DID (Pharmacology)- Antiprotozoals (FINAL)

What bacteria cause Malaria?

- plasmodium vivax

- plasmodium ovale

- plasmodium falciparum

What is the Malaria Life Cycle?

1) bite of infected female mosquito

2) entry into hepatocytes

3) exoerythrocytic stage- hypnozoite

4) hepatocyte ruptures

5) asex erythrocytic stage- symptoms

6) cyclic fever pattern

7) erythrocytic form

Malaria Pharmacotherapy is needed to...

erdicate erythrocytic AND hepatic parasite

T or F: P. vivax and P. ovale have a dormant hepatic stage (hypnozoite)

True

- can lead to relapse

What are the various categories of antimalarials?

1) Tissue schizonticides

- liver forms

2) Blood schizonticides

- erythrocyte forms

3) Gametocide

- sex stage and prevent transmission to mosquito

4) Prophylactic drugs

- when traveling to Africa, Asia, S. America

What are the diff classes of antimalarials?

- arteminisinins

- quinolines, quinine, quinidines

- folate synthesis inhibitors

- abx (tetra)

- lumefantrine

Erythocytic Schizonts include...

- artemisinins

- chlorowuine

- mefloquine

- quinine

- quinidine

- pyrimethamine

- suldafoxine

- tetracycline

Erythocytic and hepatocyte Schizonts include...

- atovaquone

- proguanil

What is an example of a primary and latent liver stage gametocyte?

primaquine

What areas of the globe tend to be chloroquine resistant?

africa, s. america, and asia

What chemoprophylaxis tx should be used in chloroquine-resistant areas?

- malarone

- artemisinin

- mefloquine

- quinine

- haflofantrine

*chloroquine can be used in non-resistant areas

MOA of Artemisinin

reactivity with heme produces oxidative stress in parasites (heme toxicity and ROS) -sesquiterpene lactone endoperoxide - endoperoxide bridge -

PK of Artemisinin

- synthetic have better solubility and efficacy

- t1/2= 1-3 hrs (not good for prevention)

- active metabolite it dihydroartemisinin

- induce CYP2B6 and CYP3A4

Therapeutic aspects of Artemisinin

- very potent and fast-acting

- best parasite clearance and fever resolution

- standard therapy for falciparum

T or F: Artemisinin Combo therapy (ACTs) are recommended for UNCOMPLICATED falciparum malaria

True

AE of Artemisinin

- NVD

- dizziness

- neutropenia

- anemia

- hemolysis

Artemisin in contraindicated in...

1) pregnant pts

- cause abortion, congenital defects, stillbirth

- not recommended in 1st trimester

2) children

- especially those <5kg

MOA of Chloroquine

Induce MDR1 pump and Pfcrt expression

- Lysosmotropic prevents heme detox

PK of Chloroquine

- 100% absorbed PO

- GIVE DOSE AFTER MEAL

- deposited in tissues

- needs loading dose

- slow infusion for IV

- metabolized by CYPs (desethylchloroquine)

- eliminated in URINE

- t1/2= 3-5 days

Therapeutic aspect of Chloroquine

- not active against liver stage

- drug of choice for uncomplicated nonfalciparum and sensitive falciparum

- reduced fever in 1-2 days

- clears parasitemia in 2-3 days

**SAFE IN PREGNANCY!

AE of Chloroquine

- pruritus

- NVH

- urticaria

- anorexia

- retinopathy

- hemolysis in G6PDH deficient

- cardiac arrrhythmias and arrest

T or F: Chloroquine can also be used to RA

True

- can cause irreversible ototoxicity

Chloroquine in contraindicated in/with...

- pts w/ psoriasis, porphyria, myopathy, retinopathy

- antacids (block absorption)

- anticonvulsants

- increase risk of arrythmia

Amodiaquine Quick Facts

For short-term seasonal malaria chemoprevention

- very similar to chloroquine

- combo tx for falciparum in chloroquine-resistant malaria

- toxicities: agranulocytosis, aplastic anemia, hepatotoxicity

Piperaquine Quick Facts

Bisquinoline

- primary choice in uncomplicated falciparum in Asia

- long t1/2= 28 days

- good for post-tx prophylaxis

Quinine and Quinidine Quick Facts

blood schizonticide against all 4

- gametocidal against vivax AND ovale

- not gametocidal against falciparum and hepatic stage

T or F: Quinidine is a detrorotary stereoisomer of quinine

True

MOA of Quinine and Quinidine

Induce MDR1 pump and Pfcrt expression

- same as Chloroquine

Mechanism of Resistance of Quinine and Quinidine

attributed to PfMDR1

PK of Quinine and Quinidine

- malaria pts accumulate drugs more

- more drug is plasma bound

- prolongs half life (18 hrs)

- quinidine has shorter t1/2

- LIVER metabolism

- RENAL excretion

- metabolized by CYP3A4

Therapeutic aspects of Quinine and Quinidine

More toxic and less effective than chloroquine

- PO falciparum good for chloroquine resistant regions of uncomplicated

- PO used w/ abx

- no prophylaxic use

What is Babesiosis?

Quinine + Clindamycin

AE of Quinine and Quinidine

- cinchonism- NVDH, tinnitus

- hypoglycemia

- hypotension

- hypersensitivity rxn

- hematologic abnormalities

- cardiotoxicity

- Blackwater fever

- QT prolongation

Quinine and Quinidine contraindications

- D/C if hypersensitivity/hemolysis

- don't give w/ mefloquine OR aluminum antacids

- monitor glucose

- increases plasma levels of digoxin and warfarin

T or F: Mefloquine is used as prophylaxis and combo tx

True

- synthetic 4-quinoline methanol

- UNCOMPLICATED falciparum in CQ-resistant regions

MOA of Mefloquine

Similar to Chloroquine

- associated w/ intra-erythrocytic hemozoin

- blood schizonticidal falci. and vivax

Anti-malarial Spectrum of Mefloquine

- not active against hepatic stages or gametocytes

- resistance in Asia

Mefloquine resisitance if associated with...

PfMDR1

PK of Mefloquine

- given only PO and is well-absorbed

- 18hr peak plasma

- elimination t1/2= 20days

-

What is the BBW on Mefloquine?

- neurologic

- psychiatric

- vivid dreams

AE of Mefloquine

- NVD

- abdominal pain

- hematologic effects

- cardiac abnormalities/issues

- neuropsychiatric toxicities

Mefloquin CIs

- do not admin w. quinine, quinidine (causes heart issues)

- pts w/ psych conditions

- pts w/ seizures

- pts with heart probs

Primaquine is used to...

eradicate DORMANT forms of vivax and ovale

- synthetic 8-aminoquinoline

Anti-malarial Spectrum of Primaquine

Gametocidal against latent hepatic forms

- weak activity against blood schizonts

- chemoprophylaxis

- prevents relapse

- radical cure of acute vivax and ovale

PK of Primaquine

- PO

- metabolized and excreted in URINE

- metabolites are less effective and more toxic

AE of Primaquine

- Leukpenia

- Agranulocytosis

- Leukocytosis

- Cardiac arrythmia

- hemolysis and methhemoglobinomia (G6PH deficiency)

Primaquin CIs

- avoid in pts w. blood cell disorders and myelosuppression (quinine)

- don't give IV (hypotension)

- monitor G6PDH levels

**AVOID IN PREGNANT PTs

MOA of Atovaquone

inhibits parasite mitochondrial ETC of parasite

- active against tissue and blood schizonts

Mechanism of Resistance of Atovaquone

SNP (Y268S/C/N) in mitochondrial sytochromeb gene

- + proguanil decreases resistance

PK of Atovaquone

- PO absorption increase w/ fatty food

- t1/2= 2-3 days

- excreted unchanged in FECES

- tx and prophylaxis of falciparum

AE of Atovaquone

- NVD

- rash

- fever

- tetra and rifampin decrease plasma conc. by 1/2

**DO NOT USE IF PREGNANT!

Lumefantrine MOA

similar to chloroquine

- does not cause cardiac complications like Meflo or Quinidine

Lumefantrine (coartem) quick facts

first line therapy for chloroquine-resistant flaciparum

- give PO w/ food

- t1/2= 3-4 days

- CYP3A4

AE of Coartem

- rash

- N/H

MOA of Pyrimethamine and Proguanil

Inhibits folate biosynthesis

- SELECTIVE inhibition of plasmodial DHFR

- used w/ sulfa drugs which block DHPS

- slow acting

- NOT gametocidal

- always used in combo

MOA of Abx for anti-malarial tx (tetra, doxy, clindamycin)

Block protein sysnthesis in apicoplast

- act slowly and always combined

- Blood schizonts

- can be used for amebiasis and toxoplasmosis

What are the determinants of drug resistant malaria?

- t1/2

- PK

- host immunity

- vector and environment

- transmission

- mutation in parasite

- cross-resistance

- multi-resistance

What is Amebiasis?

Caused by Entameoba histolytica

- colitis and dysentery

- ab pain

- bloody diarrhea

- tissue death

Drugs that treat Extraluminal vs luminal

Extraluminal

- metronidazole

- tinidazole

Luminal

- diloxanide

- iodoquinol

- paromomycin

What drug class are Metronidazole and Tinidazole in?

Nitromidazoles

MOA of Metronidazole and Tinidazole

Inhibits nucleic acid synthesis by disrupting DNA and causing strand breakage

- action dependent on reduction of nitro group in protozoa

- kills trophozoites (NOT CYSTS)

PK of Metronidazole and Tinidazole

- PO t1/2= 8hrs (M); 12-14hrs (T)

- eliminated in teh URINE

- tinidazole is better

AE of Metronidazole and Tinidazole

- NVDH

- dry mouth

- metallic taste

- pancreatitis

- severe CNS toxicity

- BBW= possible carcinogenic effect

CIs of Metronidazole and Tinidazole

- avoid alc (NV)

- potentiates coumarin anticoags

- phenyto and phenobabr increase elimination

**AVOID IN PREGNANT PTs

T or F: Iodoquinol is a hydroxyquinoline

True

- effective luminal amebicide

MOA of Iodoquinol

Inteferes w/ heme metabolism of protozoa

- not active against trophozoites and extraintestinal

- retained in intestine

- excreted through FECES

AE and CIs of Iodoquinol

- NVD

- pain

- take w/ meals

- neropathy, renal, thyroid

- D/C w/ signs of iodine toxicity

T or F: Paromomycin Sulfate is an Aminoglycoside abx

True

- luminal amebicide

- USA main choice

- used in amebiasis and leishmaniasis

AE of Paromomycin

- NVD

- GI distress

- renal tox in pts w/ renal probs