CHEMOTHERAPY OF HELMINTHIC INFECTIONS

Dwi Indria Anggraini Medical School Lampung University

Chemotherapy of Helminthic Infections

Chemotherapy of Nematodes
Mebendazole

Chemotherapy of Trematodes

Chemotherapy of Cestodes

Pyrantel Pamoat
Thiabendazole Diethylcarmabazine

Praziquantel

Niclosamide

I. Chemotherapy of Nematodes
Elongated roundworms that possess a complete digestive system, including both a mouth and an anus. Cause infections of the intestine, the blood, and tissue
Whipworm (Trichuris trichiura), Pinworm (Enterebius vermicularis), Hookworm (Necator americanus, Ancylostoma duodenale)

MEBENDAZOLE
Broad spectrum D.O.C of :
Whipworm (Trichuris trichiura) Pinworm (Enterobius vermicularis) Hookworm (Necator americanus, ancylostoma duodenale) Insoluble in aquous solution (Water insoluble), little of an oral dose is absorbed by the body Free of toxic effects

MEBENDAZOLE
Mechanism of action:
BINDING TO AND INTERFERING WITH THE SYNTHESIS OF THE PARASITES MICROTUBULES AND ALSO BY DECREASING GLUCOSE UPTAKE

Affected parasites are expelled with the faeces S.E : mild GIT upset; abdominal pain & diarrhea C.I : pregnant women (embryotoxic & teratogenic)

PYRANTEL PAMOAT
Effective for: Roundworm (ascariasis), pinworm (E. vermicularis), hookworm (A. duodenale, N. americanus) MOA: RESULT PARALYSIS OF THE WORM (depolarising neuromuscular blocking agent, causing persistent activation of nicotinic rec) Poorly absorbed orally and exerts its effects in the intestinal SE: Mild GIT dissorder (nausea, vomiting, diarrhea)

Thiabendazole
Effective for: strongyloidiasis cutaneus larva migrans and trichinosis. infection of Strongyloides stercoralis Its structural similarity to mebendazole It has more limited usefulness because of its potential toxicity. Though nearly insoluble in water, thiabendazole is readily absorbed on oral administration.

Thiabendazole
Affects microtubular aggregation Adverse effect: dizzines, anorexia, nausea, vomitting, have been reports of CNS symptomatology, eryhema multiforme and Stevens Johnson Syndrom

DIETHYLCARBAMAZINE (DEC)
DOC OF FILARIASIS (caused by Wuchereria bancrofti or Brugia malayi) The organism become immobilized (dying parasites). Their surface membranes then undergo alterations that render them more susceptible to host defense mechanism. The precise MOA : unknown

DIETHYLCARBAMAZINE (DEC)
Rapidly absorbed from the GIT, partially metabolized, excreted in the urine SE : mild The dying parasites cause some reactions (affect the skin: pruritus, wheals, can also be systemic)

Characteristics and therapy for commonly encountered nematode infections

II. Chemotherapy of Trematodes

The trematodes (flukes) are leaf-shaped flatworms that are generally characterized by the tissue they infect. For ex : categorized as liver, lung, intestinal, blood flukes DOC = praziquantel

Lifes Cycle of Trematodes

PRAZIQUANTEL
DOC of ALL FORMS OF SCHISTOSOMIASIS Another : Taeniasis, H. nana, Neurocysticercosis MOA : permeability of the cell membrane to Calcium is increased, causing contracture & paralysis of the parasite Rapidly absorbed after oral adm Distributes into the CSF

PRAZIQUANTEL
High levels occur in the bile The drug is extensively metabolized oxidatively, resulting a short half-life The metabolites are inactive and are excreted through the urine ADR : drowsiness, dizziness, malaise, anorexia, GIT upset C.I : pregnant women or nursing mother

III. Chemotherapy of Cestodes

Cestodes or true tapeworms, typically have a flat, segmented body and attach to the hosts intestine DOC = NICLOSAMIDE

NICLOSAMIDE
DOC of most cestode (tapeworm) infections
Also E. granulosus and E. vermicularis

MOA : inhibit anaerobic phosphorylation of ADP Lethal for scolex & segment, but not for the ova SE : rarely mild GIT upset No risk given to pregnant women or debilitated patient

Lifes Cycle of Cestodes (T. Saginata, T.solium)

The intestine infected by Cestodes

SULFONAMIDES, TRIMETHOPRIM AND QUINOLONES

Inhibitor of Nucleic Acid Synthesis

Overview

NA of the cells are DNA and RNA

RNA (mRNA, tRNA, rRNA) DNA double helix (2 chain of a linear polymer of nucleotides) and supercoil with the core Nucleotide consists of

base (purine (A ,G) and pyrimidine (T, C)

precursor: folate sugar (deoxyribose) + P sulfonamides

Overview

synthesis needs enzymes

to separate supercoil: DNA gyrase (topoisomerase II)
to replicate DNA: DNA polymerase

rifampicin

quinolones

Overview

without FA cell cant growth or divide

sulfa: D acts as inhibitor for FA synthesis

cheap and effective

BUT: D-resistance, allergics Sulfa + trimethoprim co-trimoxazole

SULFONAMIDES & TRIMETHOPRIM

a. Inhibitors of folate synthesis (= SULFONAMIDES)

Sulfacetamide eyes infection

Sulfadiazine skin infection

Sulfasalazine collitis ulcerative, crohns disease (colon inf) Sulfamethoxazole gram (-) enteric rods

b. Inhibitors of folate reduction

Trimethoprim = sulfamethoxazole Pyrimethamine -- toxoplasmosis

c. Both
Co-trimoxazole

 sulfanilamides is a structural analogue of PABA (precursor of FA in bacteria) bacteria has to synthesis FA (but we get it from food)

soonly inhibit growth, NOT to kill (bacteriostatic)

spectrum: enterobacteria, chlamidia, toxoplasma (sulfadiazine, pyrimethamine)

 Random mutations Plasmids Irreversible

Mechanism:
a. Altered enzyme ( affinity to sulfa) b. uptake of sulfa c. PABA synthesis (overcome inhibition enzymes by sulfa)

A : oral , supp (for crohns disease), iv (p.o is not possible), NOT topical (allergic) D: can cross P-BB and B-BB (in non-inflammed condition) M: liver inactive excreted through kidney (crystalluria)

Mild moderate (nausea, vomiting)

Met-Hb-emia cyanosis
Serious SE: hepatitis (Kern icterus in the baby-sulfa displaces bilirubin from albumin), hypersensitivity, BM depression, crystalluria

Inhibitor of dihydrofolate reductase (folate 4-h-folate) So..inhibit growth (bacteriostatic) More potent than sulfamethoxazole

= sulfamethoxazole A: oral , supp (for crohns disease), iv (p.o is not possible) D: can cross P-BB and B-BB (in non-inflammed condition) M: liver inactive excreted through kidney (crystalluria)

Mild moderate (nausea, vomiting)

Anemia megaloblastic

Sulfamethoxazole + trimethoprim Still bacteriostatic, but more potent and wider spectra

UTI (incl. prostate & vaginal infection), RTI

Pneumocystis carinii (in HIV) prophylaxis (high dose) GI inf. (Typhus abdominalis, shigellosis)

Need 2 simultaneous processes to become resistant So, less frequent

A: oral , supp (for crohns disease), iv (severe cases) D: high conc. in lung and kidney M: liver inactive excreted through kidney

Rash, GI upset (nausea, vomit) Anemia megaloblastic DI with warfarin, phenitoin

QUINOLONES

Enter the cells through porins Bind to enzyme AND DNA Inhibit action of topoisomerase II (a DNA gyrase) So, supercoil in DNA cant be open cant be transcript and there will be a cleavage of the DNA cell death

A: well absorbed p.o Al, Mg, Fe, Zn /antacida/sucralfate inhibit absorption Concentrated in phagocyte Not cross BBB D: well distributed (to joint, sof tissue, lung, etc)

M: hepatic (CYP-450)

E: through kidney

Bactericid Broad spectrum Gram (+) and (-) Indication: Complicated UTI Respiratory Tract Infection STI (GO)

Soft tissue, bone, skin infection

TB infection (second line drug)

Chromosom mutations Spreading through plasmid Cross-resistance among quinolones

How?
Altered target (enzyme) affinity porins and efflux

GI problem (nausea, vomit, diarrhea) CNS disturbance (headache, dizziness, lightheadedness) !! Epilepsy Nephrotoxic, photosensitivity

Quinolone: CYP inhibitor

plasma conc. of some drugs (theophylin)

Cimetidine will plasma conc. of quinolones

Quinolone is metabolised by CYP

Pregnancy and lactation Children < 18 y-o Renal insufficiency

INHIBITOR OF CELL WALL SYNTHESIS

Dwi Indria Anggraini1, Rovina Ruslami2 1Dept. Pharmacology Faculty of Medicine, Lampung University; 2Dept. Pharmacology Faculty of Medicine, Padjajaran University

Overview

INHIBITOR OF CELL WALL SYNTHESIS

INTRODUCTION:
M.O is classified as gram (+) or (-) gram staining BUT: not that simple; difference in structure of cell wall Gram (+)
Relatively simple structure 50% peptidoglycan, 40% acidic polymer (highly polar) and 10% protein& polysaccharides

Gram (-)
Much more complex Periplasmic space Peptidoglycan layer Outer membrane Complex polysaccharide

 Periplasmic space
contain enzymes & other component

Peptidoglycan layer
forming 5% of cell wall

Outer membrane
contain protein molecules and lipoprotein that linked to peptidoglycan

Complex polysaccharide

in different strains, determine antigenicity of m.o endotoxins inflamm reactions, fever, etc porins hydrophylic A.M can move freely

 Difficulty to penetrate complex outer layer

reasons why some A.M are less effective against gram (-) m.o than against gram (+)

LPS of cell wall is a major barrier to penetration for:

penicillin G methicillin vancomycin rifampicin

Inhibitor of cell wall synthesis

Beta Lactam ( = BL ) AM:

- Penicillins - Cephalosporins - Carbapenems - Monobactams Others Glycopeptides

Thiazolidine ring

B-lactam ring

B-lactam ring Thiazolidine ring

B-lactam ring Thiazolidine ring susbtituent are added in R1, 2 or 3

B-lactam ring only

B-lactam ring Thiazolidine ring: S was replaced by C

PENICILLIN:
1928: Alexander Flemming Staph + penicillium growth of staph was inhibited

Extraction of the substance

1941: Tested to pts with septicemia 5 days improved well Nowits widely used, very effective BUT..destroyed by B-lactamase & amidase

 inhibit synthesis of cell wall peptidoglycan

bind to P-BP of bacteria inhibit transpeptidase inactivation of an inhibitor autolytic enzymes in cell wall

lysis of bacterium

1. Natural penicillin: Pen-G and Pen-V 2. Anti satph penicillin

> Stable to penicillinase

3. Extended spectrum penicillin

> ampicillin, amoxillin > (+) B-lactamase inhibitor (clavulanic acid or sulbactam)

4. Anti pseudomonas penicillin 5. Penicillin + AMG > has synergitic effect

Broader spectra

1. Natural have no peptidoglycan or cell wall that impermiable to the drugs 2. Acquired (by plasmid) a. Produce B-lactamase destroy the drug b. permeability to drug D cant reach P-BP c. Altered P-BP

1. A to gastric acid and severity of infections 2. D: Cross PBB BUT non-teratogenic Do not Cross BBB Except in inflammed meningens Through kidney (tubular secretion) p.o, iv, im, i.t, depot (PP-G, BP-G) Empty stomach (ampi), amox ()

3. M & E

1. Are given p.o unless severe infection 2. Uses include: Bacterial meningitis

Bone & joint infection

Skin & soft tissue infection URTI, UTI (including GO), Endocarditis, etc 3. Empirical, emerge of drug resistance !!

Cephalosporins
Penicillin Cephalosporin: chemically, m.o.a, & toxicity > stable to B-lactamase broader spectrum of activity

Cephalosporin classification:
4 generation (~ spectrum AM activity) against gr(+) also against gr(-)

1st
Cephadroxil Cephalexin Cephazolin

2nd
Cefuroxime Cefoxitin

3rd
Cefotaxime Ceftazidime Ceftriaxone Cefepime Cefoperazone

4th
Cefepime

better activity against gr (+)

improved activity against gr (+) more resistant to B-lactamase

Cephalosporins

Cephalosporins
1. A most of all must be given iv (poor oral absorption) 2. D: Cross BBB for 3rd generation Through kidney (tubular secretion) 3. M & E p.o: cefalexin, cefuroxime

Ceftriaxone & cefoperazone bile

Other B-lactam AM
Imipenem, meropenem, ertapenem Very broad spectrum (aerobic (gr (+), (-),anaerobic) Resistant to B-lactamase

PK: iv, renal excretions

AEs: nausea, vomit, diarrhea

Other B-lactam AM
Has only B-lactam ring (exp: aztreonam) Narrow spectrum (gr (-) cant for empirical th/ Resistant to B-lactamase

PK: iv and im, renal excretions

AEs: non toxic, little cross-sensitivity allergic (alternative for pts who allergic to penicillin)

Other inhibitor of Cell wall synthesis

A glycopeptide, effective for MRSA BUT now: emerging of resistance to Vancomycin M.O.A: inhibit synthesis of phospholipids

A.M spectrum: serious infection only

Allergic to B-lactam;, AB-associated collitis (p.o)

PK: slow iv ; renal excretion AEs is a serious problem (fever, phlebitis, hearing loss, shock, redman syndrome) slow infusion

Other inhibitor of Cell wall synthesis

Very toxic for systemic So..only to topical application Effective for gram (+) m.o

Basic Principles of Antimicrobial Therapy

Dwi Indria Anggraini1, Rovina Ruslami2 1Dept. Pharmacology Faculty of Medicine, Lampung University 2Dept. Pharmacology Faculty of Medicine, Padjajaran University

Overview
Selective toxicity of antimicrobial (AM)
ability to kill invading m.o without harming hosts cells

Effective treatment in infectious disease

BUT it requires an appropriate concentration to attack the m.o while tolerabled by the host

Terms
Chemotheraphy:
Drugs with selective toxicity against invading parasites (virus, bacteria, protozoa, fungi and helminth)

Antibiotics:
Substances produced by some microorganism (or by pharmaceutical chemists) that kill/inhibit the growth of other microorganism (m.o) = antimicrobial

Molecular basis of chemotherapy

chemotherapeutic drugs should be toxic for invading m.o in the host Selective toxicity depends on biochemical differences between parasite host Biochemical reaction as potential targets : Class I: glucose & other carbon source Class II: energy and class I compound to make amino acid,
nucleotides, etc

Class III: small molecules are built into larger molecules,

e.g. proteins, nucleic acid, peptidoglycan

Biochemical reactions as potential targets

Class I: poor targets Class II: better targets
Folate synthesis inhibited by sulfonamides Folate utilisation inhibited by folate antagonist Pyrimidine & purine analogues produce fraudulent nucleotides

Class III: important targets

Peptidoglycan synthesis B-lactam Protein synthesis work though tRNA (T-S); mRNA (AMG) Nucleic acid synthesis work though DNA (quinolon, rifampicin)

Formed structure of the cell

Plasma membrane affected by:

Amphotericine, azole (antifungal)

Microtubule function disrupted by:

Anticancer, antihelminthics

Antihelminthics increase Cl- permeability Muscle fibres affected Pyrantel (antihelminthics) causing by: paralysis

Resistance to AB
If with max dose of AM (tolerated by the host) the growth of m.o is not halted.
a. Nature of m.o (exp: gr (-) m.o are resistant to vancomycin) b. Acquired resistance Spontaneous mutation Selection

Why its happen?

inappropriate use of the drugs

Resistance to AB
Can be spread
From person person (by bacteria) From bacteria bacteria (by plasmid) From plasmid plasmid (by transposons) Plasmid: extrachromosomal genetic element Can replicate independently, Can carry genes coding for resistance to AB

Transposons: stretches of DNA

can be transported from palsmid another Also from plasmid to chromosom & v.v

Resistance to AB: mechanism?

Genetic alterations DR
Spontaneous mutation of DNA DNA transfer of DR (through plasmid)

Altered expression of proteins in DR-organism

Modification of target sites
MRSA, quinolon resistance

Decreased accumulation
Decrease permeability OR increase Efflux system that pump out the drug

Enzymatic inactivation
B-lactamase

Multidrug Resistance (MDR)

Resistance to commonly used AB
MDR- TB (resistant to >2 anti-TB drugs) Some strains of Staph. &enterococc. (resistant to most all AB)

Lead to serious untreatable infection

How to select AM?

Identity of m.o and its sensitivity to AM

What about cost of th/?

Where is site of infection?

We need information about:

Any patients factors? Availability?

How is the safety of AM well use?

However
Critically ill patient (C.I.P) need immediate AM Empiric therapy
cover infections by both gr (+), (-), &/ anaerob
To prevent worsening the condition To prevent the death

I. Empiric therapy..

When?
How?

For C.I. P pts cant wait the result of m.o identification [gram (+) / (-)] and DST Immunocompromised patients

Take the specimen for lab first!! choose broad spectrum administration: iv

Empiric therapy
Coverage by a combination of antibiotics such as, clindamycin plus gentamicin, effective against gr (), gr (-) and anaerobes, or a single broad spectrum antibiotic, such as imipenem cilastatin

Receive culture report with sensitivities

If mixed If Gram positive only

Cont. gr (+) coverage. discontinue gram (-) & anaerobic coverage

If Gram negative only

Continue therapy as initiated If anaerobic only Cont. anaerobic coverage Discontinue gr (+) & (-) coverage

Cont. gr (-) coverage

Discontinue gr (+) and anaerobic coverage

Strategic for empiric therapy

II. Pay attention to specific cond related to PK

Renal dysfunction Liver dysfunction

For AM excreted through kidney toxicity adjust the dosage orchange the drugs Dont give drugs concentrated/elimi nated by the liver (macrolides, sulfa) toxicity

Pay attention to specific cond related to PK

Poor perfusion

Pregnancy and lactation

Some AM cross placenta & excreted in the breast milk teratogenic or rise problems (toxicity)

Age
Newborn: immaturation of organs function Children: deal with growth process

Exp: diabetic foot with PAD difficult to treat infection

Exp: pyrimetamin (for toxomplasma), AMG

Geriatric pts : alteration organs function

III. Safety and Cost-benefit

Safety
Costbenefit

Both drugs and patients factors B-lactam is least toxic compared to other AM Pts factors: age, co-morbidity

Consider the efficacy AND the cost In EMG case: efficacy is the most important! Feasibility !

IV. Bacteriostatic vs. Bactericidal AM

Bacteriostatic:
Only stop growth & replication of m.o So, it limits the spread of infection Wait for immune system to solve the rest

Bactericidal:
kills the m.o decreases the amount of m.o

BUT, some AM is -statics for certain m.o while its -cidal to another m.o (chloramphenicol)

V. Spectrum of AM
narrow

single/limited group of m.o exp. INH only for m.TB

extended

Gram (+), (-) exp; ampicillin

broad

Not only to gr (+), (-) But also to other m.o Exp. TS, chloramphenicol

VI. Combination of AM
Select if possible only single AM
It prevents: Superinfections emerge of drug resistance Minimize toxicity the cost

BUT sometimes wee need drug combination

Synergism more effective (B-lactam + AMG) Wider coverage

VII. Complication of AM Therapy

1. Hypersensitivity
Ag-Ab complex reaction Mild (urticaria) severe (anaphylaxtic reaction) Exp: penicillin

2. Direct toxicity
Toxic directly to the cellular Related to the plasma conc. Exp: AMG (nepfro & oto-toxicity)

3. Superinfection
Broad spectrum AM alter Normal flora OI

VIII. Classification of AM
a. Chemical structure B-lactams AM (B-lactam ring): 1st, 2nd, 3rd, 4th generation AMG : AMK, KNM, STREPT

b. Activity against certain m.o

Anti viral Antifungal Antibacterial !!! c. Mechanism of action Inhibitors of metabolism Inhibitors of cell wall synthesis Inhibitors of protein synthesis Inhibitors of nucleic acid fct/synthesis