Download ANTIHELMINTHICS

By: Samuel Mwaniki
BACKGROUND
 Parasitic worms
 Two broad phyla:
1.Platyhelminthes
 Cestodes
 Trematodes
2.Nematodes
DRUGS
 Classified into
1.
2.
3.
4.
5.
Benzimidazoles : Albendazole, Thiabendazole,
Mebendazole.
Prazinoisoquinolines: Praziquantel.
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 ;1020mg/ 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 1st 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.
 1st 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 (2nd 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.