Ch'40 Malaria

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Ch.40 Malaria

• Malaria affects approximately 500 million people
  worldwide (1997)
• 1.7-2.5 million deaths annually (most lt 5 years
  old)
• Typically American pharmacists only face this
  disease when treating military patients following
  war overseas.
• The causative agent is the protozoa Plasmodium
  falciparum
• Loss of productivity
• One day of fever caloric intake of two days of
  hard labor
• Other problems
• Resistance to drugs is growing at an alarming
  rate
• Southeast Asia has totally drug resistant strains
• Insecticide related problems that include
• Mosquito vector resistance to pesticides (P.
  vivax chloroquine resistant)
• Human toxicity to insecticides
• Environmental toxicity due to insecticides
• Little profit margin in research and manufacture
  of pharmaceuticals
• Poor people are the victims

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Anti-Malarial Agents

• Caused by four species of Plasmodium protozoa
• P. falciparum (most lethal)
• P. vivax
• P. malariae
• P. ovale
• The vector is the female Anopheles mosquito
• Protozoa spends half of its life cycle in the
  vector
• Male mosquitos DO NOT feed on vertebrate blood
• Some mosquitos insecticide resistant (DDT,
  dieldrin)
• Symptoms
• Recurring fever every 3-4 days, nausea, vomiting,
  severe chills, delirium, high fevers,
  thrombocytopenia and severe anemia, jaundice

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Malaria Life-Cycle

• Sites of action
• Act on primary tissue forms of plasmodia within
  the liver (causal prophylaxis)
• Act on latent tissue forms of P. vivax P.
  ovale (Prevent relapse)
• Act on asexual erythrocytic stages to prevent
  schizogony (suppressive cure)
• Act against sexual erythrocytic forms to prevent
  transmission back to mosquitos (Gametocytocides)
• Act by preventing formation of sporozoites in
  infected mosquitos (Sporontocides)
• Symptoms show 1-2 weeks following a bite
• Occur when RBC rupture releasing antigenic cell
  residues and waste products

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Anti-Malarial Agents

• A requirement for the Plasmodium protozoa is a
  biochemical dependence on the host erythrocytes
• Malaria protozoa are very species specific
• Some infect only birds and others only humans
• The host erythrocytes provide the following for
  the protozoa
• A mechanism to replicate DNA and RNA
• Protozoa CAN NOT synthesize its own purines
• Must obtain both adenine and guanine bases
• Phosphate
• A.A. from digested hemoglobin (75 consumed) and
  plasma proteins
• Haemozoin is an insoluble by-product
• Pentose sugars for DNA and RNA
• Cholesterol and other fatty acids
• Glucose ? can lead to hypoglycemia
• Folic acid MUST be synthesized by the protozoa
• CAN NOT use host material ? makes the bug
  susceptible to sulfonamides

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Anti-Malarial Agents

• First agent used to treat Malaria was Chichona
  bark (natural product)
• First synthetic drug (1906) based on
  organo-arsenic compounds (dyes)
• Arphenamine (1909) as Salvarsan for treatment of
  malaria and syphilis
• WW II stimulated research into development of new
  Malaria drugs
• Why? 90 cinchona bark grown in
  Indionesia/supply cut off
• 1941-1946 over 15,000 new chemical entities were
  synthesized and tested
• 2nd research boom during the Vietnam War ?
  emergence of resistant strains
• 1968-1978 the US Army funded research that
  produced over 250,000 new drugs
• New developments
• Attempts at a malaria vaccine since 1980 have
  failed - trying recombinant DNA methods
• The entire genome of the P. falciparum has been
  sequenced just within the last year - this will
  produce a large number of potential new drug
  targets
• Problems with current situation
• Most P. falciparum infections are resistant to
  chloroquine
• The other species can produce fever for variable
  periods for up to 10 years from hidden reservoirs
  of the protozoa

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Interaction Mechanisms

• Effects of P-glycoproteins
• P-glycoprotein is a transmembrane protein located
  in many tissues that pumps an assortment of
  structurally and mechanistically unrelated
  compounds OUT OF CELLS
• The higher the affinity of a drug for
  P-glycoprotein, a smaller overall amount of drug
  will be absorbed into the cell.
• Why? Drug is pumped out of the cell following
  absorption.
• Reference
• Chemical and Engineering News June 5, 2000 pgs.
  63-73 Entitled Drug Discovery Filtering out
  failures early in the Game

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P-Glycoprotein
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P-Glycoprotein

• Some drugs induce the overexpression of
  P-glycoprotein
• Result pumping of drug out of the cell ?
  ineffective
• Located in many tissues / cells
• Controls uptake and transport of a variety of
  compounds
• Plays a role in absorption, metabolism and
  excretion
• GI tract, blood-brain barrier, liver biliary
  hepatocytes and renal proximal tubule cells,
  testis, adrenal gland and pregnant uterus
• Pharmacogenetics plays a role in P-glycoprotein
  activity
• Research ongoing

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P-Glycoprotein

• Known substrates
• Cyclosporine Neoral - Immunosuppresant
• Dexamethasone Decadron - Corticosteroid
• Digoxin Lanoxin - Chronic Heart Failure
• Diltiazem Cardizem Calcium channel blocker
  (angina)
• Etoposide VePesid - Anti-neoplastic agent
• Hydrocortisone Cortef - Corticosteroid
• Nicardipine Cardene - Calcium channel blocker
  (hypertension)
• Paclitaxel Taxol anti-neoplastic agent
• Tacrolimus Prograf - Immunosuppressant
• Verapamil Calan - Calcium channel
  blocker/hypertension/angina
• Vinblastine Velban anti-neoplastic agent
• Vincristine Oncovin anti-neoplastic agent

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Drugs for prevention

• Areas with malaria risk in Africa, South America,
  the Indian Subcontinent, Asia , and the South
  Pacific
• Atovaquone/proguanil
• Doxycycline
• Mefloquine
• Primaquine (in special circumstances).
• Areas in Mexico, Haiti, the Dominican Republic,
  and certain countries in Central America, the
  Middle East, and Eastern Europe
• Chloroquine
• Hydroxychloroquine

http//www.cdc.gov/travel/malariadrugs.htm
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Drugs for treatment
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Drug Categories

• Drugs classified by their selective actions in
  different phases of Malaria infestation
• Tissue schizonticides
• Eliminate developing or dormant liver forms
• Blood schizonticides most agents
• Act on erythrocytic parasites
• Gametocides
• Kill sexual stages and prevent transmission
• No single agent can produce a radical cure
• A few used prophylactically
• Still kill erythrocytic parasites

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Quinoline Methanol

• Cinchona alkaloids dried bark from the stem or
  root of the Cinchona succirubra
• Primary alkaloids are quinine and quinidine
• Quinine DOC for TREATMENT of uncomplicated,
  Chloroquine resistant P. falciparum - PO
• Quinidine DOC for parenteral TREATMENT of severe
  
• P. falciparum - IV
• Also an anti-arrhythmic
• Mefloquine Choice for prophylaxis in resistant
  regions.
• Blood schizonticides all 4 species
• Gametocidal vivax ovale (except mefloquine)
• Mechanism of resistance
• P-glycoprotein (pumps drug out of the cells)
• Induction of protozoan CYP-450 enzymes (increase
  clearance)

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Quinoline Methanol
More toxic that chloroquine Toxicity cinchonism
- tinnitus, headache, deafness, and occasionally,
anaphylactoid shock MOA prevents
multiplication/development of merozoites or
gametocytes in erythrocytes, antipyretic activity
by acting on the CNS temperature regulatory
center. (specifics unknown) 85 protein bound,
hepatic metabolism, renal excretion
MOA Blood schizonticide Indications
prophylaxis or treatment of acute attacks of
malaria DOC for prophylaxis - VERY useful for
chloroquine resistant strains Mixture of 4
diasteromers, 98 protein bound, hepatic
clearance Toxicity limits treatment use
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Mefloquine - Warnings

• Common side effects
• Headache, nausea, dizziness, difficulty sleeping,
  anxiety, vivid dreams, and visual disturbances.
• Rare
• Seizures, depression, and psychosis.
• Serious side effects more frequent with the
  higher doses used to treat malaria fewer
  occurred at the weekly doses used to prevent
  malaria.
• Who Should Not Take Mefloquine?
• Active depression or a recent history of
  depression
• A history of psychosis, generalized anxiety
  disorder, schizophrenia, or other major
  psychiatric disorder
• A history of seizures (does not include the type
  of seizure caused by high fever in childhood)
• Allergic to mefloquine
• Cardiac conduction abnormalities (i.e. irregular
  heartbeat).

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7-Chloro-4-aminoquinolines

• MOA Blood schizonticide
• Drug binding to ferriprotoporphyrin IX results
  in lysis of erythrocytes and malaria protozoan
  cells
• Drug itself is not a potent lysis agent
• Drug (pKa 8-9) gets trapped in protozoan lysosome
  where pH is lower (pH 4.8-5.2).
• Drug increases lysosome pH, inactivates
  hemoglobin-digesting enzymes
• Readily absorbed from the GI tract, 50 protein
  bound, accumulate in the liver, spleen, the
  heart, kidneys and brain, hepatic metabolism with
  rapid urine excretion and both unchanged and
  metabolized drug
• Toxicity nausea, vomiting, anorexia, abdominal
  cramps, diarrhea, headache, dizziness, skin
  rashes
• Use caution in hepatic dysfunction
• Other uses intestinal ambiasis (with Flagyl)

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7-Chloro-4-aminoquinolines
Indications Prophylaxis or treatment of
non-resistant malaria, amebiasis DOC for
treatment of non-falciparum and susceptible
falciparum malaria. Still used in Africa due to
low cost. Off-label use suppression of
rheumatoid arthritis and others Indications
Suppressive treatment of acute attacks of malaria
due to Plasmodium vivax, P. malariae, P. ovale,
and susceptible strains of P. falciparum. Also
useful in patients with discoid and systemic
lupus erythematosus and rheumatoid arthritis who
havent responded to drugs with less potential
for side effects
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7
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8-Aminoquinolines
Indications DOC for erradication of dormant
liver forms of P. vivax and P. Ovale Tissue
Schizonticide MOA Disrupt parasites
mitochondria, binds to DNA Major metabolic
disruption in erythrocyte development Hepatically
metabolized to active form (carboxylic
acid) Toxicity hemolytic anemia Travelers must
be tested for G6PD deficiency (glucose-6-phosphate
dehydrogenase) and have a documented G6PD level
in the normal range before primaquine use.
(Mediterranean or Asian decent likely to be
deficient)
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Other Anti-Malarials
Indications Susceptible strains only, NOT for
prophylaxis, best used in combo with a
sulfonamide (see Fansidar) Toxoplasmosis MOA
Folic acid antagonist inhibits dihydrofolate
reductase 87 protein bound, hepatic
metabolism Given as single dose treatment
Indications Prophylaxis for lt 4 months in
travelers exposed to resistant strains MOA
Inhibit protein synthesis Modest activity blood
schizonticide Discuss in depth with the
tetracyclines
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Dihydrofolate Reductase
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Other Anti-Malarials

• Halofantrine HCl - Halfan - New drug used for
  mild to moderate malaria,
• 4-substituded quinoline isostere - Blood
  schizonticide
• Contraindicated with other QT elongation drugs
  (EKG)
• Sulfadoxine and Pyrimethamine - Fansidar -
  Single dose blood schizonticide
• Atovaquone and Proguanil HCl - Malarone New
  drug combo
• Indications prophylaxis and treatment of acute
  P. falciparum

MOA for Atovaquone selective inhibitor of
parasite mitochondrial electron transport MOA for
Proguanil the metabolite cycloguanil is a
dihydrofolate reductase inhibitor Both act at the
erythrocyte stage of parasite development - blood
schizonticide
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Ch.41 Other Anti-protozoal Agents

• In the USA and other countries minor importance
  but that may be changing due to contamination of
  water supplies
• Very prevalent in tropical Third World countries
• Common diseases in the USA
• Malaria - Covered in Chapter 40
• Amebiasis
• Giardiasis
• Trichomoniasis
• Toxoplasmosis
• Pneumocystis pneumonia (AIDS)

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Other Anti-protozoal Agents

• Amebiasis causative organism is Entamoeba
  histolytica
• Invades colon wall, liver, lungs, skin
• Fecal Oral transmission - dysentery
• Giardiasis Caused by flagellate Giardia lamblia
• Enteritis and diarrhea
• Fecal Oral transmission
• Trichomoniasis caused by Trichomonas vaginalis
• Sexually Transmitted Disease
• Possible asymptomatic male carriers
• Toxoplasmosis caused by Toxoplasma Gondii
• Best known for neonatal blindness
• Obtained from cyst-ridden undercooked meat
• Can lead to disseminated disease of lymph,
  skeletal muscle, heart, brain, eye and placenta
  (immunocompromised patients)
• Pneumocystis pneumonia Caused by Pneumocystis
  carinii
• Opportunistic pathogen found in lungs of humans
• Classified as a protozoa but based on RNA
  evidence a fungi
• 60-85 of AIDS patients will get this infections

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Amebiasis Treatment

• Activity against anaerobic bacteria and protozoa
  is exhibited by several agents.
• Metronidazole for symptomatic, invasive disease.
• Paromomycin for noninvasive disease.
• Because parasites persist in the intestine of
  40-60 of patients treated with metronidazole,
  follow it with Paromomycin to cure luminal
  infection.
• Do not give the 2 medications at the same time
  because the diarrhea that often results from
  paromomycin might be confused with continuing
  active intestinal disease from the parasite.

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Amebiasis Agents
Avoid unnecessary use - carcinogenic!!!! Indicatio
ns Anaerobic infections, intra-abdominal
infections, skin and skin structure infections,
gynecological infections, septicemia, CNS
infections, lower respiratory tract infections,
endocarditis, prophylaxis for colorectal surgery,
hepatic coma, Crohns disease, pseudo colitis,
Heliobacter pylori DOC for Entamoeba
histolytica Reduce dosage based on hepatic
function, renally excrete metabolites, avoid
alcohol, may cause metallic taste MOA
Reduction of the nitro group by bacteria and
sensitive protozoans appears to be key in the
pharmacologic activity of this nitroimidazole. It
is believed to also bind DNA and prevents
replication (post-metabolic) Vaginal gel
Metro-Gel, Topical use products also
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Amebiasis Agents
Indications Acute and chronic intestinal
amebiasis. Used post metronidazole MOA Covered
with aminoglycosides Intestinal absorption is
very poor Inadvertant absorption through
ulcerative bowel lesions can lead to similar side
effects as seen with aminoglycosides - ototoxic
and renal damage
Indications intestinal ambebiasis ONLY (with
Metronidazole) MOA Unknown Do not use in
children ? optic atrophy and peripheral
neuropathy Contraindicated in hepatic damage
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Giardiasis Agents
Avoid unnecessary use - carcinogenic!!!! Indicatio
ns Anaerobic infections, intra-abdominal
infections, skin and skin structure infections,
gynecological infections, septicemia, CNS
infections, lower respiratory tract infections,
endocarditis, prophylaxis for colorectal surgery,
hepatic coma, Crohns disease, pseudo colitis,
Heliobacter pylori DOC for Giardia lamblia Reduce
dosage based on hepatic function, renally excrete
metabolites, avoid alcohol, may cause metallic
taste MOA Reduction of the nitro group by
bacteria and sensitive protozoans appears to be
key in the pharmacologic activity of this
nitroimidazole. It is believed to also bind DNA
and prevents replication (post-metabolic) Vaginal
gel Metro-Gel, Topical use products also
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Trichomoniasis Agents
Avoid unnecessary use - carcinogenic!!!! Indicatio
ns Anaerobic infections, intra-abdominal
infections, skin and skin structure infections,
gynecological infections, septicemia, CNS
infections, lower respiratory tract infections,
endocarditis, prophylaxis for colorectal surgery,
hepatic coma, Crohns disease, pseudo colitis,
Heliobacter pylori DOC for Trichomonas vaginalis
single 2g dose MOA Reduction of the nitro
group by bacteria and sensitive protozoans
appears to be key in the pharmacologic activity
of this nitroimidazole. It is believed to also
bind DNA and prevents replication (post-metabolic)
Reduce dosage based on hepatic function, renally
excrete metabolites, avoid alcohol, may cause
metallic taste Vaginal gel Metro-Gel, Topical
use products ONLY EFFECTIVE AGENT IN US!
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Toxoplasmosis Agents
Indications Many including Toxoplasmosis DOC
for Toxoplasma Gondii (Oral or IV use) MOA
binds to the 50S subunit of the bacterial
ribosome to suppress protein synthesis Eliminated
at gt90 hepatically Use with caution in
renal/hepatic failure Erythromycin
antagonizes Patient info If diarrhea occurs
notify MD immediately, take each dose with a full
glass of water
Indications Toxoplasmosis Malaria
(remember?) MOA Folic acid antagonist
inhibits dihydrofolate reductase 87 protein
bound, hepatic metabolism
Use BOTH drugs with folinic acid to maximize
effectiveness
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Pneumocystis Pneumonia Agents
Use with caution in renal/hepatic
failure Phenytoin action is increased due to
inhibition of hepatic metabolsim MOA Folate
reductase inhibitor - Some affinity for human
folate reductase - side effects Microbes CAN
NOT use dietary folic acid
MOA Competitive inhibitors of PABA drug is
bacteriostatic Prevent folate coenzyme synthesis
? no deoxythymidine for DNA synthesis
Use of two together results in a synergistic
antimicrobial effect ? blocks 2 points in the
folate pathway
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Pneumocystis Pneumonia cont.
Indications Pneumocystis carinii pneumonia
(PCP) in patients intolerant of TMP-SMZ (also
TMP-SMX) MOA inhibition enzymes involved in
umbiquinone mediated electron transport 99.9
protein bound, excreted unchanged in the feces
with extensive enterohepatic recirulation to
afford a 77 hour half life Take drug with food to
improve absorption
Indications Treatment of PCP Injection and
inhalation dose forms, extensive tissue binding,
use caution in renal failure MOA inhibits
synthesis of DNA, RNA, protein and lipids
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Other Anti-Protozoal Agents
Indications Sleeping sickness caused by
Trypanosoma brucie gambiense obtained from
blood-sucking insects MOA inhibits the enzyme
ornithine decarboxylase - Conversion of
ornathine ? putrescine (polyamine) - Regulates
DNA Synthesis Adjust dosage as a function of
creatinine clearance IV use only agent, monitor
for hematological problems
Trypanosomiasis in the Americas known as Chagas
Disease
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Ch.42 - Anthelmintic Agents

• Parasite infections whose causative agents are
• Nematodes
• Intestinal - pinworms, hookworms, roundworms
• Tissue Trinchinosis (Trichinella spiralis)
• Cestodes
• Tapeworms
• Trematodes
• Intestinal flukes

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Benzimidazoles
Indications Versatile. Particularly effective
against GI nematodes cestodes MOA inhibits
microtubule formation and prevents glucose uptake
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Anti-Helmintics
Indication Prevent and treat filarial (species
of nematode) infection MOA Unknown Indic
ation Nematodes including pinworm, roundworm
(ascaris), hookworm Single dose treatment of
trichuriasis MOA depolarizing neuromuscular
blocking agent spastic worm paralysis
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Anti-Helmintics
Indication Primarily used for flukes
(trematodes) and tapeworms (cestodes) MOA
increases cell membrane permeability leading to
loss of Ca2 resulting in paralysis
MOA prevents female schistosomes (species of
trematode) from laying eggs
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Anti-Helmintics
Indication Used for roundworms (nematodes) DOC
Strongyloidiasis (threadworm), onchocerciasis MOA
binds to glutamate-gated Cl- channels resulting
in nerve hyperpolarization and paralysis
Experimental drugs can be obtained for
compassionate use by calling the CDC, Drug
Service, Division of Host Factors, Center for
Infectious Disease
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Scabicides Pediculicides

• Our friends - head lice, crab lice, scabies
• Topical use products ONLY

Pyrethrin
MOA Synthetic pyrethroid based agents disrupt
nerve cell membranes via disruption of Na
channels leading to paralysis
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What should I focus on?

• Simple answer EVERYTHING!
• Drug Class
• Study start broad and narrow focus with
  repetition
• Mechanism of Action
• General Indication
• Unique structure function relationships
• Generic and Trade names (matching)
• Toxicity
• Major Drug interactions
• Unique characteristics