CLI 302 LECTURE PPT-Dr_ Adeyemi.pptx

CLI 302 Dr. O. I. Adeyemi Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria  CHEMOTHERAPY OF PARASITIC INFECTIONS 1. Antibacterial drugs. 2. Antituberculous & Antileprotic drugs. 3. Antiprotozoal drugs (antiamoebic & a...

CLI 302 Dr. O. I. Adeyemi Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria  CHEMOTHERAPY OF PARASITIC INFECTIONS 1. Antibacterial drugs. 2. Antituberculous & Antileprotic drugs. 3. Antiprotozoal drugs (antiamoebic & antimalarial). 4. Antihelmenthic drugs. Ehrlich’s Magic Bullets Fleming and Penicillin  Chemotherapy The use of drugs to treat a disease Selective Toxicity (General Principle): A drug that kills harmful microbes without damaging the host  Antibiotic/Antimicrobial Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms  ANTIBACTERIAL DRUGS Classification: Inhibitors of bacterial cell wall formation as B- lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams), vancomycin & bacitracin. Inhibitors of protein synthesis as tetracyclines, aminoglycosides, macrolides, clindamycin and chloramphenicol. Inhibitors of nucleic acid synthesis as quinolones and rifampicin. Inhibitors of metabolic pathways (folate antagonist) as sulphonamides, trimethoprim and co-trimoxazole. Drugs affecting cell membrane permeability as polymyxin.  Mechanisms of Antimicrobial Action Classification is based on this Bacteria have their own enzymes for – Cell wall formation – Protein synthesis – DNA replication – RNA synthesis – Synthesis of essential metabolites  Note: Viruses use host enzymes inside host cells Fungi and protozoa have own eukaryotic enzymes The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have Modes of Antimicrobial Action  Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis Penicillin (over 50 compounds) –Share 4-sided ring (b lactam ring) Natural penicillins Narrow range of action Susceptible to penicillinase (b lactamase) Penicillins  B-lactam antibiotics I.Penicillins Mechanism of action: Bactericidal by inhibiting transpeptidation (last step in bacterial cell wall synthesis) through binding to penicillin binding proteins (PBP). B-lactamase is an enzyme secreted by some bacteria e.g staphylococci leading to inactivation of B-lactam antibiotics (resistance developed). Preparations of penicillins:- Members of this family of antibiotics differ from each other due to different groups attached to B-lactam ring. These differences include spectrum, stability to gastric acidity and susceptibility to bacterial B- lactamase enzyme. 1.Natural penicillins [penicillin G (benzyl penicillin) and penicillin V. 2.Anti-staph penicillins e.g oxacillin,cloxacillin and flucloxacillin. 3.Extended-spectrum penicillins e.g ampicillin and amoxicillin. 4.Antipseudomonal penicillins e.g ticarcillin and carbenicillin Penicillinase (b Lactamase)  Therapeutic uses of penicillins: Streptococcal infections as acute tonsillitis,wound sepsis, puerperal sepsis and subacute bacterial endocarditis. (2)Staphylococcal infections. (3)Pneumococcal infections. (4)Meningococcal meningitis:Penicillin G or ampicillin IV+chloramphenicol (5)Syphilis and gonorrhea. (6)Typhoid fever:amoxicillin & ampicillin. (7)Diphtheria,tetanus and gas gangrene + specific antitoxins. (8)Prophylaxis to: (a)Prevent recurrence of rhumatic fever e.g benzathine penicillin 1.2 million units given monthly IMI. (b)Prevent subacute bacterial endocarditis with aminoglycosides.  Adverse effects: 1. Hypersensitivity (most important) as rashes,angioedema and anaphylactic shock. 2.Diarrhea specially with ampicillin. 3.Neurotoxicity as seizures specially if intrathecally injected. 4.Platelet dysfunction.  Semisynthetic Penicillins Penicilinase-resistant penicillins Carbapenems: very broad spectrum Monobactam: Gram negative Extended-spectrum penicillins Penicillins +  -lactamase inhibitors  Other B-lactam antibiotics III.Carbapenems e.g Imipenem. The broasest spectrum B-lactam.It is effective against gm+ve, gm-ve organisms and anaerobes. It is resistant to B-lactamase. It is given IV,metabolized in the renal tubules to inactive nephrotoxic metabolite and Cilastatin is combined with imipenem to inhibit renal metabolism. It has extensive cross allergy with penicillin. IV.Monobactams e.g Aztreonam Has a narrow spectrum against aerobic gram-ve organisms. It is resistant to B-lactamase. It is given IM and IV and relatively non-toxic. No cross allergy with other B-lactam antibiotics.  Other Inhibitors of Cell Wall Synthesis Contd. Cephalospori ns – 2nd, 3rd, and 4th generations more effective against gram-  Cephalosporins B-lactam antibiotics similar to penicillins in their mode of action but are more resistant to B-lactamase.There is cross allergy & cross resistance with penicillins→better avoided in patients allergic to penicillins or infections resistant to penicillins. Classification of cephalosporins: 1stgeneration active on gm+ve cocci (strept-staph) and gm-ve organisms (E coli-Klebsiella).members include cephalexin (oral) & cefazolin (parenteral) which is used in orthopedic surgery (due to good penetration into bone & resistance to B-lactamase producing staph.). 2ndgeneration less active on gm+ve organisms than 1st generation with extended spectrum on gm-ve organisms e.g cefuroxime & cefoxitin which is used in H.influenza and B.fragillis. 3thgeneration with increased spectrum against gm-ve organisms e.g pseudomonas.Most agents cross the BBB so useful in serious infections of meningitis.Examples include cefoperazone,cefotaxime and ceftriaxone.  Ceftriaxone has the longest half life with good bone penetration, crosses the BBB so used in meningitis,40% excreted in the bile so can be used in biliary tract infections & in patients with renal dysfun- ction.It is used in a single dose in treatment of gonorrhea and used in treatment of resistant cases of typhoid fever. 4thgeneration cefepime which is resistant to all subtypes of B-lactamase enzyme & used in treatment of penicillin resistant streptococci. It is broad spectrum against resistant gm –ve bacilli. Adverse effects of cephalosporines: 1.Hypersensitivity reactions. 2.Nephrotoxicity especially if given with aminoglycosides. 3.Local irritation→severe pain after IMI and thrombophlebitis after IVI. 4.Platelet dysfunction & hypoprothrombinemia with cefoperazone→ bleeding (avoided by vitamin K). 5.Intolerance to alcohol (cefoperazone)→disulfiram like reaction.  Other Inhibitors of Cell Wall Synthesis Contd Polypeptide antibiotics – Bacitracin Topical application Against gram-positives – Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus  Other agents inhibiting cell wall synthesis Contd: (Vancomycin & Bacitracin) Vancomycin is bactericidal acting by inhibition of cell wall synthesis at an earlier stage than B-lactam antibiotics.It is effective against gm+ve organisms. Pharmacokinetics of vancomycin: -Given by IV infusion but given orally in antibiotic-induced pseudo- membraneous colitis due to clostridium deficile. -Excreted renally so we adjust the dose in renal dysfunction. Therapeutic uses of vancomycin: 1.Oxacillin-resistant staph aureus (ORSA) drug of choice. 2.Serious allergy to penicillins. 3.Pseudomembraneous colitis following antibiotic use. Adverse effects of vancomycin: 1.Fever,rigors and phlebitis. 2.Shock with rapid infusion→red man syndrome due to histamine release. 3.Hearing affection or loss. 4.Renal dysfunction. Bacitracin: Effective against gm+ve organisms.Restricted to topical application because it is potentially nephrotoxic. Tetracyclins (Tetracyclin-Doxycyclin-Minocyclin-Demeclocyclin) Mechanism of action by binding to 30s ribosomal bacterial subunit leading to inhibition of binding of tRNA and inhibition of protein synthesis. Therapeutic uses: Chlamydial infections – Cholera – Amoebiasis - Acne vulgaris -Mycoplasma pneumonia - Meningococcal carriers - Brucellosis - Demeclocyclin is used in treatment of syndrome of inappropriate ADH secretion as it antagonizes the effect of ADH on renal tubules. Adverse effects & contraindications: 1.Epigastric pain due to gastric irritation (non-compliance). 2.Teeth discoloration & bone hypoplasia as it chelate calcium (contraindicated in pregnancy,lactation and children less than 8 y). 3.Hepatotoxicity. 4.Phototoxicity. 5.Suprainfection with candida,clostredium deficile or resistant staph  Aminoglycosides (streptomycin-gentamycin- tobramycin-amikacin-netilmicin-neomycin) Mechanism of action by irreversible binding with 30s ribosomal bacterial subunits leading to inhibition of protein synthesis. Spectrum & activity: effective against aerobic organisms but ineffective against anaerobes as it requires oxygen for transport into cells. Act mainly against gm-ve organisms e.g E.coli, pseudomonas and cholera. Gentamycin is also effective against Staph. Therapeutic uses: 1.Peritonitis,septicemia & pneumonia. 2.Subacute bacterial endocarditis. 3.Complicated urinary tract infections. 4.Streptomycin is used in tuberculosis. 5.Amikacin & Netilmicin are reserved for resistant cases.  Pharmacokinetics: 1.They are not absorbed orally and have to be given parenterally. 2.They don`t cross the BBB even when the meninges are inflammed. 3.They are concentrated in the renal cortex,perilymph and endolymph of the inner ear→nephrotoxicity & ototoxicity. 4.They are excreted unchanged through the kidneys so caution should be taken in patients with renal dysfunction. Adverse effects of aminoglycosides: 1.Nephrotoxicity as acute tubular necrosis which may be irrevesible.Risk ↑by dehydration, old age,↑dose,↑duration of treatment and concurrent use of nephrotoxic drugs. 2.Ototoxicity which may be irreversible. 3.Neuromuscular paralysis especially after intraperitoneal infusion of large doses (inhibits acetyl choline release). 4.Allergy as contact dermatitis with topically applied neomycin. Spectinomycin: Is structurally related to aminoglycosides and inhibits protein synthesis at 30s ribosomal subunit. Its use is limited to gonorrhea in patients allergic to penicillins or patients with penicillin-resistant gonococcal infection (single deep IMI).  Macrolides (Erythromycin, Clarithromycin, Azithromycin and Roxithromycin) Mechanism of action is inhibition of protein synthesis by binding with 50s bacterial ribosomal subunits. Spectrum and uses of erythromycin: 1.Drug of choice in patients having spirochetes or gm+ve coccal infections with allergy to B-lactam antibiotics. 2.Drug of choice in urogenital chlamydial infection in pregnancy and mycoplasma pneumonia in children (tetracyclines contraindicated). Adverse effects of erythromycin: 1.Epigastric pain & intestinal colic. 2.Cholestatic jaundice (contraindicated in liver disease). 3.Ototoxicity & transient deafness. 4.Thrombophlebitis if injected IV. Azithromycin: 1.Less effective on gm+ve & more effective on gm-ve organisms than erythromycin. 2.Potent against chlamydia. 3.Long half life allowing once daily dose. 4.Excreted through the bile.  Clindamycin & Chloramphenicol It acts by binding to 50s ribosomal subunit inhibiting protein synthesis. It is used specifically against anerobic infections and it is also effective against gm+ve organisms as staph and strept.infections. It is used in bone infection as it has good penetration into bones. Adverse effects: 1.Pseudomembraneous colitis. 2.Skin rash. 3.Diarrhea. 4.Liver dysfunction. Chloramphenicol: Acts by binding to 50s ribosomal subunits inhibiting protein synthesis. Therapeutic uses of chloramphenicol: 1.Typhoid fever but replaced by fluorinated quinolones. 2.Bacterial meningitis (H. influenza) + penicillin. 3.Topically in eye infections e.g conjunctivitis. 4.Anerobic infections e.g anaerobic brain abscess. Adverse effects of chloramphenicol: 1.GIT upset & superinfection. 2.Bone marrow depression (dose independent or idiosyncrasy). 3.Grey baby syndrome in neonates. 4.Optic neuritis. 5.Inhibition of hepatic microsomal enzymes →drug interaction.  Inhibitors of Nucleic Acid Synthesis Rifamycin – Inhibits RNA synthesis – Antituberculosis Quinolones and fluoroquinolones – Ciprofloxacin – Inhibits DNA gyrase – Urinary tract infections  Inhibitors of nucleic acid synthesis (Fluoroquinolones: Others:-ofloxacin-norfloxacin & pefloxacin) Mechanism of action by inhibiting DNA gyrase enzyme which is responsible for unwinding of double stranded DNA leading to inhibition of DNA replication. Therapeutic uses: 1.Typhoid fever. 2.Urinary tract infections (gm-ve bacilli) & prostatitis. 3.Gonorrhea (ofloxacin single dose). 4.Respiratory tract infections not responding to B-lactam antibiotics. 5.Bone and soft tissue infections. Adverse effects & contraindications: 1.CNS symptoms as headache, dizziness & phototoxicity. 2.Nephrotoxicity. 3.Arthropathy in children less than 18 years. 4.Inhibit liver microsomal enzymes → dangerous drug interaction as ↑ level of theophylline & warfarin.  Inhibitors of nucleic acid synthesis (II.Rifampicin) Mechanism of action by inhibiting the enzyme DNA- dependent RNA polymerase in mycobacteria (but not in human cells)→ inhibition of RNA synthesis. Therapeutic uses: 1.Potent bactericidal drug against mycobacteria tuberculosis at all sites (600mg/d with other antituberculous drugs for 6-18 months). 2.Treatment of leprosy. 3.Prophylaxis of meningitis. 4.Oxacellin-resistant Staph aureus. Adverse effects: 1.Skin rash,fever and GIT upset. 2.Liver damage & jaundice. 3.Enzyme induction→serious drug interaction. 4.An influenzae-like syndrome (malaise,headache and fever). 5.Red discoloration of the urine,tears and sputum. 6.Resistance rapid due to modification  Competitive Inhibitors – Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum  Folate-Antagonists (Sulfonamides,Trimethoprim & Co- Trimethoprim) Sulfonamides: sulfadiazine,sulfadoxine, sulfacetamide, sulfasalazine and sulfamethoxazole. Mechanism of action: sulfonamides are structural analogues of PABA. They compete with it for the enzyme dihydropteroate synthetase leading to inhibition of folic acid synthesis with consequent inhibition of DNA & RNA synthesis (human cells utilize already formed folic acid). Therapeutic uses: 1.Eye infection (topical sulfacetamide). 2.Burns (topical silver sulfadiazine). 3.Ulcerative colitis (sulfasalazine). 4.Malaria (sulfadoxine combined with pyrimethamine).  Adverse effects: 1.Hypersensitivity reactions. 2.Crystalluria & nephrotoxicity due to insoluble metabolite precipita- tion and can be avoided by ↑ fluid intake & alkalinization of urine. 3.Hemopoietic disturbances as granulocytopenia, thrombocytopenia and hemolytic anemia in patients with G6PD deficiency. 4.Kernicterus as sulfonamides displaces bilirubin from plasm protein → cross BBB in premature infants→CNS depression. 5.Drug interaction as it ↑ plasma level of oral hypoglycemic & anticoagulants due to plasma protein displacement. Trimethoprim: It inhibits dihydrofolate reductase which converts folic acid into folinic acid (tetrahydrofolic acid) which is essential for DNA synthesis It is combined with sulfamethoxazole to form co-trimoxazole. Adverse effects: 1.Megaloplastic anemia due to folate deficiency & avoided by folinic acid administration. 2.Granulocytopenia & leucopenia.  Co-Trimoxazole: It is a combination of sulfamethoxazole(400mg) +trimethoprim(80mg) Mechanism of action: as sufonamides and trimethoprim. Advantages of Co-trimoxazole: 1.Synergestic combination. 2.More potent. 3.Less and delayed bacterial resistance. 4.Bactericidal & wider spectrum including proteus,salmonella,shigella,Hemophilus influenza & gonococci. Theraapeutic uses: 1.Urinary tract infections,gonococcal urethritis and prostatitis. 2.Salmonella & shigella infections. 3.Respiratory tract infections due to H.influenza & pneumococci. Adverse effects: As sulfonamides and trimethoprim.  ANTI-TUBERCULOUS DRUGS First-line drugs: Isoniazid-Rifampicin-Pyrazinamide-Ethambutol. Second-line drugs: Streptomycin-Capreomycin-Clarithromycin- Ciprofloxacin and cycloserine.They are used only in patients with infection resistant to the first line drugs or patients can`t tolerate the first line drugs. To prevent drug resistance we use combination of drugs. To prevent relapse after treatment continue treatment for 18-24 months with two drugs isoniazid & rifampicin are the best. Effective course regimens: THE ESSENCE OF DOTS 1.Initial phase for 2 months give 3 drugs together isoniazid,rifampicin & pyrazinamide (+ethambutol if the organism is suspected to be resistant). 2.Continuation phase with two drugs isoniazid & rifampicin for 4-6 months or long term treatment for 18-24 months for patients with TB meningitis,bone & joint affection or drug-resistant cases. Isoniazid (Isonicotinic acid hydrazide;INH) Mechanism of action: 1.Inhibition of cell wall synthesis by inhibiting enzymes essential for mycolic acid synthesis (an important constituent of mycobacterial cell wall). 2.Disorganization of cell metabolism. Therapeutic uses: 1.Treatment of active cases of TB (5mg/kg/d) with other anti-TB drugs & pyridoxine 10mg/100 mg INH to avoid neurotoxicity. 2.Chemoprophylaxis as the sole drug (300mg/d for 9-12 months) in Close contacts to active TB case. Adverse effects of INH: 1.Allergic skin eruption (commonest). 2.Hepatotoxicity occuring more in elderly. 3.Neurotoxicity with slow acetylators (due to B6 deficiency) →peripheral neuritis, insomnia, memory impairment, optic neuritis and convulsions. 4.Hemolytic anemia in G6PD deficiency. 5.Systemic lupus erythematosis (SLE)-like syndrome (vasculitis & arthritis). 6.Enzyme inhibition in the liver →↑serum phenytoin & carbamazepine levels.  Ethambutol (single daily dose 15mg/kg) It is a selective anti-TB drug, taken up by the actively growing mycobacteria, to inhibit RNA synthesis & growth. It is less active than INH & rifampicin. Adverse Effects: Optic neuritis (dose related & reversible) starts by red/green color blindness followed by a decrease in visual acuity. Pyrazinamide: It is a tuberculo-static and inhibits intracellular mycobacteria present inside macrophages (mechanism of action is unknown). Adverse effects: 1.Hyperuricemia & arthralgia (monitor serum uric acid level & give NSAIDs). 2.Hepatotoxicity in high doses (assess liver function before treatment). 3.GIT disturbances, malaise and fever.  LEPROSY Leprosy Organism – mycobacterium leprae Infection of – skin – nerves LEPROSY  Drugs used in leprosy Dapsone Inhibits folate synthesis. Well absorbed orally,widely distributed. Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney. Excreted into bile and reabsorbed in the intestine. Excreted in urine as acetylated. It is well tolerated.  Clinical uses Tuberculoid leprosy. Lepromatous leprosy in combination with rifampin & clofazimine. To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).  Adverse effects Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever,pruritus,rashes. Erythema nodosum leprosum  Clofazimine It is a phenazine dye. Unknown mechanism of action ,may be DNA binding. Antiinflammatory effect. Absorption from the gut is variable. Given orally , once daily. Excreted mainly in feces. Stored mainly in reticuloendothelial tissues and skin. Half-life 2 months. Delayed onset of action (6 weeks).  Clinical uses Multidrug resistance TB. Lepromatous leprosy Tuberculoid leprosy in : – patients intolerant to sulfones dapsone-resistant bacilli. Chronic skin ulcers caused by M.ulcerans.  Adverse effects – Skin discoloration ranging from red-brown to black. – Gastrointestinal intolerance. – Red colour urine. – Eosinophilic enteritis  Treatment of TB in pregnant women INH ( pyridoxine should be given ), Rifampicin , ethambutol Pyrazinamide is given only if : Resistant to other drugs is documented Streptomycin is contraindicated. Breast feeding is not contraindication to receive drugs , but caution should be observed.  Antiprotozoan Drugs Protozoa are eukaryotic cells Many drugs are experimental and their mode of action is unknown  Amoebiasis An infection with Entameba histolytica produced by ingestion of cysts of this parasite. In the intestine the cysts develop into trophozoites (active invasive form) which adhere to colonic epithelial cells. Trophozoites lyse host cells & invade the submucosa resulting in: (A) Bowel lumen amebiasis: – Asymptomatic but cysts pass in the stool transmit infection to others. – Treatment is directed at eradicating cysts with luminal amebicidal drugs:  Diloxanide-Iodoquinol-Paromomycin-Tetracyclin.  Amoebiasis Contd (B)Tissue invating amebiasis may give rise to – Dysentery – amebic granuloma in the intestinal wall – hepatitis or liver abscess and – extra-intestinal diseases. Use tissue amebicidal drugs: – Nitroimidazole (metronidazole or tinidazole)- Dehydroemetine-Chloroquine.  Metronidazole Mechanism of action: Within an aerobis bacteria & sensitive protozoa the nitro group of the drug is reduced into toxic O2 product which bind to DNA causing its damage,disrupting transcription & replication. Therapeutic uses: 1.Antiprotozoal as it is the drug of first choice in treatment of (a)Amebiasis: trophoziticidal but ineffective against luminal cysts so it should be used with diloxanide. (b)Giardiasis. (c)Trichomoniasis 2gm as a single oral dose. 2.Anti- anerobe e.g dental infection,pseudomembraneous colitis and anerobic brain abscess. Adverse effects: 1.GIT disturbances,glossitis with metalic taste in the mouth. 2.CNS manifestations:headache,dizziness,insomnia and sensory neuropathy. 3.Dysuria and dark urine. 4.Rash & neutropenia. 5.Teratogenic so not used in pregnancy. 6.Inhibits liver metabolizing enzymes potentiating warfarin and disulfiram reaction with alcohol.  Malaria A life-threatening parasitic disease 40% of the world’s population is at risk 90% of the deaths due to Malaria occur in Sub-Sahara Africa, mostly among young children. Around 400-900 million people are affected At least 2.7 million deaths annually. It is one of the major public health concerns  Organism Malaria is caused by species of Plasmodium. The genus Plasmodium contains 172 species – Five species are known to infect humans. Plasmodium falciparum Plasmodium malariae Plasmodium ovale Plasmodium vivax Plasmodium Knolesi Plasmodium parasites are highly specific with female Anopheles mosquitoes  Malarial Parasite (Plasmodium) Two interdependent life cycles Sexual cycle: occurs in the mosquito Asexual cycle: occurs in the human – Knowledge of the life cycles is essential in understanding antimalarial drug treatment – Drugs are effective only during the asexual cycle  Plasmodium Life Cycle Asexual cycle: two phases Exoerythrocytic phase – Occurs “outside” the erythrocyte – Also known as the tissue phase Erythrocytic phase – Occurs “inside” the erythrocyte – Also known as the blood phase  Treatment of Malaria Malaria is a protozoal infection caused by 4 species of plasmodia (vivax, ovale, malariae & falciparum). The female anopheles mosquito injects sporozoites which can develop in the liver into tissue schizonts →merozoites →RBCs transformed into blood schizonts containing numerous merozoites Rupture of infected RBCs and release of merozoites → clinical attack,then merozoites re-enter fresh RBCs. Some merozoites are differentiated inside RBCs into male & female gametocytes (the sexual form of the parasite),where they remain until taken by female anopheles mosquito, where sexual cycle takes place to form sporozoites, which are stored in the salivary gland of the mosquito for re-infection. Hypnozoites (resting form) formed in the liver and lasts for months or years to be reactivated and release merozoites again → relapse. This occurs with Plasmodium vivax & ovale (relapsing malaria).  Antimalarial Drugs I.Blood schizontocides: (a)Chloroquine,quinine,quinidine & mefloquine). (b)Antifolates (pyrimethamine,proguanil,sulfadoxine & sulfone). II.Tissue schizontocides:Primaquine. III. Gametocytocides (prevent transmission): Primaquine. CHLOROQUINE: blood schizonticide,that kills erythrocytic forms & prevents clinical attacks. It has no effect on hepatic forms of the parasite. Mechanism of action: It is concentrated in infected RBCs → 1.Inhibits parasite hemoglobin digestion→↓ nutrient amino acids for the parasite. 2.Inhibits heme polymerase (converts toxic free heme into harmless hemozoin) → accumulation of toxic heme. Therapeutic uses of chloroquine: 1.Antimalarial used in treatment of acute attacks,given orally, SC, IM & slow IV infusion.It is also used in chemoprophylaxis in all forms except chloroquine resistant falciparum. 2.Amebic hepatitis or abscess. 3.Anti-inflammatory in rheumatoid arthritis and lupus erythematosus.  Adverse effects: 1.Itching especially in Africans (common). 2.GIT disturbances (anorexia, nausea & vomiting) so given after meals. 3.Headache,dizziness & blurring of vision. 4.Bone marrow depression & hemolytic anemia in G6PD ↓ (rare). 5.Ototoxicity, confusion, psychosis & seizures (rare). 6.Hypotension & fatal arrhythmias with high IV dose. 7.Corneal deposits & retinopathy (prolonged high dose). 8.Myopathy & peripheral neuritis (prolonged high dose). QUININE: Its mechanism of action as chloroquine. It is the main drug for resistant P. falciparum strains. It is not used for chemoprophylaxis. Adverse effects: (A)Common 1.Compliance is poor due to bitter taste & GIT irritation (nausea & vomiting).  (B)Rare 1.Hypoglycemia as it stimulates insulin release, so in patients with falciparum infection and treated with quinine we should differentiate between coma caused by cerebral malaria & hypoglycemic coma. 2.Hypersensitivity reactions. 3.Hemolytic anemia (black water fever) → renal failure which may be fatal. III.Mefloquine: Blood schizontocid effective against resistant organisms to chloroquine. In P. vivax & ovale it should be followed by a course of primaquine. Mechanism of action as chloroquine. Used in treatment of chloroquine resistant cases & in chemoprophylaxis. Adverse effects & contraindications: 1.GIT disturbances. 2.Teratogenic (contraindicated in pregnancy). 3.Delayed A-V nodal conduction (contraindicated with BB & CCB). 4. Leucocytosis,thrombocytopenia & elevated hepatic enzymes. 5.CNS stimulation with headache, insomnia up to convulsions (contraindicated in epilepsy). IV. Halofantrine: It is a blood schizontocide active against all species of malaria, including multi-resistant P. falciparum.It is given orally. Its side effects include abdominal pain, headache, pruritus and serious cardiac problems (use limited to resistant organisms).  Antifolates: (A)Drugs inhibiting folate synthesis (sulfonamides mainly sulfadoxine) inhibit conversion of PABA to folic acid (compete with PABA for the enzyme dihydropteroate synthetase). (B)Drugs inhibiting folate utilization (pyrimethamine & proguanil) inhibit conversion of folic into folinic acid by inhibiting dihydrofolate reductase.We use a combination of the two groups to inhibit two sequential steps → synergistic action. Therapeutic uses of antifolates: 1.Antimalarial to treat chloroquine resistant P.falciparum,sulfadoxine + pyrimethamine (Fansidar),unreliable in P. ovale or P. malariae or in severe malaria. It can be also used in chemoprophylaxis in all types. 2.Toxoplasmosis (pyrimethamine + sulfadiazine). 3.Pneumonia due to pneumocystis carinii (fatal fungal infection in patients with AIDS ,fungus is structurally similar to protozoa) Adverse effects of antifolates: (a) Pyrimethamine or proguanil: 1.GIT upset, skin rash & itching. 2.Mouth ulcers & alopecia. 3.Megaloblastic anemia. b)Sulfonamides: as stated earlier.  PRIMAQUINE: Tissue schizontocide (for p.vivax & ovale) & gametocide in all species.Its mechanism of action is unknown. Therapeutic uses: 1.Radical cure of vivax & ovale ,usually given after blood schizontocide to eradicate the hypnozoites. 2.Prevent transmission in all species (gametocides). Adverse effects: 1.Dose-related GIT disturbances. 2.Methemoglobinemia with cyanosis. 3.Hemolytic anemia in G6PD deficiency. 4.Dysrhythmias & bone marrow depression. COMBINATION TREATMENTS Why? Resistance Drugs: Artemisin and its Derivatives plus either of – Amodiaquine – Lumefantrine, etc – Artesunate alone not recommended because of resistance Antihelminthic Drugs  Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms  Antihelminthic Drugs Prevent ATP generation (Tapeworms) Alters membrane permeability (Flatworms) Neuromuscular block (Intestinal roundworms) Inhibits nutrient absorption (Intestinal roundworms) Paralyzes worm (Intestinal roundworms)  Anthelmintics Pyrantel- Pin worm Mebendazole- ?? Albendazole- ?? Ivermectin- ?? Praziquantel- ?? Thiabendazole- ?? etc  Quiz Selection of appropriate antiparasitic agent is as important as its side effects in chemotherapy. Discuss. Explain the specific principles behind combination chemotherapies in malaria using at least three examples List ten (10) anthelmintics of different mechanism of action; and describe their clinical uses and side effects