Dr.

Ahmed AL-Arwali

Pharmacology of Chemotherapy
Principles of therapy

Definition of Chemotherapy:
Is the term used to describe the use of drugs that are selectively toxic to invading
micro-organisms while having minimal effects on the host. Also this term used to
embraces the use of drugs that target tumor (cancer).

20th Century definition: (Antibiotic)

Use of synthetic chemicals to destroy infective agents.
Kill or inhibit the growth of micro-organism or cancer.
Toxic for pathogenic organism or cancer cells.

Antibacterial Dugs
- Lactams
Penicillins
Mechanism of Action:
Bacterial Cell Wall inhibition

Natural Penicillins:(Narrow spectrum).

Penicillin G (Benzyl Penicillin):
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Dr. Ahmed AL-Arwali

Activity: against Gram +ve bacteria e.g.: Niesseria, Bacillus anthracis, Treponema
palladium, collstridium prefrings, C. Tetani, Corynebacterium diphtheriaetc.

Clinical Use:
Acute RTI (respiratory tract infection), syphilis, tetanus, diphtheria and anthrax.

Dose:
1-5 million Unit per 6 hours, IV,IMor IV infusion.

Disadvantages of Natural Peicillins:

1.

Short acting duration from 4 to 6 hours.

2.

Acid sensitive (not effective orally).

3.

-lactamase sensitive.(not effective against -lactamase productive

bacteria e.g. staphylococcus strains.

4.

Narrow spectrum(for Gm+ve not Gm-ve) not effective against gram ve e.g.
E.coi, H.infl., H.pylor, shigella and salmonella.

Long acting Penicillins:

They lack No. 1 disadvantage but they have the rest(2,3,4).
They are also natural.
- Procaine penicillin: 600,000 unit per 12-24 hours.
- Fortified procaine penicillin: 100,000 unit of penicillin G + 300,000 unit
of procaine penicillin.(quick onset and longer duration).
- Benzathine Penicillin 1.2 million unit per 1-4 weeks,
o First week the drug level is therapeutic.
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Dr. Ahmed AL-Arwali

o From 2nd week till 4th week the drug level is prophylactic.

Activity:
Same as penicillin G

Clinical use:
Same as penicillin G and bacterial artheritis.

Acid Resistant Penicillins:

Oral Penicillin V ( Phenoxymethyl penicillin)
250,000, 500,000,1000,000 unit per 4-6 hours

Activity:
Same as penicillin G

Clinical Use:
Mild RTI.

- lactamase (Penicillinase) and acid Resistant penicillins:

Oxacillins: they lack 1,2,3 disadvatages but they still narrow spectrum.
- Oxacillin ( parenteral has S.E: hepatitis).
- Cloxacillin, dicloxacillin, flucloxacillin.(flucloxacillin used in bone
and joints infections)
- Nafcillin: parenteral (IV) use in severe staph. Infection, biliary excretion
and may cause neutropenia as side effect.

Activity:
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Dr. Ahmed AL-Arwali

Same Penicillin G + B-lactamase productive species.(staph., strepto. &

pneumococci).

Clinical Use:
RTI.

Broad spectrum Penicillins:

Still have No. 3 disadvatage.

Activity:
Same as Penicilline G and gram ve species e.g. salmonella, shigella, H.Pylori,
HH.Influenza and E.Coli.

Clinical Use:
RTI, UTI & typhoid.
1.

2.

Ampicillin:

Incompletely absorbed orally . that is make it effective in case of

enteritis but also disturb intestinal flora which lead to diarrhea.

Affected by the presence of food.

Pro-Ampicillin(esters of ampicillin):

Pro-drugs so they are inactive, so no effect on intestinal flora &

better absorption than ampicillin(not useful in enteritis).

Not affected by food.

De-esterified (release ampicillin) in gut mucosa & liver.

Pivampicillin, Bacampicillin, Talampicillin, Hetacillin & Epicillin.

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Dr. Ahmed AL-Arwali

3.

Amoxicillin:

Same as ampicillin esters.

B-lactmase inhibitors:
They havent antibacterial effect or its minimal.
They bind to the enzyme, cause irreversible inhibition for the enzyme(suicide
substrate).
Protect B-lactams from the bacteria enzyme of PEPSI(Proteus, E.Coli,
Pseudomonas, Staph. & H.Infleunza).

B-lactamase inhibitor

Combined penicillin

Route.

Clavulanic Acid

Amoxicillin

Oral and parenteral

Sulbactam

Ampicillin

Oral and parenteral

Tazobactam

piperacillin

Parenteral

Extend Spectrum Penicillins( Antipseudomonal):

Broad spectrum + Pseudomonas & proteus (B-lactmase sensitive so we ad Blactamase inhibitors see the previous table-)
1.

Ureido Penicillin:

Mezlocillin, azlocillin & Piperacillin.

We combined this group with gentamycin to give synergetic effect

and to avoid resistance.
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Dr. Ahmed AL-Arwali

They are expensive.

Used for resistant UTI..

Adverse effects of Penicillin:

1.

Allergy that may cause anaphylactic shock.

2.

Jarish-Herxheimer reactions:(allergy at the site of injection)

3.

Diarhea (may cause super infection).

4.

CNS irritation(seizures): long duration use or intra-thecal injection.

5.

Pain, induration and tenderness at the site of injection(benzthine

penicillin).

6.

Skin Rash(Ampicillin).

7.

Bleeding(Carboxy penicillins).

CEPHALOSPORINS AND CEPHAMYCINS

Cephalosporins N and C, which are chemically related to penicillin, and
cephalosporin P, a steroidal antibiotic that resembles fusidic acid, were first
isolated from Cephalosporium fungus.
The cephamycins are -lactam antibiotics produced by Streptomyces organisms,
and they are closely related to the cephalosporins.
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Dr. Ahmed AL-Arwali

They have the same mechanism of action as penicillins (see above).

Clinical uses of the cephalosporins

Cephalosporins are used to treat infections caused by sensitive organisms. As with other
antibiotics, patterns of sensitivity vary geographically, and treatment is often started
empirically. Many different kinds of infection may be treated, including:
o - septicaemia (e.g. cefuroxime, cefotaxime)
o - pneumonia caused by susceptible organisms
o - meningitis (e.g. ceftriaxone, cefotaxime)
o - biliary tract infection
o - urinary tract infection (especially in pregnancy or in patients unresponsive to other
drugs)
o - sinusitis (e.g. cefadroxil).

Antibacterial spectrum
Cephalosporins have been classified as first, second, third, and fourth generation,
based largely on their bacterial susceptibility patterns and resistance to lactamases [Note: Commercially available cephalo sporins are ineffective against
MRSA, L. monocytogenes, Clostri dium difficile, and the enterococci.]

Clinical Uses
First-Generation Drugs
Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup. They
are active against gram-positive cocci, including staphylococci and common
streptococci. Many strains of E coli and K pneumoniae are also sensitive. Clinical
uses include treatment of infections caused by these organisms and surgical
prophylaxis in selected conditions. These drugs have minimal activity against
gram-negative cocci, enterococci, methicillin-resistant staphylococci, and most
gram-negative rods.

Second-Generation Drugs
Drugs in this subgroup usually have slightly less activity against gram-positive
organisms than the first-generation drugs but have an extended gram-negative
coverage. Marked differences in activity occur among the drugs in this subgroup.
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Dr. Ahmed AL-Arwali

Examples of clinical uses include infections caused by the anaerobe Bacteroides

fragilis ( cefotetan, cefoxitin ) and sinus, ear, and respiratory infections caused by
H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor ).

Third-Generation Drugs
Characteristic features of third-generation drugs (eg, ceftazidime,cefoperazone,
cefotaxime ) include increased activity against gram-negative organisms resistant
to other beta-lactam drugs and ability to penetrate the blood-brain barrier (except
cefoperazone and cefixime). Most are active against Providencia,Serratia
marcescens, and beta-lactamase-producing strains of H influenzae and Neisseria;
they are less active against Enterobacter strains that produce extended-spectrum
beta-lactamases. Ceftriaxone and cefotaxime are currently the most active
cephalosporins against penicillin-resistant pneumococci (PRSP strains), but
resistance is reported. Individual drugs also have activity against
Pseudomonas(cefoperazone, ceftazidime) and B fragilis ( ceftizoxime ). Drugs in
this subclass should usually be reserved for treatment of serious infections.
Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in
gonorrhea, are exceptions. Likewise, in acute otitis media, a single injection of
ceftriaxone is usually as effective as a 10-day course of treatment with amoxicillin.

Fourth-Generation Drugs
Cefepime is more resistant to beta-lactamases produced by gram-negative
organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillinresistant pneumococci. Cefepime combines the gram-positive activity of firstgeneration agents with the wider gram-negative spectrum of third-generation
cephalosporins.

Adverse effects :
1.

2.
3.

Hypersensitivity reactions, very similar to those seen with penicillin, may

occur, and there may be some cross-sensitivity; about 10% of penicillinsensitive individuals will have allergic reactions to cephalosporins.
Nephrotoxicity has been reported (especially with cefradine), as has druginduced alcohol intolerance.
Diarrhoea is common and can be due to C. difficile.

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Protein Synthesis Inhibitors

Macrolides

Drug

Antimicrobial activity

Use

Erythromycin

gram positive bacteria., Staphylococci ,

diphtheria, community O/P

anorexia, N,V,D,

Streptococci, Pneumococci,

acquired pneumonia,

cholestatic jaundice, Haemophilus influenzae is

Corynebacteria, gram positive bacteria,

RTI, endocarditis

metabolic inhibition less susceptible,

Neisseria, Bordetella pertussis, Legionella,

prophylaxis in dental

Rickettsia, Campylobacter, H pylori,

procedures, pertussis,

others, Chlamydia, Mycoplasma

peptic ulcer with others

above + Toxoplasma gondii, M avium,

similar

oral

less GIT SE

adult dose 0.25-0.5 g bid

less active against gram positive and more

chlamydial infections,

O/P

far less GIT SE,

adult dose 0.25-0.5 g od

active against Chlamydia, M avium,

community acquired

T gondii, H influenzae, N gonorrheae

pneumonia, gonorrhea

Toxoplasma gondii

toxoplasmosis during

Clarithromycin

Route SE

Comments
alternative to penicillins

adult dose 0.25-0.5 g qid

M leprae
Azithromycin

Spiramycin

pregnancy

no drug interactions

oral

dose 3 g od for 3 weeks or

until delivery

Protein Synthesis Inhibitors

Aminoglycosides

Drug

Antimicrobial activity

Use

Route SE

Comments

Streptomycin

Mycobacterium tuberculosis, Enterococci

with others for TB,

Brucella, Yersinia pestis, Francisella

with tetracycline for

vestibular toxicity,

tularensis

plague, tularemia,

nephrotoxicity

ototoxicity,

and brucellosis
Gentamicin

gram positive and gram negative bacteria

plus -lactam for sepsis P/T

also for infected burns,

no activity against anaerobes

pneumonia, UTI

wounds and skin lesions

Amikacin

similar but more effective

Tobramycin

similar to gentamicin but more effective

interchangeable with

against pseudomonas

gentamicin clinically

gram positive and gram negative bacteria,

infected burns and

but not streptococci and pseudomonas

wounds

Neomycin

Kanamycin

Spectinomycin

Paromomycin

gram positive and gram negative bacteria

Entamoeba histolytica

penicillin-resistant

less nephrotoxic than

gentamicin

T/O

too toxic for

also used for bowel surgery

parenteral use

and hepatic coma

IM

only topical use

pain, fever, nausea, aminocyclitol antibiotic

gonorrhea

nephrotoxicity

dose 40 mg/kg ~ 2 g

oral: luminal amebiasis, O/P

abdominal distress,

more effective than diloxanide

IM: visceral leishmaniasis

diarrhea

and cheaper than liposomal

amphotericin

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Quinolones

synthetic antibacterial agents

Drug

Activity

frequency CU

Comments

Ciprofloxacin

gram negative >

bid

the most active against

UTI, GITI ,

gram positive

infections of bones, Pseudomonas

bacteria

soft tissues, and

aeruginosa

intrabdomen, RTI, DOC for anthrax

tuberculosis, atypical
mycobacterial infections
Gatifloxacin

gram positive =

od

gram negative

RTI and atypical

not available in USA

pneumonia

may cause hypo-

bacteria

or hyperglycemia

Gemifloxacin

od

Levofloxacin

od

also tuberculosis

Lomefloxacin

as ciprofloxacin

od

as ciprofloxacin

Moxifloxacin

as gatifloxacin

od

as gatifloxacin and also has modest activity

tuberculosis

against anaerobic
bacteria
hepatic elimination

Norfloxacin

gram negative and

bid

UTI

gram positive

no adequate systemic
concentrations

bacteria, least active

Ofloxacin

as ciprofloxacin

Nalidixic acid

gram negative

bid

UTI
UTI

no systemic effect

bacteria

MOA

they inhibit DNA replication by inhibiting DNA gyrase & topoisomerase IV

Activity

in addition to above all quinolones except nalidixic acid are active against
mycoplasmas,chlamydiae, Legionella sp., M tuberculosis, M avium

Pharmacokinetics oral absorption in impaired by di- and trivalent cations

Side effects

N,V,D, H, Dizziness, insomnia, rash, arthropathy, tendinitis, impair cartilage

growth

CI

< 18 years, pregnancy

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synthetic antibacterial agents

Sulfonamides
Drug

Onset duration of action

Route Clinical use & comments

Sulfacytine

prompt short

oral

UTI

Sulfisoxazole

short 6 h

Sulfamethazine

short 7 h

Sulfamethizole

short 9 h

Sulfamerazine

short

slow

intermediate 10-17 h

intermediate 10-12 h

with pyrimethamine for malaria

Sulfadiazine
Sulfamethoxazole
Sulfadoxine

intermed.long 7-9 days

Sulfacetamide
Sulfapyridine

short 7 h
slow

intermediate 17 h

topical eye infection

=

dermatitis herpetiformis

DHFA reductase inhibitors ( SE megaloblastic anemia)

Trimethoprim

prompt intermediate

UTI, prostatitis

Pyrimethamine

slow

malaria

MOA

they inhibit folic acid synthesis by inhibiting dihydropteroate synthase

Activity

gram positive and gram negative bacteria, nocardia (gram +ve),

long 3.5 days

Chlamydia trachomatis, Escherichiacoli, klebsiella, salmonella, shigella,

enterobacter, some protozoa, poor activity against anaerobes
Side effects

fever, rash, dermatitis, photosensitivity, N,V,D, crystalluria, hematuria (avoid

by NaHCO3 and fluid intake), anemia in G6PD deficiency, kernicterus in

newborn if taken in late pregnancy, rarely <1% Stevens-Johnson syndrome
CU of Mixed sulfonamides
Sulfamethoxazole + Trimethoprim (cotrimoxazole): Pneumocystis jiroveci , pneumonia, UTII, GITI
shigellosis, salmonellosis, prostatitis, Staphylococcus aureus , pneumococcus,

Haemophilus sp , Moraxella catarrhalis , Klebsiella pneumonia

Sulfadiazine + pyrimethamine: acute toxoplasmosis
Silver Sulfadiazine : topically for prevention of infection of wounds, burns
Sulfadoxine + pyrimethamine (Fansidar): with quinine for resistant malaria
Sulfadiazine + sulfamerazine + sulfamethazine (trisulfapyrimidines): UTI (crystalluria)
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Sulfapyridine + 5 amino salicylic acid (Sulfasalazine): inflammatory bowel disease