JD - Anthelmintics II Flashcards
What are the main criteria for a drug targeting filarial disease? (7)
- Low cost
- Oral administration
- Safe and tolerated by all ages
- Provides effective protection for months
- No drug resistance
- Effective against all parasitic life stages
- Broad spectrum
What are the mechanisms for selective toxicity? (2)
Distributional:
* Differences in drug distribution between host and pathogen
* Targets cells or tissues more accessible to the drug than non-target cells
Biochemical:
* Differences in metabolic pathways or enzymes between host and pathogen
* Drug targets a process or molecule specific to the pathogen
What are the approaches to anthelmintic drug discovery? (3)
Serendipity:
* Accidental discovery of drugs (e.g., ivermectin from soil samples, niclosamide as a pesticide)
Screening natural products:
* Screening plants, animals, and microorganisms (e.g., artemisinin from sweet wormwood, avermectins from Streptomyces avermitilis)
Target selection and rational drug design:
* Identifying worm-specific molecular targets
* Designing drugs to disrupt metabolism or reproduction
What are the approaches to define the pharmacology of anthelmintics? (2)
Pharmacological studies in model nematodes:
* Ascaris suum: Used to study drug mechanisms, physiological, and biochemical effects
Genetic studies in C. elegans:
* Small, transparent nematode easy to culture and manipulate genetically
* Identifies genes/pathways for drug resistance
* Enables high-throughput screening
What are the key points about levamisole? (4)
Discovery: First identified in 1966 at Janssen Cilag
Mechanism of Action: Causes spastic paralysis by acting on nicotinic acetylcholine receptors
Resistance: Mutations in nicotinic receptors confer resistance
Structure: A racemic mixture with the (S)-enantiomer as the active form
What was the significance of Brenner’s 1974 study on levamisole-resistant C. elegans? (3)
- Isolated C. elegans mutants resistant to levamisole
- Identified mutations in genes encoding nicotinic acetylcholine receptor (nAChR) subunits
- Demonstrated the utility of C. elegans in studying drug resistance mechanisms
What neurons (4) and neurotransmitters (2) are involved in the circuitary for control of locomotion?
Neurons:
* Dorsal Excitatory (DE): Stimulates dorsal muscle contraction
* Dorsal Inhibitory (DI): Inhibits ventral muscle contraction
* Ventral Excitatory (VE): Stimulates ventral muscle contraction
* Ventral Inhibitory (VI): Inhibits dorsal muscle contraction
Neurotransmitters:
* Acetylcholine (ACh): Excitatory, promotes contraction
* GABA: Inhibitory, prevents contraction
How does the circuitary locomotion mechanism work? (5)
- DE Activation: DE neurons release ACh, exciting the dorsal muscle, causing it to contract.
- DI Activation: Simultaneously, DE activation inhibits DI neurons, preventing them from inhibiting the ventral muscle.
- VE Activation: As the dorsal muscle contracts, it stretches the ventral muscle, activating VE neurons.
- VI Activation: VE activation also inhibits VI neurons, preventing them from inhibiting the dorsal muscle.
- Alternating Contraction: This cycle repeats, leading to alternating contraction and relaxation of the dorsal and ventral muscles, resulting in locomotion.
Describe the absorption and tolerance of Levamisole? (2)
- Absorbed via the gastrointestinal tract.
- Well-tolerated by the host, with side effects like dizziness and nausea (likely due to activation of nicotinic receptors at autonomic ganglia).
What is the mechanism of action of levamisole? (3)
Levamisole relies on differences between host and parasite nicotinic acetylcholine receptors.
It is a weak agonist at the neuromuscular junction (NMJ) receptors.
More effective against parasites with minimal side effects on the host
What is the mechanism of action of piperazine? (4)
Causes flaccid paralysis of nematodes by:
* Blocking neuromuscular transmission
* Altering membrane potential
Mimics the action of GABA as a partial agonist
What are the side effects of piperazine? (8)
Side Effects:
* Gastrointestinal: Nausea, vomiting, diarrhea
* Allergic reactions: Urticaria, Stevens-Johnson syndrome
* Neurological: Dizziness, blurred vision, seizures (in predisposed individuals)
What are the contraindications of piperazine? (4)
- Allergy: History of allergy or sensitivity to piperazine or any of its ingredients.
- Bowel Obstruction: Individuals with a bowel obstruction should avoid piperazine.
- Epilepsy: Piperazine is contraindicated in individuals with epilepsy.
- Liver or Kidney Problems: Individuals with liver or kidney problems should use piperazine with caution and under medical supervision.
