1 Anthelmintics SCHISTOSOMIASIS Alia Alshanawani Pharmacology Dep, Medical College; KSU.

2 TREMATODES also called as flukes are leaf shaped flat worms characterized by ! tissues they infect as parasite: -Lung / Liver / Intestinal / Blood FLUKES.

3 Schistosomiasis Also known as bilharzia, bilharziosis / snail fever: is a parasitic disease caused by several species of fluke of ! Genus Shistosomiasis. Caused by trematodes: 1.Schistosoma haematobium 2.S. mansoni 3.S. japonicum.

Although it has a low mortality rate, schistosomiasis often is a chronic illness that can damage internal organs &, in children, impair growth & cognitive development. The urinary form of schistosomiasis is associated with increased risks for bladder cancer in adults. Schistosomiasis is the 2 nd most socioeconomically devastating parasitic disease after malaria. 4

5 LIFE CYCLE

6 Schistosomiasis (New world) S. mansoni & S. Japonicum Primary site of infection is GIT. Damage to intestinal wall is caused by hosts inflammatory response to eggs deposited at that site. The eggs also secrete proteolytic enzymes that further damage ! tissue. Diagnosis: eggs in stools. GIT bleeding, diarrhea, Liver damage.

7 Schistosomiasis (old world) S. Haematobium ! primary sites of infection: veins of urinary bladder eggs induce fibrosis, granulomas & haematuria. transmitted by direct skin penetration. Diagnosis: eggs in ! urine / bladder wall.

8 Antischistosomal drugs 1.Praziquantel (all schistosomal diseases) 2. Metrifonate (S. haematobium) 3. Oxamniquine (S. mansoni).

9 Praziquantel a synthetic isoquinoline pyrazine derivative PK: rapid po absorption maximum plasma conc: 1-3 hr. Cross BBB. bound to plasma proteins (80%). undergoes 1 st pass metabolism to inactive metabolite.

10 T 1/2 = hr (increases in liver disease). excreted in urine & bile. Bioavailability: Increased by carbohydrate meal & cimetidine. Reduced by antiepileptics (phenytoin & carbamazepine).

Mechanism of Action of praziquantel increases trematode cell membrane permeability to Ca 2+ : contraction, paralysis, dislodgement & death. 11

Anthelminthic action; praziquantel broad spectrum anthelminthic drug effective in the Tr of schistosome infections of all species & most other trematodes + cestodes (tapeworms) but nematodes (round worms) are unaffected. effective against mature & immature stages of worms. Cure rate is up to 95%. 12

Clinical uses ; praziquantel 1. Schistosomiasis: Drug of choice for all forms For S.Japonicum infections, 20 mg/kg at intervals 4-6 hours for a total of 3 doses. For S.mansoni and S.hamatobium 40 mg /kg in two divided doses. 13

taken after meals. the interval between doses should not be than 6 hr. effective in children & adults. 14

2- Other trematodes infections: Clonorchiasis (liver), & paragonimiasis (lung) 3- Cestodes infections: Taeniasis & diphyllobothriasis ( intestine ) Neurocysticercosis ( albendazole is preferred) Hymenolepis nana Hydatid disease. 15

Adverse reactions of praziquantel : Headache, dizziness, drowsiness. GIT disturbances. Pruritus, urticaria, arthralgia, myalgia. transient elevation of liver enz. Fever, skin rashes, augmented eosinophilia may appear after several days;; release of foreign protein from dying worm. 16

In neurocysticercosis: neurologic abnormalities (headache, mental changes, seizures) increases by inflammation around dying parasite. Rx: used with corticosteroids. 17 Adverse reactions of praziquantel

Contraindication & precautions Ocular cysticercosis for fear of destruction of parasite in eye. Children < 4 years. Pregnancy& nursing mothers. Driving. Activities require alertness & physical coordination (prohibited). Reduce the dose in liver impairment. Patient should be informed not chewing; bitter taste 18

Metrifonate (TRICHLORFON) Organo-phosphate compound PK Rapid po absorption. t 1/2 = 1.5 hr. Nonenzymatic transformed to active metabolite. widely distributed to tissues. Excreted in urine. 19

Pharmacodynamics; Metrifonate produces its effect due to inhibition of cholinesterase, produces depolarizing block of S. haematobium paralyzes the adult worm & their shift from bladder venous plexus to a small arterioles of the lungs, where they are trapped by ! immune system & killed. NOT effective against S. haematobium eggs, only adult worms are killed. 20

Clinical uses; Metrifonate Safe, low cost alternative drug for S. hematobium infections ONLY. A single dose of mg /kg 3 times at 14 days intervals. effective as prophylactic when given monthly to children in a highly endemic area. In mixed infection with S. haematobium & S. mansoni: metrifonate + oxamniquine. 21

Adverse reactions of Metrifonate : Mild cholinergic symptoms: N, V, diarrhea, abdominal pain, B.spasm, headache, sweating, fatigue, weakness, dizziness, & vertigo these start after 30 min & persist up to 12 hr. 22

Contraindications & cautions; Metrifonate Pregnancy. Recent exposure to insecticides / drugs that potentiate cholinesterase inhibition. 23

Oxamniquine Semisynthetic tetra-hydro-quinoline PK: po T 1/2 = 2.5 hr extensively metabolize into inactive metabolites. excreted via kidney. 24

Anthelmintic actions: E ffective against mature & immature stages of S. mansoni ONLY. Its mechanism of action is unknown. It may cause contraction & paralysis of worms; its detachment from the mesentery & shift to the liver where worm may die. Surviving females may return to mesenteric vessels but cease to lay eggs. 25

USES of Oxamniquine Alternative to praziquantel for Tr of all stages of S. mansoni ONLY. Effective in praziquantel resistance. 26

Clinical uses Less effective in children (higher doses) better tolerated with food mg /kg twice for 1 day. In mixed infection with S.H & S.M: metrifonate + oxamniquine. 27

Adverse reactions; Oxamniquine CNS: Dizziness, headache, & drowsiness GIT disturbance Pruritus, urticaria, fever Discoloration of urine (orange-red) Proteinuria Transient elevation of liver enzymes Seizures. 28

Contraindications & Precautions; Oxamniquine Epilepsy Pregnancy Activities require alertness. 29