Lec 11- Antiprotazoal drugs Flashcards
1
Q
Trypanosomiasis
A
- Human African trypanosomiasis (sleeping sickness) is a widespread tropical disease that can be fatal if not treated. Spread by the bite of an infected tsetse fly
- Trypanosoma brucei and T.rhodesiense cause sleeping sickness (CNS)
- 50 million Africans infected
-
Agents:
- Pentamidine, Berenil, Eflornithine for prophylaxis and treatment
- Tryparsamide and Melarsoprol toxic arsenic compounds needed in advanced cases
2
Q
Trypanosomiasis- symptoms
A
- The bite erupts into a red sore and within a few weeks the person can experience fever, swollen lymph glands, aching muscles and joints, headaches and irritability
- In advanced stages, the disease attacks the central nervous system (crosses the BBB), causing changes in perosnality, alteration of the biological clock, confusion, slurred speech, seizures, and difficulty walking and talking
- If not treated the person will die
3
Q
Trypanosomiasis-treatment
A
- Depends on the stage of the disease
-
Stage 1: in subcutaneous tissues, blood and lymph
- The drugs used in the first stage of the disease are of lower toxicity and easier to administer
- The earlier the disease is identified, the better the prospect of a cure
-
Stage 2: the parasites cross the BBB to infect the CNS
- Second stage drugs have to cross the BBB to reach the parasite
- Such drugs are toxic and complicated to administer
- Four drugs are registered for the treatment of sleeping sickness and provided free of charge to endemic countries
4
Q
Pentamidine
A
- For first stage treatment of trypanosoma brucei gambiense sleep sickness
- Despite its undesirable effects (which include liver or kidney dysfunction, HTN, Hypotension, Hypoglyceami, Hypocalemia, Leukopenia, thrombocytopenia, anemia and allergic reaction), it is generally well tolerated by patients
- It is though that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids and proteins
5
Q
Suramin
A
- For first stage treatment of Trypanosoma brucei rhodesinense sleeping sickness
- Used parenterally
- It provokes certain undesirable effects in the urinary tract and allergic reactions
- Trypanocidal activity may be due to inhibition of enzymes involved with the oxidation of reduced nicotinamide-adenine dinucleotide (NADH), which functions as a co-enzyme in many cellular reactions, such as respiration and glycolysis in trypanosome parasite
- This is very polar- lots of hydrogen bond donors and acceptors reduce bioavailability
6
Q
Melarsoprol
A
- Second stage treatment for both forms of infection
- Discovered in 1949
- Crosses the BBB
- It is derived from arsenic and has many undesirable side effects
- cutaneous reactions, polyneuropathy, diarrhoea and fever and reactive encephalopathy which can be fatal (3-10%)
- An increase in resistance to the drug has been observed in several foci particularly in central Africa
7
Q
Eflornithine
A
- Second stage treatment but only for T.gambiense
- Registered in 1990
- Less toxic than melarsoprol
- Crosses the BBB
- The regimen is strict and difficult to apply
- A combination treatment of nifurtimox and eflornithine introduced in 2009
- The chiral centre doesn’t matter
8
Q
Eflornithine- Mechanism of action
A
- Enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in the conversion of ornithine to polyamines
- Polyamines are essential for nucleic acid and protein synthesis in protozoa
- Because the clearance of parasites from the bloodstream is slow, it is likely that eflornithine is cytostatic rather than cytolytic;
- In addition, animal studies have suggested that an intact immune response is probably necessary for complete elimination of the parasites from the bloodstream
9
Q
Eflornithine
Mechanism of decarboxylase
A
- Is a very similar structure to ornithine, therefore enzyme takes substrate up (KEY= Difluromethyl group)
- Attaches to the enzyme through an imine line (N triple bond C)
- Then decarboxylation (CO2 loss)
- Because there is a trifluoromethyl group, instead of its normal mechanism (with ornithine) its electron density carries on
- This causes Flouride ion to be removed
- This leaves the carbon with the remaining fluorine to become very electrophilic (attractive toward nucleophiles)
- On the enzyme, there is a cysteine360 with an S- (thiolate) and irreversibly interacts (alkylation) which permanently blocks the active site of the enzyme- this gives structure in blue
10
Q
Eflornithine- enzyme half lifes
A
- This drug inhibits both human and parasite enzyme- which is not good
- However, this is irrelevant due to the difference in half-lives between the human and parasitic enzyme
- In human the half-life is far shorter than in practice- so practice makes far less/slower
- This means we replace the faulty enzyme quickly to the point where it won’t affect us
11
Q
Leishmaniasis
A
- Leishmania tropica and Leishmania donovani cause cutaneous (Baghdad boil, Dehli sore, Oriental sore, Kala-azar, Chiclero disease) and visceral infection (liver and spleen)
- Sand fly vector
- Agents: Pentamidine, Amphotericin, Antimony compounds (sodium stibogluconate)
12
Q
Amphotericin B
A
- A polyene antibiotic
- Many chiral centres, too many steps= produced via fermentation
- Second line treatment for visceral leishmaniasis and mucocutaneous leishmaniasis especially when there is resistance to pentavalent antimonial drugs positivity for human immunodeficiency
- Use restricted by its acute toxicity, low TI and the need for parenteral administration (=> lipid-associated formulations of amphotericin B, which have reduced toxicity and an extended plasma half-life)
- Complexes with ergosterol in cell membranes, thus causing pores which alter ion balance and result in cell death
13
Q
Sodium Stibogluconate
A
- Mode of action not clearly understood
- The mechanism of action is possibly something to do with a reduction in ATP and GTP synthesis leading to decreased macromolecular synthesis
- Sb = antimony element, this is a heavy metal hence significant toxicity
14
Q
Chagas disease
A
- Trypanosoma cruzi transmitted by bits to face by reduviid bug (Mexico, South America)
- Invades heart muscle (sudden heart failure)
- Damages nerves in GI tract (mega colon)
- 12 million cases per year
- Agents: Nifurtimox And Benznidazole
- Aromatic ring with Nitro group attached in both cases are key to there mechanism of action
15
Q
Nifurtimox and Benznidazole
A
- The nitro group of both drugs is reduced to an amino group by the action of nitroreductases, with the formation of various free radical intermediates and electrophilic metabolites
- Nifurtimox: intracellular reduction => Nitro radical followed by redox cycling, and production of O2- and H2O2 is the main mechanism of action against T.cruzi
- Benznidazole: It is likely that the reduced metabolites of benznidazole are involved in its trypanocidal effects by covalent bonding of macromolecules
17
Q
Metronidazole
A
- Enters the cell as a prodrug by passive diffusion and is activated by reduction of the nitro group in specific organelles in the protozoa
- The activated forms are cytotoxic and can interact with the DNA molecule => inhibition of DNA synthesis and DNA damage by oxidation => single-strand and double-strand breaks => DNA degradation and cell death
18
Q
Tinidazole
A
- A synthetic antiprotozoal agent similar to metronidazole
- Active against the following protozoa: Trichomonas vaginalis, Giardia duodenalis and Entamoeba histolytica
- The nitro group of tinidazole is reduced in Trichomonas by a ferredoxin-mediated electron transport system
- The nitro radical generated as a result of this reduction is believed to be responsible for the antiprotozoal activity
- It is suggested that the toxic free radicals covalently bind to DNA => DNA damage => to cell death
- The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known, though it is probably similar
19
Q
Diloxanide [furoate]
A
- An anti-protozoal drug used in the treatment of Entamoeba histolytica and some other protozoal infections
- Mechanism unknown- may inhibit protein synthesis
- Destroys the trophozoites of E.histolytica that eventually form into cysts
- The cysts are then excreted by persons infected with asymptomatic amebiasis
- Diloxanide furoate is a prodrug and is hydrolysed in the GI tract to produce diloxanide, the active ingredient
21
Q
Mepacrine (quinacrine)
A
- Exact anti-parasitic mechanism unknown
- Binds to DNA in vitro by intercalation (often occurs when there are 3 aromatic rings in a row) between adjacent base pairs, inhibiting transcription and translation to RNA
- Does not appear to localize to the nucleus of Giardia trophozoites, suggesting that DNA binding may not be the primary mechanism. Other studies suggest that the outer membranes may be involved- due to its lipophilicity
- Inhibits succinate oxidation and interferes with electron transport
24
Q
Trimethoprim and trimethrexate
A
- Trimethoprime is a pyrimidine analogue that inhibits DHFR and disrupts folate synthesis (an essential part of the thymine synthesis pathway) => starves the organism of nucleotides necessary for DNA replication
- Trimetrexate is a competitive inhibitor of protozoan DHFR
26
Q
Clarithromycin
A
- Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound
- Like other macrolides, it then penetrates the bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis
- Clarithromycin is a pro-drug and methyl group is metabolised into hydroxy- which is the active compound
27
Q
Clindamycin
A
- Clindamycin inhibits protein synthesis by binding to 50S ribosomal subunit- see clarithromycin
28
Q
Azithromycin
A
- Azithromycin, a semi synthetic anti-biotic belonging to the macrolide subgroup of azalides
30
Q
Spiramycin
A
- 16-membered macrolide
- Inhibits translocation by binding to bacterial 50S ribosomal subunits
- Potent inhibitor of the binding to the ribosome of both donor and acceptor substrates
- Spiramycin induces rapid breakdown of polyribosomes
