ANTIHELMINTHICS

advertisement

By: Samuel Mwaniki

BACKGROUND

 Parasitic worms

 Two broad phyla:

1.Platyhelminthes

 Cestodes

 Trematodes

2.Nematodes

DRUGS

 Classified into

1.

2.

Benzimidazoles : Albendazole, Thiabendazole,

Mebendazole.

Prazinoisoquinolines: Praziquantel.

3.

4.

5.

Organophosphates: Metrifonate.

Piperazines: Piperazine, Diethylcarbamazine.

Others: Pyrantel, Niclosamide, Levamisole,

Ivermectin, Oxamniquine,

BENZIMIDAZOLES

MoA

Various biochemical changes in susceptible nematodes

(both adults and larvae)

 Inhibition of mitochondrial fumarate reductase in

TCA cycle.

 Reduced glucose transport.

 Inhibit microtubule polymerization by binding to beta-tubulin, hence immobilizing parasite and causing slow death.

Selective Toxicity:

 Higher affinity and binding to nematode beta-tubulin compared to human beta-tubulin.

Spectrum of Activity

1.

Thiabendazole

Cutaneous larval migrans (15% cream bd, 5/7)

 S. stercoralis

High GIT toxicity thus replaced by other members.

2. Mebendazole

 GIT nematodes (mixed infections): E. Vermicularis, A.

lumbricoides, T. trichiura, Hookworms.

 Tissue nematodes: T.spiralis

 Hydatid cyst (Albendazole superior)

3. Albendazole

 Mixed infections

 Hydatid cyst; pre- and post surgery

S.stercoralis (Ivermectin and Thiabendazole preferred)

 Neurocysticercosis caused by larva of T.solium. Give glucocorticoids to prevent reaction from death of cysticerci.

 With DEC or Ivermectin to control lymphatic

Filariasis.

Pharmacokinetics

1. Thiabendazole

 Rapidly absorbed from the GIT, metabolized in liver and excreted in urine.

2. Mebendazole

 Only 10% absorbed from GIT, fatty meal increases absorption. Rapidly metabolized and excreted in bile and urine within 24-48 hours.

3. Albendazole

 Erratic absorption from GIT. Metabolised to

Albendazole sulphoxide (active).

Unwanted Effects

 GIT disturbances: N, V and D

 CNS (rare): drowsiness, dizziness, headache

 Allergic reactions (very rare)

PRAZIQUANTEL

MoA

 Cestodes: At low concentrations, causes increased muscular activity followed by contraction and spastic paralysis, hence detachment of the worm from the host’s intestines.

 Trematodes: At high concentrations, causes influx of calcium ions across tegument resulting in damage and exposure of antigens. Host mounts immune response against the parasite.

Clinical Uses

 Cestodes: T.saginata, T.solium, D.latum, H.nana ;10-

20mg/ kg stat, repeat after 7-10 days.

 Liver, lung and intestinal flukes: F.hepatica,

P.westermani, F.buski; 25mg/kg tds, 1 day.

 Blood flukes: Schistosomes; 40-60mg/kg single dose.

 Nematodes not affected.

Pharmacokinetics

 Readily absorbed.

 Extensive 1 st pass metabolism producing inactive hydroxylated metabolites.

 Excreted in urine and bile.

 80% plasma protein bound. Half life of 1-3 hours.

Unwanted Effects:

 Abdominal discomfort

 CNS

 Others (rarely): fever, priritis, urticaria, rashes, arthralgia and myalgia

METRIFONATE

MoA

 An orgnophophate.

 Prodrug; converted to dichlorvos in vivo.

 Potent inhibitor of cholinesterase enzyme resulting in paralysis. Moves from venous plexus to small arteries and finally to lungs where they are encased hence death.

 Ova not affected.

Uses

 S.haematobium: 10mg/kg stat, repeat twice at 2 week intervals.

Pharmacokinetics

 Rapidly absorbed.

 Metabolized non enzymatically at physiological PH.

 Cleared from plasma within 8 hours.

Unwanted Effects:

 GIT disturbances.

 CNS effects.

 Inhibition of host’s cholinesterase enzyme (no significant effects)

 Foetal damage?

CAUTION! – administer with Atropine to prevent organophosphate toxicity in host.

OXAMNIQUINE

MoA

 Causes DNA intercalation.

Selective Toxicity

 Parasite accumulates drug more than host.

Uses:

 S.mansoni: both immature and mature forms affected.

Adult male more than female.

 Sensitivity differs geographically hence wide range of doses. Tropical Africa (30-60 mg/kg in 2 divided doses), S. America ( 15 mg/kg)

Pharmacokinetics

 Well absorbed.

 1 st pass effect in gut and liver – inactive metabolites.

 Excreted in urine.

 Half life of 1-2 hours. Fully eliminated within 10-12 hours.

Unwanted Effects

 GIT

 CNS stimulation – hallucinations, convulsions.

 Allergic manifestations appearing long after treatment

– antigens from dead flukes.

IVERMECTIN

MoA

 Blocks glutamate, GABA and other ligand gated chloride channels in the microfilaria, hence inducing tonic paralysis, immobilization and death .

 Prevents egression of microfilaria from uterus of the female.

Selective Toxicity

 100 fold higher affinity for nematode GABA activity compared to host.

Uses:

 Drug of choice for O.volvulus

 Mass chemotherapy in combination with Albendazole where O.volvulus, W.bancrofti, L.loa infections coexist. Single annual dose for 4-6 years.

 S.stercoralis, A.lumbricoides, T.trichiura,

E.vermicularis

 Scabies

 Head lice

 Cutaneous larval migrans

Pharmacokinetics

 Rapid absorption reaching peak plasma concentrations in 4-5 hours.

 Distributed in liver and adipose tissue.

 Metabolized to inactive metabolites in liver.

 Excreted in bile.

Unwanted Effects:

 Mild Mazzoti like reactions due to antigenic materials released by dead microfilaria – mild (itching); use H1 antagonists, severe (fever, hypotension, headache, myalgia); use glucocorticoids.

 C/I in late stage HAT; compounds CNS depression.

DIETHYLCARBAMAZINE

MoA

 Inhibition of microtubule polymerization and destruction of preformed microtubules.

 Causes release of antigens by microfilaria, hosts mounts immune response hence killing parasite.

 Interferes with parasite’s arachidonate metabolism.

 Rapidly clears microfilaria from blood. No effect on adult worms.

Uses:

 Drug of choice for Filariasis caused by: W.b, L.l, B.m,

B.t

O.v (2 nd choice)

 Cutaneous larval migrans caused by dog and cat hookworms

 Visceral larval migrans caused by dog and cat round worms.

Pharmacokineticss:

 Rapid absorption.

 Disributed in all body tissue s except adipose tissue.

 Partial metabolism in liver.

 Excreted in urine. Cleared from body within 48 hours.

Unwanted Effects:

1.

Drug related

GIT

CNS

2. Antigens released from dead microfilaria (Mazzoti reaction)

 Mild: rash, urticaria

 Severe: intense itching, lymphadenopathy, fever, tachcardia, hypotension, headache, arthralgia.

Management: H1 antagonists, Glucocorticoids.

Discuss the rationale for the widespread use of broad spectrum antihelminthics, giving examples of helminths and drugs used against them.

Download