Dr. Ahmed AL-Arwali

1

د.أحمد العرولي

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

Β- Lactams

Penicillins

Mechanism of Action:

Bacterial Cell Wall inhibition

Natural Penicillins:(Narrow spectrum).

Penicillin G (Benzyl Penicillin):

Dr. Ahmed AL-Arwali

2

د.أحمد العرولي

Activity: against Gram +ve bacteria e.g.: Niesseria, Bacillus anthracis, Treponema

palladium, collstridium prefrings, C. Tetani, Corynebacterium diphtheria…etc.

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. Β-lactamase sensitive.(not effective against β-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.

Dr. Ahmed AL-Arwali

3

د.أحمد العرولي

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.

Β- 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:

Dr. Ahmed AL-Arwali

4

د.أحمد العرولي

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. 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.

2. 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.

Dr. Ahmed AL-Arwali

5

د.أحمد العرولي

3. Amoxicillin:

Same as ampicillin esters.

B-lactmase inhibitors:

They haven’t antibacterial effect or it’s 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 B-

lactamase 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.

Dr. Ahmed AL-Arwali

6

د.أحمد العرولي

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 β-lactam antibiotics produced by Streptomyces organisms,

and they are closely related to the cephalosporins.

Dr. Ahmed AL-Arwali

7

د.أحمد العرولي

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 ß-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.

Dr. Ahmed AL-Arwali

8

د.أحمد العرولي

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 penicillin-

resistant pneumococci. Cefepime combines the gram-positive activity of first-

generation agents with the wider gram-negative spectrum of third-generation

cephalosporins.

Adverse effects : 1. Hypersensitivity reactions, very similar to those seen with penicillin, may

occur, and there may be some cross-sensitivity; about 10% of penicillin-

sensitive individuals will have allergic reactions to cephalosporins.

2. Nephrotoxicity has been reported (especially with cefradine), as has drug-

induced alcohol intolerance.

3. Diarrhoea is common and can be due to C. difficile.

Macrolides Protein Synthesis Inhibitors

Drug Antimicrobial activity Use Route SE Comments

Erythromycin gram positive bacteria., Staphylococci , diphtheria, community O/P anorexia, N,V,D, alternative to penicillins

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 adult dose 0.25-0.5 g qid

Rickettsia, Campylobacter, H pylori, procedures, pertussis,

others, Chlamydia, Mycoplasma peptic ulcer with others

Clarithromycin above + Toxoplasma gondii, M avium, similar oral less GIT SE adult dose 0.25-0.5 g bid

M leprae

Azithromycin 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 no drug interactions

T gondii, H influenzae, N gonorrheae pneumonia, gonorrhea

Spiramycin Toxoplasma gondii toxoplasmosis during oral dose 3 g od for 3 weeks or

pregnancy until delivery

9

Aminoglycosides Protein Synthesis Inhibitors

Drug Antimicrobial activity Use Route SE Comments

Streptomycin Mycobacterium tuberculosis, Enterococci with others for TB, P ototoxicity,

Brucella, Yersinia pestis, Francisella with tetracycline for vestibular toxicity,

tularensis plague, tularemia, nephrotoxicity

and brucellosis

Gentamicin gram positive and gram negative bacteria plus β-lactam for sepsis P/T also for infected burns,

no activity against anaerobes pneumonia, UTI wounds and skin lesions

Amikacin similar but more effective P

Tobramycin similar to gentamicin but more effective interchangeable with P less nephrotoxic than

against pseudomonas gentamicin clinically gentamicin

Neomycin gram positive and gram negative bacteria, infected burns and T/O too toxic for also used for bowel surgery

but not streptococci and pseudomonas wounds parenteral use and hepatic coma

Kanamycin = = T = only topical use

Spectinomycin gram positive and gram negative bacteria penicillin-resistant IM pain, fever, nausea, aminocyclitol antibiotic

gonorrhea nephrotoxicity dose 40 mg/kg ~ 2 g

Paromomycin Entamoeba histolytica oral: luminal amebiasis, O/P abdominal distress, more effective than diloxanide

IM: visceral leishmaniasis diarrhea and cheaper than liposomal

amphotericin

10

Quinolones synthetic antibacterial agents

Drug Activity frequency CU Comments

Ciprofloxacin gram negative > bid UTI, GITI , the most active against

gram positive infections of bones, Pseudomonas

bacteria soft tissues, and aeruginosa

intrabdomen, RTI, DOC for anthrax

tuberculosis, atypical

mycobacterial infections

Gatifloxacin gram positive = od RTI and atypical not available in USA

gram negative 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 no adequate systemic

gram positive concentrations

bacteria, least active

Ofloxacin as ciprofloxacin bid UTI

Nalidixic acid gram negative 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

11

Sulfonamides synthetic antibacterial agents

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 = =

Sulfadiazine slow intermediate 10-17 h = =

Sulfamethoxazole = intermediate 10-12 h = =

Sulfadoxine intermed.long 7-9 days = with pyrimethamine for malaria

Sulfacetamide short 7 h topical eye infection

Sulfapyridine slow intermediate 17 h = dermatitis herpetiformis

DHFA reductase inhibitors ( SE megaloblastic anemia)

Trimethoprim prompt intermediate = UTI, prostatitis

Pyrimethamine slow long 3.5 days = malaria

MOA they inhibit folic acid synthesis by inhibiting dihydropteroate synthase

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

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)

Sulfapyridine + 5 amino salicylic acid (Sulfasalazine): inflammatory bowel disease136