Pharmacodynamics of Antimalarial Drugs
Session 18: Pharmacodynamics of Antimalarial Drugs
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of antimalarial drugs
Describe drug interactions associated with antimalarial drugs
Describe side effects of antimalarial drugs
Describe contraindications of antimalarial drugs
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Antimalarial Drugs
Mechanism of Action of Antimalarial Drugs
2
2
45 minutes
45 minutes
Buzzing
Mechanism of Action of Antimalarial Drugs
Mechanism of Action of Antimalarial Drugs
Buzzing
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With
Drug Interactions Associated With
3
3
20 minutes
20 minutes
brainstorming
Antimalarial Drugs
Antimalarial Drugs
brainstorming
Antimalarial Drugs
Antimalarial Drugs
4
4
20 minutes
20 minutes
Presentation
Side Effects of Antimalarial Drugs
Side Effects of Antimalarial Drugs
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Antimalarial Drugs
Contraindications of Antimalarial Drugs
5
5
20 minutes
20 minutes
Brainstorming
Contraindications of Antimalarial Drugs
Contraindications of Antimalarial Drugs
Brainstorming
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 147 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Antimalarial Drugs (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do antimalarial drugs produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
The mechanisms of action for Antimalarials are as follows:
The 4-Aminoquinolines:chloroquine
Chloroquine is still used as antimalarial drugs world-wide, but increasing resistance (especially P. falciparum) has reduced its efficacy.
Its uses are now limited to malaria prophylaxis, treatment of rheumatoid arthritis or systemic lupus erythematosis
The erythrocyte stages of Plasmodium are sensitive to chloroquine.
At this stage of its life cycle, the parasite digests haemoglobin in a food vacuole to provide energy for the parasite.
The food vacuole is acidic and the weak base chloroquine is concentrated within it by
diffusion ion-trapping.
Chloroquine and other 4-aminoquinolines are believed to inhibit the malarial haem polymerase within the food vacuole of the plasmodial parasite, thereby inhibiting the conversion of toxic haemin (ferriprotoporphyrin IX) to haemozoin (a pigment which accumulates in infected cells and is not toxic to the parasite).
Ferriprotoporphyrin IX accumulates in the presence of chloroquine and is toxic to the parasite, which is killed by the waste product of its own appetite (‗hoist with its own
petard‘).
Decreased DNA synthesis: The drug can also decrease DNA synthesis in the parasite by disrupting the tertiary structure of the nucleic acid.
PST 05104 Pharmacology & Therapeutics 148 NTA Level 5 Semester 1 Facilitator Guide
Mechanisms of Resistance:
o The actions of chloroquine and related agents on heme occur at the food vacuole, and the main theory regarding resistance centers around the ability of chloroquine and others to access the food vacuole.
o Malaria may limit this through various mutations that either prevent access to the vacuole or pump drug out of the vacuole.
o One strategy being investigated to overcome resistance is to inhibit the activity of this efflux pump using another drug
.
Arylaminoalcohols (4-Aminoquinoline derivatives) o Quinine is the main alkaloid of cinchona bark.
o The mechanism of its antimalarial activity remains unclear, but may be similar to that of chloroquine
8-Aminoquinolines (Primaquine)
o Primaquine is used to eradicate the hepatic forms of P. vivax or . malariae after standard chloroquine therapy, provided that the risk of re-exposure is low.
o It may also be used prophylactically with chloroquine.
o It interferes with the organism‘s mitochondrial electron transport chain.
o Intermediates are believed to act as oxidants that are responsible for the schizonticidal
action as well as for hemolysis and methemoglobinemia encountered as toxicities.
Artenusate and Artemether
o Artemesinins undergo haem-mediated decomposition of the endoperoxide bridge to yield carbon-centred free radicals.
o The involvement of haem explains why they are selectively toxic to malaria parasites. o The resulting carbon-centred free radicals alkylate haem and proteins, particularly in the membranes of the parasite‘s food vacuole and mitochondria, causing rapid death
Anti-folates (Dapsone Proguanil, Pyrimethamine)
o Combinations of these drugs are taken orally in malaria prophylaxis, but their efficacy in acute malaria treatment is limited due to resistance.
o These agents inhibit folate biosynthesis at all stages of the malaria parasite‘s life cycle, acting as competitive inhibitors of the malarial dihydropteroate synthase (dapsone) or the malarial dihydrofolate reductase (proguanil or pyrimethamine).
PST 05104 Pharmacology & Therapeutics 149 NTA Level 5 Semester 1 Facilitator Guide
STEP 3: Drug Interactions Associated With Antimalarial Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with Antimalarial Drugs?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Drug interactions include;
Arylaminoalcohols (4-Aminoquinoline derivatives)
o Retardation of absorption when quinine if taken with aluminium-containing antacids o Potentiation of neuromuscular blocking and elevation of digoxin levels if taken
concurrently with quinine.
STEP 4: Side Effects of Antimalarial Drugs (20 minutes)
The 4-Aminoquinolines:chloroquine
o Side effects are similar to those of quinine
o Chloroquine should be used cautiously in patients with hepatic dysfunction or severe gastrointestinal problems, or in patients with neurologic or blood disorders.
Arylaminoalcohols (4-Aminoquinoline derivatives)
o Retinopathy: Damage to the retina leading to deterioration of vision may occur and typically is seen only at higher doses.
o The mechanism is still unclear, but the condition may be caused by accumulation of drug in melanin or by degradation of photoreceptors.
o Ototoxicity occurs much less frequently than retinopathy; the mechanism may be similar.
o CNS: Seizures and psychosis may occur and typically are seen only at higher doses or during rapid parenteral administration.
o Cardiovascular: Arrhythmia (QT prolongation) and even cardiac arrest may occur at higher doses. Hypotension is seen with malaria but can also be exacerbated by quinolines. Mefloquine
o Intravenous quinine can produce neurotoxicity such as tremor of the lips and limbs, delirium, fits and coma.
o Quinine is fetotoxic
o Mefloquine only: Mefloquine lowers the seizure threshold.
PST 05104 Pharmacology & Therapeutics 150 NTA Level 5 Semester 1 Facilitator Guide
8-Aminoquinolines (Primaquine)
o Hemolytic anemia is potentially fatal but typically only a concern in patients who are glucose-6-phosphate dehydrogenase (G6PD) deficient or in patients with other risk factors. G6PD maintains content of reduced glutathione (GSH) in erythrocytes, and primaquine tends to reduce GSH levels.
o Methemoglobinemia may occur.
Artenusate and Artemether
o Side effects are mild and include the following: nausea, vomiting and anorexia; dizziness.
o Preclinical toxicology suggested neuro-, hepato- and bone marrow toxicity
STEP 5: Contraindications of Antimalarial Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the side effects and adverse effects of Antimalarial Drugs? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Arylaminoalcohols (4-Aminoquinoline derivatives)
o Quinine should not be used for nocturnal cramps as its adverse effects outweigh any benefit in this benign condition.
8-Aminoquinolines (Primaquine)
o Patients at risk for granulocytopenia, such as those with lupus and rheumatoid arthritis, should not take primaquine.
o Myelosuppressants: Avoid concomitant administration of agents that suppress bone marrow.
Artenusate and Artemether
o First trimester of pregnancy as there is no evidence of safety during the first trimester of pregnancy
Anti-folates (Dapsone Proguanil, Pyrimethamine)
o Patients allergic to sulphur as these agents contain sulphur
PST 05104 Pharmacology & Therapeutics 151 NTA Level 5 Semester 1 Facilitator Guide
STEP 6: Key Points (5 minutes)
Drugs for malaria prophylaxis include proguanil, artovaquone etc
Artemisinin based combination therapies are now the first line drugs world wide
Antimalaria drugs produce their actions through different mechanisms.
STEP 7: Evaluation (5 minutes)
What are the contraindications of primaquine
What is the mechanism of action of quinine?
What are adverse effects of quinine?
PST 05104 Pharmacology & Therapeutics 152 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 153 NTA Level 5 Semester 1 Facilitator Guide
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