins

[PBP] that catalyses the

transpeptidase reaction

which cross links the

Polysaccharide with

peptide

This occurs in dividing cells

only

Faulty cell wall

osmotic lysis

Bactericidal

Limitation/Drawbacks of PnG

1. Orally not very effective (acid labile)

2. Short duration of action

3. Narrow spectrum of antibacterial activity

4. Destroyed by penicillinase enzyme

5. Possibility of anaphylaxis

So semisynthetic penicillin have been developed

SAEID KASHEFI

19) Why is penicillin-G ineffective against gram –ve organism? List the therapeutic use and

adverse effect of penicillin-G? (2+4)

Antibacterial Spectrum of Penicillin G

PnG is a narrow spectrum antibiotic; activiiy is limited primarily to gram-positive bacteria and few others.

Cocci- Bacilli

Streptococci, Pneumococci,

―Staphylococci‖ (G +ve)

Neisseria (G –ve)

only G +ve sensitive

Bacillus anthracis

Corynebacterium diphtheriae

Listeria

Spirochaetes

• Poor entry of drug (G –ve bacteria)

• Porin channels

• Penicillin G –Uses

Uses

Streptococcal infections

Pharyngitis, otitis media, scarlet fever,

rheumatic fever

Sub-acute bacterial endocarditis (SABE)

Penicillin G (10-20 MU, IV, d)+

Streptomycin (0.5g IM X 2/d)

Pneumococcal infections Pneumonia & Meningitis (IV Penicillin G, 3-5 MU 6h)

Meningococcal infections Meningitis (IV Penicillin G, High doses)

Gonorrhoeae Not reliable

Syphilis Procaine Penicillin G X 10 days

Diphtheria & Tetanus As an adjuvant to Antitoxin

Prophylactic uses Rheumatic fever

Gonorrhoea

Adverse effect:

1) One of the most nontoxic; up to 60 g no direct toxicity

2) Local irritation pain, thrombophlebitis

3) Hypersensitivity incidence 1 – 10%[major ]

Most common allergenic drug [ test dose of 2-10 U is a must]

Common itching, rash, fever, wheezing, exofoliative dermatitis, angioedema

Rare [ 1-4 per 10000] anapylaxis

Allergy more in parenteral routes

Limited cross sensitivity between penicillins/ Topical use completely avoided because of high risk

SAEID KASHEFI

20) Cephalosporins? (4)

21) Compare and contrast 1st generation of CEPHALOSPORINS with the 3rd generation? (2)

Source: Cephalosporium acremonium

Oral Parental β- lactamase

enzyme

B.B.B. Uses

1st

Cephalexin

Cephaloridine

Cefadroxil

Cephradine

Cefazolin

Cephalothin

Cephapirin

Gram +Ve= +++

Gram -Ve = +

CSF penetration: Poor (+)

Not effective against Salmonella,

Shigella, Pseudomonas and

B.fragilis

Susceptible to B-lactamases

(exception: Cephalothin)

Cephalothin is

highly resistant

to

Staphylococcal

BLE

Does not

cross BBB

Skin

soft tissue infection,

Surgical Prophylaxis

(Cefazolin- long duration

action)

2nd

Cefuroxime

Cefaclor

axetil

Loracarbef

Cefprozil

Cefoxitin

Cefuroxime

Cefotetan

Cefmetazole

Ceforanide

Cefonicid

Cefamandole

against Gram +Ve= ++

against Gram -Ve = ++

CSF penetration: Good (++)

Resistant to Gram –Ve B-

lactamases

Not effective against

Pseudomonas and B.fragilis

(exception: Cefoxitin)

Less active than First generation

drugs against Gram +Ve Cocci

Cefoxitin &

cefuroxime are

resistant to

BLE

Some

(Cefuroxime)

cross the

BBB --- reach

CSF

Anaerobic infection

(Cefoxitin and cefotetan-

abdominal and pelvic

infection

RTI- Oral Cephalosporins

3rd

Cefixime

Ceftibuten

Cefdinir

Cefpodoxime

Cefditoren

Ceftriaxone

Ceftizoxime

Ceftazidime

Cefoperazone

Cefotaxime

Moxalactam

against Gram +Ve= +

against Gram -Ve = +++

CSF penetration: Very Good

(+++)

Highly resistant to Gr-Ve B-

lactamases

Ceftazidime has max

anti-pseudomonal action

Cefotaxime toxic to aerobic

organisms

Ceftriaxone has long duration of

action

Most of them

highly resistant

to most of BLE

(except

Cefoperazone)

Most of them

cross BBB-

high con in

CSF (

Cefotaxime,

ceftriaxone)

Gram –Ve infection

Urinary, RTI,

Soft tissue infection

Thyphoid fever

Meningitis

Mixied aerobic and

anaerobic

Penicillinase producing

S. Aureus infection

Gonococcal infection

Septicaemia, Nosocomial

infection

4th

Cefepime

Cefpirome

Cefozopran

Cefepime:

Properties similar to III

generation

with enhanced B-lactamases

resistant activity and CSF

penetration property

Effective against Streptococci

and Staph

Not effective against MRSA

Used against serious Gram-Ve

infections like hospital acquired

pneumonia, febrile neutropenia,

bacteremia, etc.,

Cefpirome:

Zwitterion, thus, better

penetration

Resistant to many B-

lactamases

More potent than III

generation drugs against

Gram +Ve and some Gram-

Ve organisms

Useful against many serious

infections including

septicaemias, LRT infections

5th Ceftobiprole

Ceftaroline

SAEID KASHEFI

Aminoglycoside

SAEID KASHEFI

22) List out the common properties of aminoglycosides antibiotics. Describe the mechanism of

action of aminoglycosides antibiotics. Describe how these drugs cause ototoxicity? (3+3+2)

Common properties:

1) All are used as sulfate salts, which are highly water soluble; solutions are stable for months.

2) All are active primarily against aerobic gram negative bacilli and do not inhibit anaerobes.

3) All, exhibit ototoxicity and nephrotoxicity.

4) All are bactericidal and more active at alkaline pH.

5) All are excreted unchanged in urine by glomerular: filtration

6) They ionize in solution are not absorbed orally; distribute only extracellularly; do not pentetate brain or CSF

7) They act by interfering with bacterial protein synthesis.

8) There is only partial cross resistance among them.

9) They have relatively narrow margin of safety.

Mechanism of action

The aminoglycosides are bactericidal antibiotics,

All having the same general pattern of action which may be described in two main steps:

(a) Transport of the aminoglycoside through the bacterial cell wall and cytoplasmic membrane.

(b) Binding to ribosomes resulting in inhibition of protein synthesis.

Transport of aminoglycoside into bacteria is a multistep process.

They diffuse across the outer coat of gram-negative bacteria through porin channels.

Penetration is dependent upon maintenance of a polarized membrane and on oxygen dependent active

processes. These processes are inactivated under anaerobic conditions; anaerobes are not sensitive and

facultative anaerobes are more resistant when O2 supply is deficient .eg. Inside big abscesses. Penetration is

also favored by high pH; aminoglycosides are -20 times more active in alkaline than in acidic medium.

Inhibitors of bacterial cell wall (β-lactams, vancomycin) enhance entry of aminoglycosides and exhibit

synergism.

Once inside the bacterial cell, streptomycin binds to 30S ribosomes, but other aminoglycosides bind to

additional sites on 50S subunit, as well as to 30S-50S interface.

They freeze initiation of protein synthesis prevent polysome formation

Binding of aminoglycoside to 30S-50S juncture causes distortion of mRNA codon recognition resulting in

misreading of the code: one or more wrong amino acids are entered in the peptide chain and or peptides of

abnormal lengths are produced.

The cidal action of these drugs appears to be based on secondary changes in the integrity of bacterial cell

membrane, because other antibiotics which inhibit protein synthesis (tetracyclines, chloramphenicol,

erythromycin) are only static.

The cidal action of aminoglycosides is concentration dependent, i.e. rate of bacterial cell killing is directly related

to the ratio of the peak antibiotic concentration to the MIC value.

They also exert a long and concentration dependent 'post-antibiotic effect'

SAEID KASHEFI

It has, therefore, been argued that despite their short t1/2 ( 24hr), single injection of the total daily dose of

aminoglycoside may be more effective and possibly less toxic than its conventional division into 2-3 doses

Ototoxicity:

Vestibular (partially reversible) or the cochlear (irreversible) part maybe primarily affected by a particular

aminoglycoside.

These Drugs are concentrated in the labyrinthine fluid and are slowly removed from it when the plasma

concentration falls.

Aminoglycoside ear drops can cause ototoxicity when instilled in patients with perforated eardrum;

contraindicated in them.

[ Ototoxicity is damage to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, by

a toxin. It is commonly medication-induced; ototoxic drugs include

Antibiotics such as the aminoglycoside gentamicin,

loop diuretics such as furosemide,

platinum-based chemotherapy agents such as cisplatin.

NSAIDS such as Meloxicam have also been shown to be ototoxic.

Either may be reversible and temporary, or irreversible and permanent.]

Mechanisms of resistance

Resistance to aminoglycosides is acquired by one of the following mechanisms:

1) Acquisition of cell membrane bound inactivating enzymes which

Phosphorylate/ adenylate / acetylate the antibiotic.

2) through Mutation;

E.Coli to streptomycin

3) By altering transporting mechanism

Pseudomonas

4) By altering receptor protein structure

bword://!!ARV6FUJ2JP,ear/

bword://!!ARV6FUJ2JP,cochlea/

bword://!!ARV6FUJ2JP,vestibulocochlear%20nerve/

bword://!!ARV6FUJ2JP,vestibular%20system/

bword://!!ARV6FUJ2JP,toxin/

bword://!!ARV6FUJ2JP,antibiotic/

bword://!!ARV6FUJ2JP,aminoglycoside/

bword://!!ARV6FUJ2JP,gentamicin/

bword://!!ARV6FUJ2JP,loop%20diuretic/

bword://!!ARV6FUJ2JP,furosemide/

bword://!!ARV6FUJ2JP,platinum/

bword://!!ARV6FUJ2JP,chemotherapy/

bword://!!ARV6FUJ2JP,cisplatin/

bword://!!ARV6FUJ2JP,Meloxicam/

SAEID KASHEFI

23) Discuss the major adverse reactions of aminoglycoside? (2)

PRECAUTIONSA ND INTERACTIONS

1) Avoid aminoglycosides during pregnancy: risk of foetal ototoxicity.

2) Avoid concurrent use of other ototoxic drugs, e.g. high ceiling diuretics, minocycline.

3) Avoid concurrent use of other nephrotoxic drugs, e.g. amphotericin B, vancomycin, cyclosporine and cisplatin.

4) Cautious use in patients past middle age and in those with kidney damage.

5) Cautious use of muscle relaxants in patients receiving an aminoglycoside.

6) Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.

24) Aminoglycosides lose their antibacterial activity in acidic environment? (2)

Penetration is also favored by high pH; aminoglycosides are -20 times more active in alkaline than in acidic

medium

25) Why are aminoglycosides bacterial unlike other protein synthesis inhibitors? (2)

The cidal action of aminoglycosides drugs appears to be based on secondary changes in the integrity of bacterial

cell membrane, because other antibiotics which inhibit protein synthesis (tetracyclines, chloramphenicol,

erythromycin) are only static.

26) Write briefly on Gentamycin? (5)

• Most commonly used aminoglycoside for acute gram –ve bacillary infections

• More potent than strepto, similar kinetics

• broader spectrum; kills P areuginosa, ineffective on M tuberculosis,

• cheapest, common first line drug in

– acute respiratory infections in immunocompromised critical patients,

– burns, UTI, pneumonia, -ve bacterial meningitis

– SABE with penicillins

• More nephrotoxic than strepto

– Requires dose adjustment in renal failure

Methicillin resistant staphylococci

SAEID KASHEFI

27) Differences between Gentamycin and streptomycin? (2 )

Gentamycin streptomycin

• Most commonly used aminoglycoside for

acute gram –ve bacillary infections

• More potent than strepto, similar kinetics

• broader spectrum; kills P aeruginosa,

ineffective on M tuberculosis,

• cheapest, common first line drug; in

– acute respiratory infections in

immunocompromised critical patients,

– burns, UTI, pneumonia, -ve bacterial

meningitis

– SABE with penicillins

• More nephrotoxic than strepto

– Requires dose adjustment in renal failure

• Strepto~: Oldest; relatively narrow spectrum

– Presently used in tuberculosis only

• Resistance:

– via plasmid, rapid esp in GIT & UTI;

– Resistance in GIT and UT emerge in 2 days!

– Some become dependent on streptomycin for translation

– E coli, H influenzae, Strep, Staph aureus mostly resistant,

– M tuberculosis develop rapid resistance if used alone

– Partial cross resistance with other aminoglycosides

• Kinetics:

– Ionized, unabsorbed by GIT;

– im injn a must ; stays in ECF; vol of distrib [0.3 /kg]

– Conc in CSF subtherapeutic, even in meningitis

– Excreted unchanged in urine by GFR; T ½ = 2-4 hr

• ADRs:

– Vestibular damage >> auditory ;

– least nephrotoxic aminoglycoside

– low superinfection

28) How dose bacterial resistances occur to the aminoglycoside antibiotics? (3)

Mechanisms of resistance

Resistance to aminoglycosides is acquired by one of the following mechanisms:

1) Acquisition of cell membrane bound inactivating enzymes which

Phosphorylate/ adenylate / acetylate the antibiotic.

5) through Mutation;

E.Coli to streptomycin

6) By altering transporting mechanism

Pseudomonas

7) By altering receptor protein structure

SAEID KASHEFI

29) Write briefly on Neomycin? (2)

30) Give reasons for the use of Neomycin in hepatic coma? (2)

Obtained from S. Fradiae

Active against most gram negative bacilli and some gram-positive cocci

Neomycin is highly toxic to the intimal ear (mainly auditory) and to kidney. It is, therefore, not used

systemically. Absorption from the G.I.T. is minimal.

Oral and topical administration does not ordinarily cause systemic toxicity.

Uses

1. Topically (often in combination with polymyxin, bacitracin, etc.) for infected wound, ulcers, burn, external ear

infections, conjunctivitis, but like other topical anti-infective preparations, benefits are limited.

2. Orally for:

(a) Preparation of bowel before surgery:

(3 doses of 1.0 g along with metronidazole 0.5 g on day before surgery) may reduce postoperative infections.

(b) Hepatic coma:

Normally NH3 is produced by colonic bacteria. This is absorbed and converted to urea by liver. In severe

hepatic failure, detoxication of NH3 does not occur; blood NH3 levels rise and produce encephalopathy.

Neomycin, by suppressing intestinal flora, diminishes NH3 production and lowers its blood level; clinical

improvement is seen within 2-3 days. However, because of toxic potential it is infrequently used for this

purpose; lactulose is preferred.

Adverse effects

Applied topically neomycin has low sensitizing potential. However, rashes do occur.

Oral neomycin has a damaging effect on intestinal villi-prolonged treatment can induce malabsorption

syndrome with diarrhoea and steatorrhea. It can decrease the absorption of digoxin and many other drugs, as

well as bile acids.

Due to marked su

ppression of gut flora, superinfection by Candida can occur.

Small amounts that are absorbed from the gut or topical sites are excreted unchanged by kidney.

This may accumulate in patients with renal insufficiency-cause further kidney damage and ototoxicity.

Neomycin is contraindicated if renal function is impaired.

Applied to serous cavities (peritoneum), it can cause apnoea due to muscle paralysing action.

SAEID KASHEFI

Tetracyclines

SAEID KASHEFI

31) List the major differences between old and newer TETRACYCLINES?

Drugs

Route

of

admin.

Absorption

from the

gut (%)

t1/2

hour

dosage Intestinal

absorption

Elimination Photo-

toxicity

Group I

short acting

Older

tetracyclines

Tetracycline

Chlortetracycline

Oxytetracycline

Oral

i.v

topical

30-60 6-12 250-500

mg q.i.d

Moderate Rapid renal

excretion

Low

Group II

intermediate

acting

Second

generation

Demeclocycline

Methacycline

Oral 60-80 6-12 300-600

mg b.d

Moderate Partial metabolism, slower renal

excretion

Highest

Group III

long acting

Highly

potent drug

Doxycyline

Minocycline

(Dox < mino)

Oral

i.v

95-100

16-24

100 mg

b.d or

o.d

Complete, no interference by food

Doxy: Primarily excreted in faces as conjugate Mino: Primarily metabolized, excreted in

urine and

bile

Doxy:

High

Liver damage Fatty infiltration of liver and jaundice occurs occasionally. Oxytetracycline and tetracycline are

safer in this regard.

All tetracyclines, except doxycycline, accumulate and enhance renal failure.

Phototoxicity a higher incidence has been noted with demeclocycline and doxycycline

Diabetes insipidus Demeclocycline antagonizes ADH action and reduces urine concentrating ability of the

kidney.

Vestibular toxicity Minocycline has produced ataxia, vertigo and nystagmus, which subside when the drug is

discontinued.

Superinfection it is common with older tetracyclines because of their incomplete absorption in the gut.

Doxycycline and minocycline are less liable to cause diarrhoea, because only small amounts reach the lower

bowel in the active form

SAEID KASHEFI

32) Enumerate TETRACYCLINES and mention their adverse effects? (2)

33) Adverse effect of oxytetracycline? (2)

drugs Adverse effect

Group I

Short acting

Older tetracyclines

Tetracycline

Chlortetracycline

Oxytetracycline

1) On GIT

Nausea, vomiting, diarrhoea

Direct local irritation

Suprainfections

Suppression of normal flora

Overgrowth of resistant ones

2) Bone structures and teeth

Bound to Ca in newly formed bone or teeth

Fluorescence, discoloration and enamel dysplasia (fetal teeth)

Bone deformity & growth inhibition

3) Liver

Ingestion of ―out-dated‖ tetracyclines cause ―Fanconi-like‖

syndrome

4) Kidney

5) Photosensitization

Demeclocycline, Doxycycline (in fair skinned)

6) Vestibular reactions

Dizziness, vertigo, nausea, vomiting

Doxycycline >100mg

Minocycline 200-400mg/d

7) Jarish- Herxheimer reaction: sudden rise of fever, rigors,

hypertension, hyperventilation

Group II

Intermediate acting

Second generation

Demeclocycline

Methacycline

Group III

long acting

Highly potent drug

Doxycyline

Minocycline

(Dox <

mino)

34) Which TETRACYCLINES are drug of choice in patient with renal impairment and why? (2)

Kidney damage it is prominent only in the presence of existing kidney disease.

All tetracyclines, except doxycycline, accumulate and enhance renal failure.

A reversible Fanconi syndrome like condition is produced by outdated tetracyclines due to proximal tubular

damage caused by degraded products-

Epitetracycline,

Anhydrotetracycline

Epianhydrotetracycline.

Exposure to acidic pH, moisture and heat favours such degradation.

SAEID KASHEFI

35) Tetracyclines are contraindicated in children below 12 years? (2)

Tetracyclines have chelating property. Calcium-tetracycline chelate gets deposited in developing teeth and

bone.

Given from mid pregnancy to 5 months of extrauterine life, the deciduous teeth are affected: brown

discoloration, ill-formed teeth, more susceptible to caries.

Tetracyclines given between 3 months and 6 years of age affect the crown of permanent anterior dentition.

Repeated courses are more damaging.

Given during late pregnancy or childhood, tetracyclines can cause temporary suppression of bone growth.

The ultimate effect on stature is mostly insignificant, but deformities and reduction in height are a possibility

with prolonged use.

36) Mention the drug interaction of tetracyclines? (2)

1) Al3+

, Ca2+

, Zn2+

, Mg2+ and iron preparations decrease tetracycline absorption by chelation.

2) Tetracyclines may reduce insulin requirements and may alter lithium blood levels.

3) Tetarcyclines inhibit intestinal flora that produces vitamin K, and therefore may potentiate the anticogulant

effects of warfarin.

4) Enzyme inducers such as barbiturates, phenytoin and carbamazepine reduce serum levels of tetracyclines.

SAEID KASHEFI

37) Describe the mechanism of action of TETRACYCLINES. How do bacteria develop resistance

to tetracyclines? (4)

Mechanism of action

The tetracyclines are primarily bacteriostatic; inhibit protein synthesis by binding to 30S ribosomes in susceptible

organism.

Subsequent to such binding, attachment: of aminoacyl-t-RNA to the mRNA-ribosome Complex is interfered with.

As a result the peptide chain fails to grow.

The sensitive organisms have an energy dependent active transport process which concentrates tetracyclines

intracellularly. In gram negative bacteria tetracyclines diffuse through porin channels as well. The more lipid-

soluble members (doxycycline, minocycline) enter by passive diffusion also (this is partly responsible for their

higher potency).

The carrier involved in active transport of tetracyclines is absent in the host cells. Moreover, protein synthesizing

apparatus of host cells is less sensitive to tetracyclines. These two factors are responsible for the selective

toxicity of tetracyclines for the microbes.

1) Aminoglycosides bind to several sites at 30S and 50S subunits as well as to their interface-freeze initiation

interfere with polysome formation and cause misreading of mRNA codon

2) Tetracyclines binds to 30S ribosome and inhibit aminoacyl tRNA attachment to the A site

3) Chloramphenicol binds to 50S subunit-interfere with peptide bon formation and transfer of peptide chain from

P site

4) Erythromycin and clindamycin also bind lo 50S ribosome and hinder the translocation of elongated peptide

chain back from A site to P site and the ribosome does not move along the mRNA to expose the next codon.

Resistance

1) Nearly complete cross resistance is seen among different members of the tetracycline group

2) Partial cross resistance between tetracyclines and chloramphenicol has been noted.

3) Plasmid mediated synthesis of a 'protection' protein which protects the ribosomal binding site from

tetracycline.

SAEID KASHEFI

CHLORAMPHENICOL

SAEID KASHEFI

38) Mechanism of action, uses of CHLORAMPHENICOL and their toxic effect? (2)

MOA

Chloramphenicol acts primarily by binding

reversibly to the 50 S ribosomal subunit.

Prevents the binding of the amino-acid-

containing end of the aminoacyl tRNA to the

acceptor site on the 50 S ribosomal subunit.

Interaction between peptidyl transferase and

its amino acid substrate cannot occur, and

peptide bond formation is inhibited

In eukaryotes, inhibits mitochondrial 70s

ribosomes→ host toxicity

Erythropoietic cells very sensitive

Resistance Therapeutic uses Adverse effects Drug interactions

Inactivation by

acetyltransferase

Acetyl derivative

fails to bind to

ribosomes

Decreased

permeability

(E coli,

pseudomonas)

Mutation

Typhoid fever (1g QID

X 4 weeks)

Bacterial meningitis

Anaerobic infections

Rickettsial infections

Brucellosis

Bone marrow depression

Hypersensitivity reactions

Irritative effects

Superinfections

Gray baby syndrome

Inhibition of Cytochrome

p450 leads to prolongation of

t1/2 of

o Warfarin

o Dicumarol

o Phenytoin

o Chlorpropamide

o Protease inhibitors

Kinetics

Absorbed rapidly orally

Well distributed even to CSF

50% plasma protein binding

Bile, milk , crosses placenta , aqueous humor

Hepatic metabolism

39) Why are the Erythropoietic cells very sensitive to chloramphenicol? (2)

At high doses, it can inhibit mammalian mitochondrial protein synthesis as well. Bone marrow cells are especially

susceptible.

SAEID KASHEFI

Macrolides

SAEID KASHEFI

40) Uses and adverse effects of Erythromycin? (2)

Erythromycin (prototype)

Streptomyces erythreus

Bacteriostatic at low & bactericidal at high concentration

Concentrated intracellularly by active transport

More active in alkaline medium

Mechanism of Action

Inhibits bacterial protein synthesis

Binds to 50s ribosomal subunit

Interferes with ‗translocation‘ of nascent peptide chain from A

site to P site

Premature termination of protein synthesis

Highly active against:

Strep. pyogenes, Strep. pneumoniae, N. gonorrhoeae

Clostridia, Listeria, Legionella

Cornybacterium diphtheriae, Campylobacter

Mycoplasma

Cross resistance with other macrolides, clindamycin,

chloramphenicol

Adverse Effects

G.I.T. stimulates motilin receptors-epigastric pain

Hearing impairment (Reversible)

Hypersensitivity

Hepatitis with estolate ester

SAEID KASHEFI

Interactions

Enzyme inhibitor

↑ plasma levels of theophylline, carbamazepine, valproate, ergotamine, warfarin, terfenadine, astemizole.

7- E

1) Erthromycin

2) Enteric coated tablets

3) Enterohepatic cycling

4) Erythromycin Estolate

5) Enteranal toxicity mainly

6) Epigastric pain

7) Enzyme inhibitors

Uses

As alternative to penicillin As first choice drug in As second choice drug

1. Streptococcal infections:

Tonsillitis, pharyngitis,

cellulitis, pneumonia

2. Diphtheria

3. Tetanus

4. Syphilis & gonorrhoea

1. Mycoplasma pneumoniae

2. Whooping cough (Pertussis)

3. Chancroid

1. Campylobacter enteritis

(fluoroquinolones)

2. Legionnaire‘s pneumonia

(azithromycin/ ciprofloxacin)

3. Chlamydia trachomatis (azithromycin)

4. Penicillin resistant staphylcoccal

infections

Mnemonic-MLCDPTS

(Uses of Erythromycin)

Mycoplasma Pnemoniae infections

Legionnaire‘s pneumonia

Chlamydial infections

Diphtheria

Pertussis

Tetanus

Streptococcal infection

Prophylatic uses

SAEID KASHEFI

41) Write briefly on newer macrolides as antibacterial agents? (4)

Newer Macrolides

1. Clarithromycin

2. Azithromycin

3. Roxithromycin

Adverse Effects Uses

Clarithromycin

Spectrum includes MAC,

Mycobacterium leprae, anaerobes

More active against gram +ve cocci,

Moraxella, Legionella, Mycoplasma

pneumoniae, Helicobacter pylori

Active metabolite produced

Metabolised by saturation kinetics

Pseudomembranous

enterocolitis

Hepatic dysfunction

Drug interaction profile

similar to erythromycin

1. RTI, ENT infections,

atypical pneumonia

2. Skin infection due to Strep

pyogenes & Staph aureus

3. H. pylori

4. MAC in AIDS patients

5. Leprosy

Azithromycin

Expanded spectrum

Improved pharmacokinetics

Better gastric tolerance

↓ drug interaction

1. Legionnaire‘s pneumonia

2. Chlamydia trachomatis

3. RTI, ENT, skin, soft tissue

infections

4. Gonorrhoea, MAC

5. Potential uses typhoid,

toxoplasmosis, malaria

Roxithromycin

Long acting, acid stable

↓ G.I. intolerance, ↑ tissue

penetration

↓ drug interactions

Less active against B. pertussis

Uses- alternative to erythromycin for

RTI, ENT, skin, soft tissue & genital

tract infections

SAEID KASHEFI

42) Which of the macrolide antibiotics is free from drug-drug interaction? Explain. (2)

Because clarithromycin is metabolized by hepatic cytochrome P450 microsomal enzymes, it, like

erythromycin, has the potential to interact with other drugs.

However, clarithromycin is less potent P450 inhibitor than erythromycin.

Erythromycin inhibits hepatic oxidation of many drugs. The clinically significant interactions are-rise in plasma

levels of theophylline, Carbamazepine, valproate, ergotamine and warfarin.

Several cases of Q-T prolongation, serious ventricular arrhythmias and death have been reported due to inhibition

of CYP3A4 by erythromycin/clarithromycin resulting in high blood levels of concurrently administered

terfenadine/astemizole/cisapride.

Azithromycin is unlikely to interact with drugs metabolized via the hepatic cytochrome P450 enzyme system,

and few interactions have been reported clinically. Interaction with Theophylline, carbamazepine, warfarin,

terfenadine and cisapride are not likely.

43) Clindamycin-Erythromycin combination is unsuitable for antibacterial therapy? (1)

Cross resistance with other Macrolides, Clindamycin, Chloramphenicol

SAEID KASHEFI

Miscellaneous

Antibiotics

Lincosamide antibiotics*

1. Clindamycin

2. Lincomycin

Glycopeptide antibiotics

3. Vancomycin

4. Teicoplanin

Oxazolidinone

5. Linezolid*, Radezolide, Torezolide

Streptogramins (Pristinamycin)*

6. Quinupristin/Dalfopristin [KWIN-yoo-pris-tin/DAL-foh-pris-tin]

7.Mupirocin

8. Fusidic acid

9.Polypeptide antibiotics

9. Polymyxin B

10. Colistin

11. Bacitracin

12.Tyrothricin

SAEID KASHEFI

Pharmacokinetics Adverse effects Uses

Clindamycin

Lincosamide antibiotic

Mechanism of action–

similar to erythromycin-

Inhibits protein synthesis-

binding to 50S ribosomes

Spectrum:

Susceptible organisms

Gram +Ve cocci including

Staph

diphtheriae and Nocardia

Toxoplasma and B.

fragilis

Non-susceptible

organisms:

Gram –Ve bacilli

Good oral

absorption

Poor CSF

penetration

Good penetration

into Skeletal

muscles and soft

tissues

Accumulates in

macrophages

Abdominal pain

Diarrhoea

Pseudomembran

ous enterocolitis

(Suprainfection)

from C. difficile

(Treatment –

metronidazole /

vancomycin)

1) Doc for anaerobic and

mixed infections

2) Bone infections from

anaerobes

3) With Pyrimethamine

for toxoplasmosis in

AIDS patients

4) With Primaquine in P.

carinii infections

5) Topically for infected

acne vulgaris

6) Note: Erythromycin +

clindamycin:

Irrational

Lincomycin

From Streptomyces

lincolnensis

Inhibits protein synthesis,

bacteriostatic

Mainly against G +ve

o Staphylococci

o Pneumococci

o Streptococci

diphtheriae

Largely replaced by

clindamycin

Orally effective

Vancomycin

Glycopeptide obtained

from Streptococcus

orientalis

Mechanism:- Binds to

terminal dipeptide

sequence of

peptidoglycan unit

prevents its release from

carrier inhibits cell wall

synthesis, bactericidal

Spectrum:

MRSA, S. Viridans

Enterococci, Cl. difficile,

Neisseria, Diphtheria and

Clostridia

Resistance - Alteration of

dipeptide target

(Methicillin resistant

Staphylococcus aureus)

Water soluble &

stable

Poor oral

absorption,

Route of

administration:

I.V

Excretion:

Glomerular

filtration

Toxicities:

Oto and

Nephrotoxicities

(dose rated)

Hypotension &

‗Red man

syndrome‘ (rapid

i.v injection has

caused chills,

fever, urticaria and

intense flushing)

Skin allergy

Oral application:

Pseudomembranous

enterocolitis

Systemic uses:

1. MRSA

2. Substitute to

penicillin for

enterococcal

endocarditis

SAEID KASHEFI

Teicoplanin

Spectrum gram +ve organisms

Mechanism similar to vancomycin

Active against vancomycin resistant strains

also

SABE,

MRSA,

penicillin resistant

streptococcal infections

Linezolid

Binds to 23S ribosomal RNA of 50S ribosome.

Inhibits protein synthesis by preventing

formation of N- formyl methionine tRNA – 70s

initiation complex

Bacteriostatic

Spectrum MRSA, VRSA, VRE, penicillin

resistant Strep. pyogenes, Strep. viridans, Strep.

pneumoniae, C. diphtheriae, Listeria, Bact.

fragilis

Adverse Effects:

Candida

superinfection

Interactions:

It is a MAO

inhibitor

hypertensive

crisis with

tyramine & other

adrenergic drugs

Hospital acquired

infections

infections caused

by multidrug

resistant gram +ve

bacteria

Quinupristin

/Dalfopristin

a mixture of two streptogramins (B,A) in a ratio

of thirty to seventy, respectively.

-derived from a streptomycete and then

chemically modified.

-MOA-Each component of this combination drug

binds to a separate site on the 50S bacterial

ribosome, forming a stable ternary complex.

The drug is

normally reserved

for the treatment of

vancomycin-

resistant

Enterococcus

faecium (VRE)

Fusidic Acid Steroidal

Narrow spectrum gram +ve

Inhibits protein synthesis

Used topically for cutaneous infections

Polymyxin B

& Colistin

Spectrum gram –ve

Cationic detergents

Bind to membrane phospholipids

pseudopore formation ↑ permeability

A/E: Kidney damage, neurological disturbance,

N-M blockade

1) Topically for skin

infections, otitis

externa, conjunctivitis,

corneal ulcer

2) Orally for gram –ve

bacillary diarrhea,

pseudomonas

superinfection

Bacitracin

Spectrum gram +ve bacteria, Neisseria, H.

influenzae

Inhibits cell wall synthesis

Used topically for infected wounds, ulcers

Bacitracin is not absorbed orally.

It is not used parenterally because of high toxicity to the kidney.

Tyrothricin Mixture of gramicidin & tyrocidin

↑ membrane permeability, uncouples

oxidative phosphorylation

Used topically

SAEID KASHEFI

Methenamine Converted to formaldehyde in acidic pH

Almost all bacteria are sensitive to free

formaldehyde

Urine can be acidified with hippuric acid,

mandelic acid

Methenamine + Mandelic acid

methenamine mandelate

Urea splitting organisms (proteus) ↑ urinary

pH ↓ formaldehyde formation

A/E: G.I. distress, painful & frequent

micturition, albuminuria, hematuria, rashes

Methenamine

mandelate

contraindicated in

renal & hepatic

insufficiency

Drug interaction :

Sulfonamides

Uses: Chronic

UTI, esp. due to

E.coli

Nitrofurantoin More active in acidic pH

Causes DNA damage, bacteriostatic

Effective against E.coli, enterococci

A/E: G.I. distress, hypersensitivity, liver

damage, megaloblastic anemia

Uses: UTI- prophylaxis & recurrent cases

Phenazopyrid

ine Analgesic

Symptomatic relief of burning sensation,

dysuria

Azo dye colors urine orange red

Treatment of UTI

Treatment of STD

SAEID KASHEFI

44) Uses and toxicities of vancomycin, MOA? (2)

Pharmacokinetics Adverse effects Uses

Vancomycin

Glycopeptide obtained

from Streptococcus

orientalis

Mechanism:- Binds to

terminal dipeptide

sequence of

peptidoglycan unit

prevents its release from

carrier inhibits cell wall

synthesis, bactericidal

Spectrum:

MRSA, S. Viridans

Enterococci, Cl. difficile,

Neisseria, Diphtheria and

Clostridia

Resistance - Alteration of

dipeptide target

(Methicillin resistant

Staphylococcus aureus)

Water soluble &

stable

Poor oral

absorption,

Route of

administration:

I.V

Excretion:

Glomerular

filtration

Toxicities:

Oto and

Nephrotoxicities

(dose rated)

Hypotension &

‗Red man

syndrome‘ (rapid

i.v injection has

caused chills,

fever, urticaria and

intense flushing)

Skin allergy

Oral application:

Pseudomembranous

enterocolitis

Systemic uses:

3. MRSA

4. Substitute to

penicillin for

enterococcal

endocarditis

SAEID KASHEFI

TB

SAEID KASHEFI

45) Classified anti-TB drugs with examples. MOA of any two first line anti-TB, rational behind the

multi-drug treatment of TB? (10)

46) Discuss the role of INH as a first line drug in the chemotherapy of TB? (4)

First Line

(Primary agents)

Second Line

(Reserved drugs)

Newer Drugs

High antitubercular efficacy and

low toxicity which are used

routinely.

1. Isoniazid (H)

2. Rifampin (R)

3. Pyrazinamide (Z)

4. Ethambutol (E)

5. Streptomycin (S)

- Low antitubercular efficacy

- or High toxicity or both

1. Cycloserine (Cys)

2. Para-aminosalicylic acid (PAS)

3. Kanamycin (Kmc)

4. Amikacin (Am)

5. Ethionamide (Etm)

6. Thiacetazone (Tzn)

7. Capreomycin (Cpr)

1. Ciprofloxacin

2. Ofloxacin

3. Clarithromycin

4. Azithromycin

5. Rifabutin

SAEID KASHEFI

Isoniazid (INH)

Rifampin Semisynthetic derivative of rifamycin-B obtained from

Streptomyces mediterranei

Mode of action: Rapid Tuberculocidal

Site of action: Intra and Extra cellular

Effective Media: Acidic and alkaline

Susceptible population:

Kills rapidly multiplying organisms

Inhibits quiescent organisms

Resistant organisms: A typical Mycobacteria

Mode of action: Tuberculocidal

Site of action: Intra and Extra cellular

Effective Media: Acidic and alkaline

Susceptible population:

Rapidly multiplying organisms

Spurters and slow growing

Quiescent organisms

Effective against many atypical Mycobacteria

Mechanis

ms of

action

Unknown, but the hypothesis includes effects

on lipids, nucleic acid and biosynthesis.

Primary action seems to inhibit the biosynthesis

of mycolic acids which are the unique fatty acid

component of mycobacterial cell wall.

INH has high selectivity for mycobacteria

The lipid content of mycobacteria exposed to

INH is reduced

A gene labeled with inh A which encodes for a

fatty acid syntheses enzyme is the likely target

of INH action

The sensitive mycobacteria concentrate INH

and convert it by a catalase peroxidase enzyme

into an active metabolite that appears to

interact with the inh A gene

Site of action: repo-B gene

Effect: Inhibits DNA-dependent RNA

polymerase enzymes‘ expression & thus can

block transcription (inhibits RNA synthesis)

Other susceptible organisms:

Gram +Ve (Strepto and Staphylococci)

and –Ve rods (H. influenzae, Proteus, E.

coli, Pseudomonas)

M. leprae

Pharmaco

kinetics

About 75-95% of a dose is excreted in the urine

in 24 hr.

State: As a metabolite.

The excretory product: Acetyl-isoniazid.

Pathway: Enzymatic acetylation.

Note: Isoniazid metabolism is under genetic

control. There are 2 groups of people. Fast and

slow acetylators

Fast acetylators: Those that have high acetyl

transferase activity. May produce more toxic

(hepatotoxicity) intermediate. t 1/2 will be about

1 hours

Slow acetylators: Those that have slow acetyl

transferase activity. t 1/2 will be about 3 hours

(chances of drug interaction)

Ethnicity: Eskimos, Native American Indians,

and Asians are fast acetylators

Absorption: Excellent following PO

Distribution: Well penetration into caseous

masses, CSF, Placental and other body fluids

Metabolism: Deacylation into an active drug

Elimination: Rapidly eliminated in the bile

and reabsorbed (enterohepatic circulation).

Half-life: 6 hours.

SAEID KASHEFI

Drug Interaction

Aluminium hydroxide inhibits INH absorption

INH inhibits Phenytoin, Carbamazepine,

Diazepam and Warfarin metabolism (rise their

blood levels)

PAS inhibits INH metabolism and prolongs its

duration of action

Rifampin does induce microsomal drug

metabolizing enzymes

Consequences:

1. Increases its own metabolism

2. Decreases the half-life of some other drugs

(eg., Phenytoin, digitoxin)

3. Causes failure of contraception if given

with OCs

Adverse

Effects

Hepatitis

more frequent in fast acetylators and

alcoholics

Age-dependent, aged are at high risk

Peripheral neuritis:

Paresthesia, Numbness, Mental

disturbances and convulsions

Pyridoxine (vitB6) (10mg/day) to overcome

this

Allergic reactions

Rashes

Fever

aches

Serious: (preclude drug-continuation)

Hepatitis

Respiratory syndrome

Less serious:

G.I. Syndrome: Anorexia, Nausea

,Vomiting Mild abdominal pain

Flu syndrome: Fever, Skin Eruptions,

Rash, Pruritis

Cutaneous syndrome

Note: Imparts red orange color to fluids

Therapeutic

applications

In TB therapy

In the therapy of Leprosy

Against meningitis (treatment and

eradication) from H. influenzae and

meningococcal

For methicillin resistant staphylococci

With doxycycline in brucellosis

47) Explain the pharmacological basis for the INH with Pyridoxine in TB therapy? (1)

INH is well tolerated by most patients. Peripheral neuritis and a variety of neurological manifestations

(paresthesias, numbness, mental disturbances, rarely convulsions) are the most important dose-dependent toxic

effects.

These are due to interference with utilization of pyridoxine and its increased excretion in urine.

Pyridoxine given prophylactically (10 mg / day) prevents the neurotoxicity even with higher doses, but routine use

is not mandatory. INH neurotoxicity is treated by pyridoxine 100 mg/day.

Due to formation of Hydrazone, the renal excretion of pyridoxine compounds is increased. Thus, isoniazid therapy

produces a pyridoxine deficiency state.

SAEID KASHEFI

48) Ethambutol should not be prescribed for children. Why? (2)

Loss of visual acuity/color vision

Because young children may be unable to report early visual impairment, it should not be used below 6 years of

age.

49) Describe the short course therapy of TB, explaining the rational antitubercular drugs? (4)

50) Rational behind combining 4 first line drugs for the initial therapy of TB? (2)

Short course therapy of TB

Duration: 6 – 9 Months

Initial intensive phase Continuation Phase

Duration: 2 – 3 months

Drugs: H, E, R, Z or S

Why this?

For rapid killing of the TB bacilli

For sputum conversion

For symptomatic relief

Duration: 4 – 6 months

Drugs: H, R and E (in a few cases)

Objectives:

To eliminate the residual bacilli

To prevent the relapse

Summary: Rationale of drug-combinations

To prevent emergence of resistance

To obtain maximum synergism

To enhance pts compliance (OD)

Quick relief form symptoms

To make Pt non-contagious

To prevent relapse

To eradicate the disease

SAEID KASHEFI

Leprosy

SAEID KASHEFI

51) Why is multi-drug therapy followed for leprosy treatment? (2)

1) Effective in dapsone resistance cases

2) Prevents emergence of dapsone resistance

3) Affords quick symptomatic relief

4) Makes Multibacillary non-contagious

5) Prevents relapses

6) Reduces total duration of therapy

52) Lepra reaction and drugs used to treat it? (2)

Reaction in Leprosy

Treatment of Lepra reaction : Drugs

Lepra

reaction

– Occurs in lepromatous leprosy

– Two types:

1) Jarish Herxheimer type reaction

Life threatening

Erythema Nodosum Leprosum

2) Sulfone syndrome:

Fever, Malaise, Jaundice, anaemia, Lymph node enlargement

Clofazimine

Chloroquine

Thalidomide

Corticosteroids

Reversal

Reaction

– Seen in Tuberculoid Leprosy – Delayed hypersensitivity type – Skin Ulceration – Multiple nerve involvement – Sudden occurrences

Clofazimine or

Corticosteroids

Lepra reaction: Type-I

During Dapsone therapy for leparamatous leprosy some reactive episodes may occur. These are known as

Lepra reaction.

These are of two types. Type-I Lepra reaction are also known as reversal reaction.

There are delayed hypersensitivity reactions to M. Leprae antigens (Type IV hypersensitivity).

It is characterized by cutaneous ulcerating and multiple nerve involvement.

It can also be seen during dapsone therapy for tuberculoid leprosy.

Prompt treatment with corticosteroids is necessary to prevent nerve damage.

Lepra reaction: Type –II

Also known as erythema nodosum leprosum, represent a humoral antibody response (Type-III

hypersensitivity) to dead bacteria.

Lepra reaction is of abrupt onset, existing lesions enlarge, become red, inflamed and painful.

This reaction can be treated with clofazimine or corticosteroid or thalidomide.

If Lepra reaction relapse 1-2 months after dapsone use, it is called ―Sulfone syndrome‖ this is characterized

by fever, lymph node enlargement, general malaise, jaundice and anaemia

SAEID KASHEFI

Antiviral

SAEID KASHEFI

72) Classify antiviral drugs and mechanism of any 2 which are effective against DNA-virus at

different stages? (10)

Classification

Drugs

Anti-Herpes

simplex virus

Acyclovir, Idoxuridine, Famciclovir, Ganciclovir, Foscarnet

Anti-Retrovirus

(3)

Entry

inhibitors

Nucleoside reverse

transcriptase inhibitors

(NRTIs)

Non-nucleoside reverse

transcriptase inhibitors

(NNRTIs)

Protease inhibitors

Enfuvirtide

Zidovudine (AZT)

Lamivudine

Didanosine

Zalcitabine

Stavudine

Abacavir

Nevirapine

Efavirapine

Efavirenz

Delavirdine

Ritonavir

Indinavir

Saquinavir

Amprenavir

Lopinavir

Anti-Influenza

virus

Amantadine

Rimantadine

Nonselective

Antiviral Drugs

Lamivudine,

Ribavirin,

Interferon α

Steps for Viral Replication

1) Adsorption and penetration into cell

2) Un-coating of viral nucleic acid

3) Synthesis of regulatory proteins

4) Synthesis of RNA or DNA

5) Synthesis of structural proteins

6) Assembly of viral particles

7) Release from host cell

SAEID KASHEFI

Anti-Herpes virus

Herpes viruses 2 type:- Herpes simplex type I and II

1) Type I cause disease of mouth, face & skin

2) Type II affects genitals, rectum and skin

Vidarabine- 1st agent to be developed, Too toxic

Idoxuridine, Acyclovir, Famciclovir, Ganciclovir, Foscarnet

Antiviral Agents

1) Acyclovir- prototype

2) Valacyclovir

3) Famciclovir

4) Penciclovir

5) Trifluridine

6) Vidarabine

MOA (Acyclovir)

It is an acyclic guanosine derivative

Selectively pickup by viral infected cell

Phosphorylated by viral thymidine kinase to Di- and tri-phosphorylated by host cellular enzymes

It Inhibits viral DNA synthesis by:

1) competing with dGTP for viral DNA polymerase

2) chain termination

Mechanism of Resistance Acyclovir

Alteration in viral thymidine kinase and viral DNA polymerase

Cross-resistance with valacyclovir, famciclovir, and ganciclovir

Uses

Herpes Simplex Virus 1 and 2(HSV)

Varicella-zoster virus (VZV)

Side Effects:

Nausea, diarrhea, headache, tremors, skin rash and delirium

Drug Interaction

SAEID KASHEFI

73) Write briefly on interferons as antiviral agents? (5)

What are interferons?

A family of inducible proteins synthesized y mammalian cells as part of immune system

Types of interferons:

1) Interferon -α (used in hepatitis B and C and in cancer)

2) Interferon-β (used in multiple sclerosis)

3) Interferon- γ (used in chronic granulomatous disease)

Mechanism of action:

Activate the cytokine receptors of the host cell to transcribe interferon induced protein (IIP)

Induction of the production of enzyme such as :

1) Protein kinase

2) Oligoisoadenyl synthetase

3) PDE

Result: inhibition of the translation of viral-mRNA

Antiviral actions:

Broad spectrum anti-viral agent

Inhibit the viral replication by interfering into all major steps of replications

Adverse effects:

Allergic effect: alopesia, flu syndrome

Neurotoxicity: tremors, sleepiness

Myelosuppression: dose related effect

CVS effect: hypotension, cardiac arrhythmia

Thyroid dysfunction

Uses:

To prevent the reaction of HSV

INF α-2a is used for croninc hepatitis B

INF α-2b is used fo hepatitis C

SAEID KASHEFI

74) Mechanism of HIV replication in host, MOA of anti-HIV drugs? (8)

Anti-

Retrovirus

(3)

Entry

inhibitors

Nucleoside

reverse transcriptase

inhibitors

(NRTIs)

Non-nucleoside

reverse transcriptase

inhibitors

(NNRTIs)

Protease inhibitors

Enfuvirtide

Zidovudine (AZT),

Lamivudine

Didanosine

Zalcitabine

Stavudine

Abacavir

Nevirapine

Efavirapine

Efavirenz

Delavirdine

Ritonavir

Indinavir

Saquinavir

Amprenavir

Lopinavir

SAEID KASHEFI

Reverse Transcriptase Inhibitors

Mechanism of

Action

Side Effects Mechanism

of

Resistance

Clinical Uses

Entry

inhibitors

Enfuvirtide

NRTIs

Zidovudine

(AZT)

Lamivudine

Didanosine

Zalcitabine

Stavudine

Abacavir

MOA of Zidovudine (AZT)

A deoxythymidine analog, enters the cell via passive diffusion,

it must be converted to the triphosphate form by mammalian thymidine kinase, then competitively inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme, causes chain termination

Myelosuppression, including anemia and neutropenia

GI intolerance, headaches, myalgia and insomnia common at the start of therapy

Myopathy, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent.

Due to mutations in the reverse transcriptase gene

more frequent after prolong therapy and in persons

Available in IV and oral formulations

activity against HIV-1, HIV-2, and human T cell lymphotropic viruses

mainly used for treatment of HIV, decreases rate of progression and prolongs survival

prevents mother to newborn transmission of HIV

NNRTIs

Nevirapine

Delavirdine

Efavirenz

Bind to site on viral reverse transcriptase, different from NRTIs, this results in blockade of RNA and DNA dependent DNA polymerase activity

do not compete with nucleoside triphosphates do not require phosphorylation these drugs cannot be given alone substrates and inhibitors of CYP3A4

Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery

Delavirdine- teratogenic, therefore cannot be given during pregnancy Efavirenz- teratogenic, therefore cannot be given during pregnancy

Protease

Inhibitors

The protease enzyme cleaves precursor molecules to produce mature, infectious virions

these agents inhibit protease and prevent the spread of infection

These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia

Diarrhea

Nausea

Fatigue

Headache

SAEID KASHEFI

75) Zidovudine plus Zalcitabine plus Indinavir in HIV therapy? (2)

Life-long therapy is required.

Minimum of 3 drugs

A triple-drug regimen consisting of two NRTIs and PI is recommended for percutaneous blood exposure.

2 NRTI‘S + NNRTI / PI.

SAEID KASHEFI

Antifungal

SAEID KASHEFI

53) Antifungal drugs- Classification (5)

54) Mention major topical anti-fungal drugs? (2)

AZOLES

Imidazoles Triazole

(Systemic) Topical Systemic

Clotrimazole,

Miconazole

Econazole

Ketoconazole Itraconazole

Fluconazole

Antibiotics Polyene antibiotics Heterocyclic benzofuran

Amphotericin B, (AMB)

Nystatin,

Hamycin

Natamycin

Griseofulvin

Antimetabolites 5-Fluorocytosine (5-FC)

Allylamine Terbinafine

Other topical

agents

Tolnaftate, Benzoic acid, Sod. Thiosulfate.Undecylenic acid, Quiniodochlor, Ciclopirox

olamine,

SAEID KASHEFI

55) MOA and uses of Amphetamine B and Mebendazole? (2)

MOA Drug interaction Uses

Amphotericin B

In fungi: Ergosterol in membranes:

higher affinity than mammalian

cholesterol for AMB

Ergosterol: Only present in fungal

cell membrane and not in animal

cell

Ergosterol: Polyenes combine

with it, get inserted into the

membrane and several molecules

together orient themselves and

form a micropore.

The hydrophilic side forms the

interior of the pore through which

ions, amino acids and other water

soluble substances move out

(leakage of cell contents)

The micropore is stabilized by

membrane sterols which fill up the

spaces b/n the AMB on the

lipophilic side

Alters cell permeability selectively

to K+ and Mg2+.

Synergism with:

Flucytosine

Rifampicin

Enhanced renal

toxicity:

Aminoglycosides

IV: Serious systemic

fungal infections

Topically for oral,

vaginal & cutaneous

candidiasis

Leishmaniasis: Reserve

drug for Kala azar

The drug of choice for:

Cryptococcal meningitis

Mucormycosis

(zygomycosis)

Invasive fungal infection,

not responding to other

therapy

Adverse effect

Acute: Infusion-related

Chills, fever, dyspnea,

nausea, vomiting,

bronchospasm,

hypotension,

convulsions

Chronic

Nephrotoxicity

azotemia, impaired

concentration, impaired

urinary acidification, K &

Mg wasting with

hypokalemia and

hypomagnesemia

Normochromic,

normocytic anemia,

↓ erythropoietin

Mebendazole

A broad spectrum anthelmintic.

It is poorly absorbed when given

orally.

It acts by binding to and interfering

with the synthesis of the parasite‘s

microtubules and by decreasing

the glucose uptake.

Affected parasites are expelled

with faces.

It is relatively free of toxic effects.

It is contraindicated in pregnancy,

because of its embroyotoxic and

teratogenic effects.

Cestodes (Tapeworms)

Nematodes

SAEID KASHEFI

56) Brief note on ketoconazole? (4)

In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for the conversion of

lanosterol to ergosterol

Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol

Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in

mucosal infections only

Pharmacokinetics

Variable oral absorption, dependent on pH (often given with cola or fruit juice)

T1/2 7-10 hours

Protein binding > 99%

Hepatic, bile and kidney elimination

H2 blockers, antacids--- decrease absorption

Hepatoxicity (2-8%), increase in transaminases, hepatitis

Dose related inhibition of CYP P450 responsible for testosterone synthesis

Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

Ketoconazole –Drug interactions

Hepatic enzyme inhibitors

Ketoconazole + Sulfonylureas

Ketoconazole + Phenytoin

Ketoconazole + Warfarin

Ketoconazole + Cyclosporine

Increase plasma levels

SAEID KASHEFI

57) Consequents of co-administration of ketoconazole and cisapride? (2)

The dangerous interaction with terfenadine, astemizole and cisapride resulting in polymorphic ventricular

tachycardia due to excessive rise in plasma levels of these drugs has resulted in withdrawal of these drugs from

the market in many countries.

SAEID KASHEFI

Anti-protozoal Anti-amebiosis

Anti-malaria

SAEID KASHEFI

58) Why is diloxanide furoate combined with tinidazole for amoebiasis? (2)

59) A course of Metronidazole treatment is often followed by treatment with Diloxanide. Give

reason? (2)

Diloxanide furoate

It is a highly effective luminal amoebicide: directly kills trophozoites responsible for production of cysts.

The furoate ester is hydrolyzed in intestine and the released diloxanide is largely absorbed.

Diloxanide is a weaker amoebicide than its furoate ester

No systemic antiamebic activity is evident despite its absorption.

Diloxanide furoate exerts no antibacterial action.

It is less effective in invasive amoebic dysentery, because of poor tissue amoebicidal action.

Side effects are flatulence, occasional nausea, itching and rarely urticaria. It is the drug of choice for mild

intestinal,/asymptomatic amoebiasis, and is given after any tissue amoebicide to eradicate cysts.

Combined use with metronidazole/ tinidazole is quite popular.

60) Adverse effects and uses of emetine? (2)

Adverse effect Uses

Emetine and

Dehydroemetine

Emetine is an alkaloid, DHE-

semisynthetic

They are irritant, bitter in taste and nauseating---- Emetine cannot be given orally because it will be emitted out It is administered by s.c. or i.m injection: only i.m route

Kill tissue trophozoites and

have no effect on cysts

DHE is less toxic than

emetine

60 mg once daily for 5 days

Emesis (vomiting)-due to

the stimulation of CTZ

Muscle weakness and

stiffness

ECG changes- T-wave

inversion and prolongation

of PR interval

Tachycardia, hypotension

and cardiac arrhythmias

Itching and skin rashes

Nausea

Eczematoid lesions may

occur at the injection site

Tissue amoebicides

A) Intestinal and

Extraintestinal

Ameoebicides

Because of the drawbacks, emetine is now seldom used as a reserve drug in severe intestinal or extraintestinal amoebiasis, or for patients not responding to or not tolerating metronidazole

SAEID KASHEFI

61) Why should you abstain from alcohol during treatment with metronidazole? (2)

Interactions: A disulfiram-like intolerance to alcohol occurs in some patients taking metronidazole; they

should be instructed to avoid drinking.

Enzyme inducers (phenobarbitone, rifampin) may reduce its therapeutic effect.

Cimetidine can reduce metronidazole metabolism: its dose may need to be decreased.

Metronidazole enhances warfarin action by inhibiting its metabolism. It can decrease renal elimination of

lithium.

SAEID KASHEFI

Malaria

SAEID KASHEFI

62) Classify antimalarials with examples? (4)

4-Aminoquinoline

Chloroquine Amodiaquine

Active against all plasmodial species except p.falciparum Does not have effect on pre and exoerythrocytic phase –not given as

radical cure 1. Chloroquine is uncharged at neutral pH and hence diffuses freely into the parasite lysosome. 2. At the acidic pH of the lysosome, it is converted to a protonated membrane impermeable form, and is trapped inside the parasite. 3. Being a weak base, it gets concentrated in the acidic food vacuole of parasite, increases its pH and causes rapid clumping of pigment. 4. Chloroquine inhibits plasmodial heme polymerase (which converts toxic heme into nontoxic hemozoin) and forms toxic drug heme complex which damages the parasite

Quinoline-methanol

Mefloquine Mefloquine acts on the erythrocytic stage of the parasite. It forms toxic complex that damages membrane. It is given orally as it causes severe local irritation. Adverse effects: neuropsychiatric disturbances, visual and auditory

disturbances, teratogenicity and allergic reactions. Mefloquine is contraindicated in epilepsy, children below 2 years and

pregnancy. Is used as an alternate agent for multidrug resistant malaria. In addition, it is preferred for chemoprophylaxis of malaria.

Cinchona alkaloid

Quinine Quinine is highly effective against all the four species of plasmodium but not active for liver hypnozoite and sporozoite.

It has irritant action and causes myocardial depression MOA- like chloroquine

Biguanides

Proguanil Proguanil is a slow acting erythrocytic schizonticide Proguanil's antimalarial action is due to its conversion into the active

metabolite, cycloguanil. Cycloguanil inhibits plasmodial dihydrofolate reductase. Thus, proguanil inhibits tetrahydrofolate synthesis.

Diamino-pyrimidines

Pyrimethamine A diamino-pyrimidine that acts slowly on the erythrocytic forms of the parasite and inhibits plasmodial dihydrofolate reductase.

It is used as a slow acting agent.

With sulfadoxine, used in the acute attack of chloroquine resistant malaria Used in the chemoprophylaxis of malaria.

8-Aminoquinoline

Primaquine, Bulaquine

Primaquine is effective against vivax (hypnozoites), pre-erythrocytic and sexual forms of all species

It is converted into electrophiles, which act as oxidation reduction mediators and generate reactive oxygen species or interfere with the electron transport chain of parasite.

Sulfonamides and Sulfone

Sulfadoxine Dapsone

Tetracyclines Tetracycline Doxycycline

Tetracycline is Weak erythrocytic schizontocide Use: with quinine or Pyrimethamine+sulfonamide for treatment of

Chloroquine resistant malaria

Sesquiterpine lactones (Artemisinin derivatives)

Artesunate Artemether Artemether

Artemisinin: active principle form Artemisia annua Prodrug----dihydroartemisin Active against P. falciparum Potent and rapidly acting erythrocytic schizontocide

Mannich Base Pyronaridine

Phenanthrene Halofantrine

Napthoquinone Atovaquone

SAEID KASHEFI

63) Neat labeled diagram of life cycle of malaria parasite, explain its various stages and drugs

affecting them. MOA of quinine and adverse effects? (6+4+2)

Life cycle of the Malarial Parasite

1) Pre- or exoerythrocytic cycle in liver

2) Erythrocytic cycle in blood

3) Sporozoite

4) Merozoite

5) Trophozoite

6) Schizont

7) Gametocytes

(M-microgamatocytes, F-macrogamatocytes)

8) Hypnozoite

9) Haemozoin-malarial pigment

SMTSGHH

SAEID KASHEFI

Against

Pre-erythrocytic

schizogony

Against

Exo-erythrocytic

schizogony (V)

Against

Erythrocytic

schizogony

Against

Gametes

Proguanil (F + V)

Primaquine (F + V)

Tetracyclines (F)

Pyrimethamine

Primaquine

Chloroquine

Pyrimethamine

Primaquine

Quinine

Proguanil

Mefloquine

Mepacrine

Sulfonamides

Tetracyclines

Artemisinin

Halofantrine

Atovaquone

Chloroquine (V)

Mepacrine (V)

Quinine (V)

Primaquine (F + V)

Artemisinin (F + V)

Proguanil (F + V)*

Pyrimethamine (F + V)*

SAEID KASHEFI

64) Mechanism and uses of chloroquine? (4)

MOA:

1. Chloroquine is uncharged at neutral pH and hence diffuses freely into the parasite lysosome.

2. At the acidic pH of the lysosome, it is converted to a protonated membrane impermeable form, and is trapped

inside the parasite.

3. Being a weak base, it gets concentrated in the acidic food vacuole of parasite, increases its pH and causes

rapid clumping of pigment.

4. Chloroquine inhibits plasmodial heme polymerase (which converts toxic heme into nontoxic hemozoin) and

forms toxic drug heme complex which damages the parasite

Adverse effects Contraindications Pharmacogenetics

Variation in Drug

response due to

enzyme deficiency

Uses

Safe drug - proper doses

CVS and CNS:

hypotension,

vasodilatation,

suppression of

myocardial function,

cardiac arrhythmia and

eventual cardiac arrest.

GI Intolerance,

headache, blurring of

vision,

High doses- leads to

irreversible retinopathy,

ototoxicity, toxic

myopathy, cardiopathy

and peripheral

neuropathy

Used cautiously in patients

with severe neurological,

gastrointestinal and blood

disorders

Not recommended for

patients with epilepsy,

myasthenia gravis and

glucose-6-phosphate

deficiency.

Not recommended for

patients with psoriasis and

other exfoliative skin

conditions.

Glucose -6-phosphate

dehydrogenase deficiency

American Blacks,

Mediterranes Jews, Middle

East and South East races

– deficient in G6PD

Responsible for supply of

NADP ---acts as cofactor

for glutathion reductase

NADP---oxidised

glutathion to reduced

gutathion-------convertes

Fe+++ to Fe++ in

hemoglobin---also stability

to RBC

Oxidising drugs

Primaquine, Sulfone,

nitrofurantoin----hemolytic

anaemia

Resistant strain is

suspected if the

patient does not

respond during the

second day of

treatment.

Malaria

Ameoebiasis-hepatic

Lepra reactions

A

R

Infectious

mononucleosis

Autoimmune disorder-

discoid lupus

erythematous (DLE)

SAEID KASHEFI

Quinine

Quinine is the alkaloid derived from the bark of Cinchona tree.

It is a traditional remedy for malaria since 1820

Quinidine, the dextrorotatory stereo-isomer of quinine, is as effective as quinine for falciparum malaria

Quinine is highly effective against all the four species of plasmodium but not active for liver hypnozoite and

sporozoite.

It has irritant action and causes myocardial depression

MOA- like chloroquine

Adverse effects

Cinchonism- Swetting, tinnitus, blurred vision, diarrhea, and cardiac arrhythmias.-high plasma level

Dizziness, headache and nausea.

Quinine causes insulin release from ß cells leading to hypoglycemia

Black water fever includes marked hemolysis, hemoglobinemia and hemoglobinuria in the settings of

therapy for malaria.

65) Rationale for the use of primaquine in vivax malaria? (2)

It is effective against vivax (hypnozoites), pre-erythrocytic and sexual forms of all species

Is a causal prophylactic for all species of malaria, but has not been used in mass programmes, because of its

toxic potential.

Primaquine and Artemisinin are gametocidal to all species of Plasmodia, while chloroquine and quinine are

active against vivax but not falciparum gametes.

Primaquine differs from all other available antimalarials in having a marked effect on primary as well as

secondary tissue phases of the malarial parasite. It is highly active against gametocytes and hypnozoite.

SAEID KASHEFI

66) MOA and adverse effects of primaquine? (6)

Radical cure and terminal prophylaxis of infections with P.vivax and P.ovale


MOA:

It is converted into electrophiles, which act as oxidation reduction mediators and generate reactive oxygen

species or interfere with the electron transport chain of parasite.


Radical Cure:

Drugs active against Exo/Hypnozoites

Aims to achieve complete eradication of parasite

Needed in vivax (relapsing malaria)

Primaquine 15mg/day for 2 weeks

(Primaquine 45mg+Chloroquine 300mg)/week for 8 weeks

SAEID KASHEFI

Anthelmintics

SAEID KASHEFI

67) Classify the anthelmintics?

68) MOA of pyrantel pamoate and niclosamide and uses? (2)

drugs


(Tape: beef, pork,

fish, dwarf worm)

Mebendazole

Niclosamide

Chloroquine

Praziquantel

Cestodes have a flat, segmented body and they attach to the

host‘s intestine.

They lack a mouth and a digestive tract through their life

cycle.

Infestation by tapeworms or cestodes is transmitted by

ingestion of infected beef or pork.

So thorough cooking

Nematodes (Round Worms)

(Round: hook, whip, thread, pin, filaria, guinea worms)

Mebendazole

Piperazine

Pyrantel Pamoate

Levamisole

Albendazole

Ascariasis is the infection of the intestinal tract by the roundworm.

Symptoms: nausea, abdominal pain and cough. Live worms are passed through stool or vomit.

Nematodes are transmitted through the faecal – oral route, or by fingers contaminated by soil seeded with the eggs of the round worm.

Trematodes (flukes: blood, lungs, intestinal)

praziquantel

SAEID KASHEFI

Mechanism of action Uses

Mebendazole


It is poorly absorbed when given orally.

It acts by binding to and interfering with the synthesis of the parasite‘s

microtubules and by decreasing the glucose uptake.

Affected parasites are expelled with faeces.


It is contraindicated in pregnancy, because of its embroyotoxic and

teratogenic effects.


Nematodes

Niclosamide

Vermicidal drug for all varieties of taeniasis.

Inhibits anaerobic phosphorylation of ADP of the parasite

To prevent digestion of segments and liberation of ova, it is mandatory to use a purge within 1-2 hours after the drug is administered.


praziquantel

Causes strong muscular contractions, thereby forcing the worm to detach from the wall of the vein.

Rapidly absorbed orally Excreted within 24 hours. Adverse effects : anorexia, drowsiness and allergic reactions

Tapeworm

Pyrantel

pamoate

acts as a depolarizing neuromuscular blocking agent, causing persistent activation of nicotinic receptors

Which leads to spastic paralysis of the worms

The adverse effects of the drug are mild

Nematodes (Round

Worms)

Piperazine

Piperazine competitively blocks the acetylcholine-produced

contractions of the ascaris muscle.

This leads to flaccid paralysis of the worms, due to which they are easily

expelled out by intestinal peristaltic movements.

The drug has a wide margin of safety

Adverse reactions: diarrhoea and urticaria.

Nematodes

Levamisole

causes sustained contracture of somatic muscles of the worm by

an irreversible,

non-competitive,

depolarization type of neuromuscular block

resulting in paralysis of the worm

Nematodes

SAEID KASHEFI

69) What is DEC? How is it useful in filariasis? (2)

Drug Therapy of Filariasis

Filarial infections are caused by tissue dwelling filarial nematodes, which are transmitted by the bites of

insects such as mosquito, blackfly and being fly.

Drugs for filarial infection:

Diethylcarbamazine citrate (DEC) Ivermectin

Diethylcarbamazine

Has a highly selective effect on microfilariae (Mf).

Leads to the rapid disappearance of microfilariae of Wuchereria bancrofti, Brugia malayi and

loa loa from the human peripheral blood.

Diethylcarbamazine sensitizes the microfilaria and entraps them in the reticuloendothelial system.

Thereby, it enhances phagocytosis and killing of the microfilaria.

Diethylcarbamazine also enhances cell mediated immunity of human hosts and thus their resistance to the

infestation.

Diethylcarbamazine is rapidly adsorbed from the gastrointestinal tract.

The products are eliminated within 30 hours.

Diethylcarbamazine causes fever, lymphadenopathy, muscular pain, tachycardia and skin rashes.

It also causes allergic reactions, which are sometimes severe.

Hence, it is recommended to start therapy with a small dose and then increase it gradually.

70) MOA of Mebendazole. List its uses and adverse effects? (4)


It is poorly absorbed when given orally.

MOA:

It acts by binding to and interfering with the synthesis of the parasite‘s microtubules and by decreasing the glucose uptake.

Affected parasites are expelled with faeces.

Uses:

Nematodes (Round Worms)

Adverse effect:


It is contraindicated in pregnancy, because of its embroyotoxic and teratogenic effects.

71) Write briefly on Albendazole as anthelmintic? (2)

Is effective against many common intestinal worms in a single dose.

The drug is well tolerated

Albendazole and thiabendazole are effective in treating larva migrans.

SAEID KASHEFI

Anticancer

SAEID KASHEFI

72) Classify anticancer drugs based on MOA short note on their adverse effects? (6+4)

73) Adverse effects of anti-cancer drugs? (5)

A. Drugs acting directly on cells (Cytotoxic drugs)

Alkylating agents

Nitrogen-mustards

Cyclophosphamide Chlorambucil Mechlorethamine (MustineHCl) Ifosfamide Melphalan

Ethylenimine Thio-TEPA

Alkyl-sulfonate Busulfan

Nitrosoureas Carmustine (BCNU) Lomustine(CCNU)

Triazine Triazine Dacarbazine (DTIC)

Platinum-containing drugs

Cisplatin Carboplatin

Antimetabolites

Folate antagonist Methotrexate (Mtx)

Purine antagonist 6-MercaPtoPurine (5-MP) 6-Thioguanine (6-TG) Azathioprine Fludarabine

Pyrimidine antagonist S-Fluorouracil (5-FU) Cytarabine

Natural products

Vinca alkaloids Vincristine (Oncovin) Vinblastine

Taxanes Paclitaxel, Docetaxel

Epipodophyllotoxin

Etoposide

Camptothecin analogues

Topotecan Irinotecan

Antibiotics

Actinomycin D (Dactinomycin) Doxorubicin Daunorubicin (Rubidomycin) Mitoxantrone Bleomycin,

Mitomycin C

Miscellaneous

Hydroxyurea Procarbazine L-Asparaginase Imatinib

SAEID KASHEFI

B. Drugs altering hormonal milieu

Glucocorticoids Prednisolone and others

Estrogens Fosfestrol Ethinylestradiol

Selective estrogen receptor modulators Tamoxifen Toremifene

Selective estrogen receptor down regulators Fulvestrant

Aromatase inhibitors

Anastrozole Exemestane Letrozole

Antiandrogen Flutamide Bicalutamide

5-α reductase inhibitor Finasteride Dutasteride

GnRH analogues

Nafarelin Triptorelin

Progestins Hydroxyprogesterone Acetate etc.

GENERAL TOXICITY OF CYTOTOXIC DRUGS Majority of the cytotoxic drugs have more profound effect on rapidly multiplying cells, because the most important

target of action are the nucleic acids and their precursors; rapid nucleic acid synthesis occurs during cell division'

Many cancers (especially large solid tumours) have a lower growth fraction (lower percentage of cells are in

division) than normal bone marrow epithelial linings, reticuloendothelial (RE) system and gonads. These tissues

are particularly affected in a dose-dependent manner by majority of drugs; though, there are differences in

susceptibility to individual members.

1. Bone marrow

Depression of bone marrow results in granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anaemia.

This is the most serious toxicity; often limits the dose that can be employed. Infections and bleeding are the usual

complications.

2. Foetus

Practically all cytotoxic drugs given to pregnant women profoundly damage the developing Foetus abortion,

fetal death, and teratogenesis.

3- Skin

Alopecia occurs due to damage to the cells in hair follicles. Dermatitis is another complication.

4. Gonads

Inhibition of gonadal cells causes oligozoospermia and impotence in males; inhibition of ovulation and

amenorrhoea are common in females.

Damage to the germinal cells may result in mutagenesis.

SAEID KASHEFI

5-Lymphoreticular tissues

Lymphocytopenia and inhibition of lymphocyte function results in suppression of cell mediated as well as humoral

immunity.

Because of action (1) and (2) + damage to epithelial surfaces, the host defence mechanisms (specific as well as

nonspecific) are broken down susceptibility to all infections is increased. Of particular importance are the

opportunistic infections due to low pathogenicity organisms Infections by fungi (Candida and others causing deep

mycosis), viruses (Herpes zoster, cytomegalo virus), Pneumocystis jiroveci (a fungus) and Toxoplasma re seen

primarily in patients treated with anticancer drugs.

6- Oral cavity:

The oral mucosa is particularly susceptible to cytotoxic drugs because of high epithelial cell turnover. Many

chemotherapeutic drugs produce stomatitis as an early manifestation of toxicity. The gums and oral mucosa are

regularly subjected to minor trauma, and breaches are common during chewing. Oral microflora is large and can

be the source of infection. Neutropenia and depression of immunity caused by the drug indirectly increase re

chances of oral infections. Thrombocytopenia may cause bleeding gums. Xerostomia due to the drug may cause

rapid progression of dental caries.

7- GIT

Diarrhoea, shedding of mucosa, hemorrhages occurs due to decrease in the rate of renewal of the mucous lining.

Drugs that frequently cause mucositis are-bleomycin, actinomycin D, daunorubicin, doxorubicin, fluorouracil and

methotrexate.

Nausea and vomiting are prominent with many cytotoxic drugs. This is due to direct stimulation of CTZ by the drug

as well as generation of emetic impulses/mediators from the upper g.i.t. and other areas.

8. Carcinogenicity

Secondary cancers, especially leukemias, lymphomas and Histiocytic tumours appear with greater frequency

many years after the use of cytotoxic drugs. This may be due to depression of cell mediated and humoral blocking

factors against neoplasia.

9. Hyperuricemia

This is secondary to massive cell destruction (uric acid is a product of purine metabolism). Gout and urate stones

in the urinary tract may develop. Allopurinol is protective by decreasing uric acid synthesis. In addition to these

general toxicities, individual drugs may produce specific adverse effects, e.g. neuropathy by vincristine,

cardiomyopathy by doxorubicin, cystitis and alopecia by cyclophosphamide.

SAEID KASHEFI

74) Mechanism of alkylating and their adverse effects? (5)

ALKYLATING AGENTS

These compounds produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular

macromolecules by forming covalent bonds.

The position 7 of guanine residues in DNA is especially susceptible, but other molecular sites are also involved.

Alkylation results in cross linking/abnormal base pairing/ scission of DNA strand. Cross linking of nucleic acids with

proteins can also take place.

Alkylating agents have cytotoxic and radiomimetic (like ionizing radiation) actions. Many are cell cycle non-specific,

i.e. act on dividing as well as resting cells. Some have CNS stimulant and cholinergic properties.

Adverse effect:

1. Depress bone morrow

2. GI disturbance

3. Depression of gametogenesis in male

SAEID KASHEFI

75) Give examples MOA of cyclophosphamide use, adverse effect? (6)

Cyclophosphamide

It is inactive as such: produces few acute effects and is not locally damaging.

It‘s activated in liver by CYP450

Transformation into active metabolites (aldophosphamide, phosphoramide mustard) occurs in the liver, and

a wide range of antitumour actions is exerted.

Uses:

It has prominent immunosuppressant property.

Thus, it is one of the most popular anticancer drugs.

Breast cancer, ovarian cancer, non-Hodgkin's lymphoma, CLL, soft tissue sarcoma, neuroblastoma,

Wilms' tumor, rhabdomyosarcoma

Adverse effect:

It is less damaging to platelets, but alopecia and cystitis (due to another metabolite acrolein) are

prominent. Chloramphenicol retards the metabolism of cyclophosphamide.

76) Use of MESNA in cyclophosphamide toxicity? (2)

Mercapto-ethane-sulfonate (mesna) "traps" acrolein released from cyclophosphamide and thus reduces the

incidence of hemorrhagic cystitis.

SAEID KASHEFI

77) Mechanism of action anti-cancer antibiotics? (4)

Mechanism of action

Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of

RNA, DNA, or both; cause DNA strand scission; and interfere with cell replication.

Drug Mechanism of Action Clinical Applications1 Acute Toxicity

Delayed Toxicity

Mitomycin

Acts as an alkylating agent and forms cross-links with DNA; formation of oxygen free radicals, which target DNA

Superficial bladder cancer, gastric cancer, breast cancer, non-small cell lung cancer, head and neck cancer (in combination with radiotherapy)

Nausea and vomiting

Myelosuppression, mucositis, anorexia and fatigue, hemolytic-uremic syndrome

Antibiotics

Actinomycin D (Dactinomycin) Doxorubicin Daunorubicin (Rubidomycin) Mitoxantrone Bleomycin,

Mitomycin C

basic principle of chemotherapy by saeid kashefi

Education

bacterial cell wall

cell wall structure

cell wall development

saeid kashefi page

subunit of bacterial

quinolonesblock dna

necessary cell compound

s subunit