Chemotherapy Of

8/2/2019 Chemotherapy Of

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CHEMOTHERAPY OF

HELMINTHIC INFECTIONS

Dwi Indria Anggraini

Medical School Lampung University


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Chemotherapy of Helminthic Infections

Chemotherapyof Nematodes

Mebendazole

Pyrantel Pamoat

Thiabendazole

Diethylcarmabazine

Chemotherapyof Trematodes

Praziquantel

Chemotherapyof Cestodes

Niclosamide


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I. Chemotherapy of Nematodes

Elongated roundworms that possess a completedigestive system, including both a mouth and ananus.

Cause infections of the intestine, the blood, andtissue

Whipworm (Trichuris trichiura), Pinworm(Enterebius vermicularis), Hookworm (Necatoramericanus, Ancylostoma duodenale)


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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


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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)


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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)


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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 itspotential toxicity. Though nearly insoluble in

water, thiabendazole is readily absorbed on

oral administration.


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Thiabendazole

Affects microtubular aggregation

Adverse effect:

dizzines, anorexia, nausea, vomitting, have beenreports of CNS symptomatology, eryhema

multiforme and Stevens Johnson Syndrom


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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


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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)


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Characteristics

and therapy for

commonly

encountered

nematodeinfections


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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


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Lifes Cycle of Trematodes


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PRAZIQUANTEL

DOC of ALL FORMS OF SCHISTOSOMIASIS

Another : Taeniasis, H. nana,Neurocysticercosis

MOA : permeability of the cell membraneto Calcium is increased, causingcontracture & paralysis of the parasite

Rapidly absorbed after oral adm Distributes into the CSF


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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


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III. Chemotherapy of Cestodes

Cestodes or true tapeworms, typically have a

flat, segmented body and attach to the hosts

intestine

DOC = NICLOSAMIDE


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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


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


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The intestine infected by Cestodes


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SULFONAMIDES, TRIMETHOPRIMAND QUINOLONES

Inhibitor of Nucleic Acid Synthesis


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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


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Overview

synthesis needs enzymes

to separate supercoil: DNA gyrase (topoisomerase II)

to replicate DNA: DNA polymerase

quinolones

rifampicin


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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


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SULFONAMIDES & TRIMETHOPRIM


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a. Inhibitors of folate synthesis (= SULFONAMIDES)

Sulfacetamideeyes 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


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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 (sulfa-

diazine, pyrimethamine)


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Random mutations

Plasmids

Irreversible

Mechanism:

a. Altered enzyme ( affinity to sulfa)

b. uptake of sulfac. PABA synthesis (overcome inhibition

enzymes by sulfa)


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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


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Inhibitor of dihydrofolate reductase (folate 4-h-folate)

So..inhibit growth (bacteriostatic)

More potent than sulfamethoxazole


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= 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


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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


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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


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QUINOLONES


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Enter the cells through porins

Bind to enzyme AND DNA

Inhibit action of topoisomerase II (a DNA gyrase)

So, supercoil in DNA cant be opencant be transcript and

there will be a cleavage of the DNA cell death


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A: well absorbed p.o

Al, Mg, Fe, Zn /antacida/sucralfate inhibit absorption

D: well distributed (to joint, sof tissue, lung, etc)

Concentrated in phagocyte

Not cross BBB

M: hepatic (CYP-450)

E: through kidney


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Bactericid

Broad spectrum Gram (+) and (-)

Indication:

Complicated UTI

Respiratory Tract Infection

STI (GO)

Soft tissue, bone, skin infection

TB infection (second line drug)


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Chromosom mutations

Spreading through plasmid

Cross-resistance among quinolones

How?

Altered target (enzyme) affinity

porins and efflux


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GI problem (nausea, vomit, diarrhea)

CNS disturbance (headache, dizziness, lightheadedness)

!! Epilepsy

Nephrotoxic, photosensitivity

Quinolone: CYP inhibitor

plasma conc. of some drugs (theophylin)

Quinolone is metabolised by CYP

Cimetidine will plasma conc. of quinolones


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Pregnancy and lactation

Children < 18 y-o

Renal insufficiency


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INHIBITOR OF CELL WALLSYNTHESIS

Dwi Indria Anggraini1, Rovina Ruslami2

1Dept. Pharmacology Faculty of Medicine, Lampung University;2Dept. Pharmacology Faculty of Medicine, Padjajaran University


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Overview


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INHIBITOR OF CELL WALL SYNTHESIS


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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


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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


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Beta Lactam ( = BL ) AM:

- Penicillins

- Cephalosporins

- Carbapenems

- Monobactams

Others Glycopeptides

Inhibitor of cell wall synthesis


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Thiazolidine ring

B-lactam ring


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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


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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


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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


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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 penicillin5. Penicillin + AMG

> has synergitic effect

Broader spectra


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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 drugD cant reach P-BP

c. Altered P-BP


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1. A to gastric acid and severity of infections

p.o, iv, im, i.t, depot (PP-G, BP-G)

Empty stomach (ampi), amox ()

2. D:

Cross PBB BUT non-teratogenic

Do not Cross BBB Except in inflammed meningens

3. M & E

Through kidney (tubular secretion)


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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, etc3. Empirical, emerge of drug resistance !!


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Cephalosporins


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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(-)


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1st 2nd 3rd 4th

Cephadroxil

Cephalexin

Cephazolin

Cefuroxime

Cefoxitin

Cefotaxime

Ceftazidime

Ceftriaxone

Cefepime

Cefoperazone

Cefepime

better activity against gr (+) improved activity against gr (+)

more resistant to B-lactamase

Cephalosporins


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Cephalosporins


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1. A most of all must be given iv (poor oral absorption)

p.o: cefalexin, cefuroxime

2. D:

Cross BBB for 3rd generation

3. M & E

Through kidney (tubular secretion)

Ceftriaxone & cefoperazone bile

Cephalosporins

Other B lactam AM


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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


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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


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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



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Very toxic for systemic

So..only to topical application

Effective for gram (+) m.o


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Basic Principles

of Antimicrobial Therapy

Dwi Indria Anggraini1, Rovina Ruslami2

1Dept. Pharmacology Faculty of Medicine, Lampung University2Dept. Pharmacology Faculty of Medicine, Padjajaran University


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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


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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/inhibitthe growth of other microorganism (m.o)

= antimicrobial


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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


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Biochemical reactions as potential targets


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Biochemical reactions as potential targets

Class I: poor targets

Folate synthesis inhibited by sulfonamides

Folate utilisation inhibited by folate antagonist

Pyrimidine & purine analogues produce fraudulentnucleotides

Class II: better targets

Peptidoglycan synthesis B-lactam

Protein synthesis work though tRNA (T-S); mRNA (AMG)

Nucleic acid synthesis work though DNA (quinolon,rifampicin)

Class III: important targets

Formed structure of the cell


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Formed structure of the cell

Amphotericine, azole (antifungal)Plasma membrane

affected by:

Anticancer, antihelminthicsMicrotubule function

disrupted by:

Antihelminthics increase Cl- permeability

Pyrantel (antihelminthics) causingparalysis

Muscle fibres affectedby:

R i AB


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Resistance to AB

a. Nature of m.o (exp: gr (-) m.o areresistant to vancomycin)

b. Acquired resistance

Spontaneous mutation

Selection

If with max doseof AM (toleratedby the host)the growth of

m.o is not halted.

inappropriate use of the drugsWhy its happen?

R i t t AB


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Can be spread

From person

person (bybacteria)

From bacteriabacteria (byplasmid)

From plasmidplasmid (bytransposons)

Plasmid:extrachromosomal

genetic element

Can replicate

independently, Can carry genes

coding forresistance to AB

Transposons:stretches of DNA

can be transported

from palsmid -another

Also from plasmidto chromosom &v.v

Resistance to AB

Resistance to AB: mechanism?


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Resistance to AB: mechanism?

Altered expression of proteins in DR-organismModification of target sites

MRSA, quinolon resistance

Decreased accumulation

Decrease permeability OR increaseEfflux system that pump out thedrug

Enzymatic inactivation

B-lactamase

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


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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?


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How to select AM?

Identity of m.o

and itssensitivity to AM

Where is site ofinfection?

How is the safetyof AM well use?

Any patientsfactors?

Availability?

What about costof th/?

We need information about:

However


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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 E i i th


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I. Empiric therapy..

For C.I. Ppts cant wait the result ofm.o identification [gram (+) / (-)] and DST

Immunocompromised patientsWhen?

Take the specimen for lab first!!

choose broad spectrum administration: ivHow?

Empiric therapy

C b bi i fReceive culture report


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Strategic for 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 asimipenemcilastatin

If Grampositive

onlyIf Gram

negative only

If mixed

If anaerobic only

pwith sensitivities

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

anaerobic coverage

Cont. gr (-) coverage

Discontinue gr (+) andanaerobic coverage

Cont. anaerobic coverage

Discontinue gr (+) & (-)coverage

Continue therapy

as initiated

II Pay attention to specific cond related to PK


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II. Pay attention to specific cond related to PK

Renal

dysfunction

Liver

dysfunction

For AM excretedthrough kidney

toxicity adjustthe dosage

orchange the

drugs

Dont give drugs

concentrated/elimi

nated by the liver(macrolides, sulfa)

toxicity


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III Safety and Cost-benefit


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III. Safety and Cost-benefit

Both drugs and patients factors

B-lactam is least toxic compared toother AM

Pts factors: age, co-morbidity

Safety

Consider the efficacy AND the cost

In EMG case: efficacy is the mostimportant!

Feasibility !

Cost-benefit

IV Bacteriostatic vs Bactericidal AM


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IV. Bacteriostatic vs. Bactericidal AM

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

m.o (chloramphenicol)

Bactericidal:

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

Bacteriostatic:

Only stop growth &replication of m.o

So, it limits the spread ofinfection

Wait for immune systemto solve the rest

V Spectrum of AM


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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


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Select if possible only single AMIt prevents:

Superinfections

emerge of drug resistance

Minimize toxicity

the cost

BUT sometimes wee need drug combination

Synergismmore effective (B-lactam + AMG) Wider coverage

VII Complication of AM Therapy


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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


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VIII. Classification of AM


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B-lactams AM (B-lactam ring): 1st, 2nd, 3rd, 4th generation

AMG : AMK, KNM, STREPT

a. Chemical structure

Anti viral

Antifungal

Antibacterial !!!

b. Activity against certain m.o

Inhibitors of metabolism

Inhibitors of cell wall synthesis

h b f h

c. Mechanism of action

Chemotherapy Of

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