Antiparasitic drugs Flashcards
1
Q
Pyrimethamine mechanism of action
A
- Pyrimethamine inhibits dihydrofolate reductase
- Ultimately interferes with folic acid synthesis, which is necessary for DNA and RNA synthesis
2
Q
Formation of tetrahydrofolic acid
A
- Look on slide for the pathway
3
Q
Spectrum of activity for pyrimethamine
A
- Toxoplasmosis in dogs and cats
- Neospora in dogs
- Sarcocystis (EPM) in horses
4
Q
Toxicity of pyrimethamine
A
- Fairly safe
- Don’t need to be concerned as much with adverse effects
- Possibly bone marrow suppression
5
Q
Pyrimethamine monitoring
A
- Recommend a CBC prior to treatment and one or two during the 6 months of treatment
6
Q
Pyrimethamine length of time and use
A
- Combination with sulfadiazine for 30-180 days once a day
7
Q
Amprolium mechanism of action
A
- Structural analog of thiamine, competing for thiamine uptake into protozoal organisms
- Parasites take up the amprolium instead of thiamine
8
Q
Amprolium spectrum***
A
- Effects are greatest against the first-generation schizont stage, so its use is primarily as a preventative rather than therapeutic medication
- Only inhibits sexual stages
9
Q
Amprolium usage
A
- Used in drinking water of poultry and cattle for prevention and treatment of coccidia
10
Q
Toxicity of amprolium
A
- Polioencephalomalacia
- Polyneuritis
- Very uncommon
11
Q
Polioencephalomalacia signs and species
A
- get from slide
12
Q
Polyneuritis signs and species
A
- get from slide
13
Q
Amprolium labeled use***
A
- Labeled for food animals
- ELDU in dogs, cats, and others
14
Q
Clindamycin mechanism of action
A
- Long-term exposure to low concentrations of clindamycin reduces the level of replication of T. gondii
- Affects the protein synthesis of free parasites
- Impairs the ability of tachyzoites to infect host cells
15
Q
Clindamycin spectrum of activity***
A
- AGENT OF CHOICE for treatment of toxoplasmosis
16
Q
Route of clindamycin
A
- PO or IM (can be a disadvantage)
17
Q
Length of treatment for clindamycin
A
- 3-6 weeks
18
Q
Toxicity for clindamycin
A
- CAUTION is advised when treating cats with pulmonary toxoplasmosis because of several unexplained feline deaths in experimental drug trial
- have client sign a consent form
19
Q
Clindamycin for anaerobic infection changes
A
- Oral or IM at higher doses than for anaerobic infections for 2-4 weeks
20
Q
Mechanism of Metronidazole
A
- Intermediate metabolites affect DNA
- Alter essential metabolic pathways critical for protozoa survival
- Anti-protozoal action effect related to this mechanism
21
Q
Spectrum of activity for Metronidazole**
A
- Often the first-line agent of treating giardiasis
- It is effective against trichomonas in cattle, but CANNOT be used in cattle
22
Q
Toxicity of Metronidazole**
A
- Dose-dependent vestibular toxicity (generally slowly reversible)**
23
Q
Metronidazole species use***
A
- While its use is considered extra-label in all veterinary species, its use in food-producing animals is prohibited
- Interesting that it’s prohibited in food animals but used in humans
24
Q
Triazines
A
- Ponazuril (Marquis)
- Diclazuril (protazil)
25
Mechanism of triazines
- Believed to act on the apicoplast of protozoal organisms; but, downstream effects are not clearly defined
26
Triazines spectrum of activity****
- Class of drug has been used as a coccidiostat in poultry
- Most recent use as FDA-approved treatment and prevention for Sarcocystis neurona in horses orally for 30 days
- This is the only option approved by FDA for treatment and prevention
27
Triazines toxicity***
- Reported toxicities in horses include blisters on nose and mouth, rash/hives, colic, and diarrhea***
- Any drug given orally can cause adverse effects
When you incorporate a treatment it can change the microbiota and lead to adverse effects
28
Ponazuril vs Diclazuril relative adverse effects
- Ponazuril > diclazuril so far, but it has been on the market longer as well
29
Nitrothiazole example
- Nitrazoxanide = navigator
30
Nitrothiazole Mechanism of action***
- According to package insert, the compound undergoes reduction to free radicals inside the organism***
- These free radicals are then thought to interfere with cellular respiration of the target organism***
31
Spectrum of Nitrothiazole***
- More recent use as an FDA-approved treatment for Sarcocystis neurona in horses, and thought to be more effective than a pyrimethamine-sulfonamide combination
- Not approved for prevention***
32
Toxicity of Nitrothiazole
- Severe and potentially fatal enterocolitis
- Needs a consent form
- <5% occurrence
- because Nitrothiazole kills other intestinal parasites (bacterial, protozoal, and helminth), its use can interfere with normal intestinal flora - resulting in severe and potentially fatal enterocolitis
33
Sulfonamides used in US for treating protozoa
- Sulfadimetoxine
- Sulfadimetoxine with ormetoprim
- Sulfadiazine with trimethoprim
- Sulfametoxazole with trimethoprim
34
Sulfonamide agent spectrum
- SEE THE TABLE IN THE NOTES
| - You must memorize this
35
Sulfonamide spectrum
- Coccidia
36
Sulfonamides + pyrimethamine
- Neospora
- Toxoplasma
- Sarcocystis
37
Amprolium spectrum
- Coccidia
38
Clindamycin spectrum
- Neospora
| - Toxoplasma
39
Metronidazole spectrum
- Giardia
| - Trichomona (Ronidazole in cats)
40
Fenbendazole/albendazole spectrum
- Giardia
41
Ponazuril/diclazuril spectrum
- Neospora (cattle)
| - Sarcocystis
42
Nitrazoanide spectrum
- Sarcocystis
43
Anthelmintic resistance most affected species
- horses, sheep and goats
| - Resistance to multiple classes of agents has been documented in cattle in New Zealand and South America
44
What are the three mechanisms of resistance to anthelmintics?***
1. Failure to reach the site of action
2. Altered target
3. Inactivation of anthelmintic agent
45
Which anthelmintics have documented resistance?***
- All major families of broad-spectrum anthelmintics
- Benzimidazoles and macrocyclic lactones are the two main groups related with resistance (mostly because they are the most used)
46
What methods are being used to optimize the efficacy of available anthelmintics?****
1. Combining or rotating drugs with different mechanisms of action
2. Using as few treatments as possible (decrease exposure of parasites to anthelmintics)
3. Use appropriate doses
47
How to use appropriate dose in a large animal?
- Try not to estimate the weight
- In practice he recommends since they are generally quite safe
- He recommends that we overestimate the dose
- Except for the drugs with a very narrow therapeutic window
48
Benzimidazole mechanism of action****
- Strongly binds to parasite free beta-tubulin molecules, affecting the tubulin polymerization and interfering microtubule-dependent processes including cell division, motility and transport
- May also inhibit enzymatic activity (fumarate reductase primarily**, succinate dehydrogenase, others) resulting in decreased energy production in parasites
49
Spectrum of activity of benzimidazoles***
Broad spectrum!
- Broadly: GI nematodes, protozoa (giardiasis), fungi, and mites
50
More info about benzimidazoles spectrum
- Look at the slides
51
Therapeutic margin of benzimidazoles***
- WIDE THERAPEUTIC margin
52
***Which drug in the benzimidazoles is most likely to cause toxicity?
- Albendazole
53
Toxicity of Albendazole in cats***
- Weight loss, neutropenia, mental dullness
54
Toxicity of Albendazole in dogs***
- Lethargy anorexia
- Bone marrow suppression
- Liver toxicity in dogs, mostly seen with prolonged or high-dose therapy (unknown mechanism)
- Might not use in combination with another drug that reduces bone marrow suppression****
55
Reproductive effects of albendazole*******
- Teratogenic effects may be possible, therefore should not be used in pregnant animals
- Package insert of albendazole states that it is NOT TO BE USED IN FEMALE CATTLE DURING THE FIRST 45 DAYS OF PREGNANCY***
- Only described in cattle but probably don't use in any pregnant animals
56
Clinical use of benzimidazoles
- At least 10 benzimidazoles marked for use in veterinary species
57
Fenbendazole efficacy***
- one of the broader spectrum agents with efficacy against: 1.) cestodes, intestinal nematodes (adults and 4th stage larvea); lungworms (adult and larval stages) in cattle, sheep, and goats
58
Methods of heard dosing for benzimidazoles and formulations**
- Incorporation of drug into water or feed blocks - no direct control
- Drenching/tubing but time consuming and expensive
- Ruminal devices - once delivered to the rumen, to coincide with prepatent period of major nematodes of cattle (up to 4 months)
59
Clinical use of benzimidazoles in SA
- Hookworms
- Whipworms
- Tapeworms
- Taenia but not Echinococcus
- Giardia
60
Clinical use of benzimidazoles in horses
- Large and small strongyles
- Pinworms
- At higher doses ascarids
61
Thiabenazole family and use
- Benzimidazole
| - Not useful against cestodes and trematodes
62
Febantel family and use
- Pro-drug of fenbendazole
63
Other benzimidazoles
- Look on the slides
64
Withdrawal times for benzimidazoles
- Highly variable depending on species, formulation, and drug
- Don't need to memorize specific times
- see slide
65
Imidazothiazole mechanism of action (levamisole)***
- Agonist at nicotinic acetylcholine receptors on nematode muscle cells (depolarization) resulting in spastic paralysis***
- Another mechanism described about interference with metabolism of the parasite but is not the primary mechanism of action of this drug
66
Spectrum of levamisole**
- Effective against a variety of GIT and lung nematodes but not cestodes or trematodes
67
Toxic side effects of levamisole
- In mammals, mostly has to do with cholinergic activity of both muscarinic and nicotinic effects
- SLUD, respiratory distress, bradycardia, asphyxia, CNS depression
68
Antidote of levamisole***
- None
| - Cannot give atropine
69
Therapeutic index of levamisole*****
- It is the most toxic anthelmintic
| - Therapeutic margin is fairly narrow - depending on species, the margin may be as low as 3x the therapeutic dose
70
What species is most sensitive to levamisole?**
- Sheep appear more sensitive than cattle, while chickens tend to tolerate levamisole quite well
71
Formulations of levamisole/imidazothiazoles
- Tablet, oral solution, oral drench, feed additive, SC injection or topical
72
Methods of herd dosing of levamisole/imidazothiazoles
- Injectable (SQ or IM) or pour on formulations are used in cattle
73
Tetrahydropyrimidines (pyrantel, morantel) MOA***
- Agonist at nicotinic acetylcholine receptors on nematode muscle cells resulting in spastic paralysis (similar to levamisole)
- Secondary mechanism related with acetylcholinesterase but less important
74
Spectrum of Tetrahydropyrimidines (pyrantel, morantel)***
- In horses, GI nematodes
- At high doses can be used against the ileocecal tapeworm of horses (Anoplocephala perfoliata)
- In cattle, dogs, and cats, GI nematodes
75
Tetrahydropyrimidines (pyrantel, morantel) toxicity***
- High margin of safety
- Doses 7x greater than the therapeutic dose produce no signs of toxicity in all major veterinary species
- Better choice than levamisole for this reason
76
Drug interactions with Tetrahydropyrimidines (pyrantel, morantel)*
- Not recommended to use with other cholinergic agonists (levamisole, others)
- Don't use with cholinergic antagonists (piperazine, others) - these cause a flaccid paralysis instead of a spastic paralysis
77
What are the two formulations of pyrantel?
- Pyrantel tartate
| - Pyrantel pamoate
78
Pyrantel tartate formulation
- Horses formulated for continuous daily administration for prolonged periods of parasite exposure
79
Pyrantel pamoate formulation in horses
- Horses: administered as suspension or paste as well as mixing with feed
80
Pyrantel pamoate formulation in dogs
- suspension and tablet forms; combined in a tablet with febantel and praziquantel
- Combined in a chewable containing ivermectin (will affect nematodes, cestodes, and trematodes)
81
Which tetrahydropyrimidine is available for cattle?
- Morantel tartrate
| - Cattle-sustained release bolus for both beef and dairy cattle
82
Heterocyclic compounds (piperazine) MOA
- GABA agonist - induces flaccid paralysis in susceptible nematodes
- Hyperpolarization due to influx of chloride
83
Spectrum of activity of Heterocyclic compounds (piperazine)
- Primarily ascarids
| - VERY NARROW SPECTRUM
84
Margin of safety of Heterocyclic compounds (piperazine)
- Wide margin of safety
| - Available over the counter
85
Heterocyclic compounds (piperazine) toxic effects
- Wide margin of safety
| - Signs of toxicity involve CNS depression (ataxia, weakness, muscle tremors)
86
Piperazine indication
- Dogs, cats, horses for control of ascarids
87
Diethylcarbamazine indication ***
- First heartworm preventive that had to be administered daily (disadvantage)
- Current use is limited to dogs that don't tolerate monthly preventatives
- It's a heterocyclic compound
88
Melarsomine (arsenical) mechanism of action
- presumed to affect glycolysis
89
Spectrum of activity of Melarsomine (arsenical)
- Adult and 4-month-old heartworms ***
90
Efficacy of single regimen of 2 injections one month apart of Melarsomine (arsenical)
>90%
91
Efficacy of second regimen 4 months later of Melarsomine (arsenical)
98%
92
Margin of safety of Melarsomine (arsenical)****
- Very low margin of safety
93
Toxicity of Melarsomine (arsenical)****
- Liver toxicity
- Nephrotoxicity
- Aldulticide-induced thromboembolic pneumonia (if heavy parasite load)
94
Adverse reactions specific with melarsomine***
- Injection site reactions
- Coughing/gagging
- Depression/lethargy
- Anorexia/inappetence
- Pyrexia (fever)
95
About how long can it take for some of the adverse effects with melarsomine to occur?
- Can take about a week for some of them
96
What drug can you use to treat adverse effects of melarsomine?****
- Dimercaprol
| - Can be used as a possible antidote
97
When should you administer dimercaprol for it to be effective?***
- Only within the first 3 hours of melarsomine administration (but reduces the effective of melarsomine)
98
MOA of Dimercaprol*******
- Binds melarsomine and prevents absorption
- This is why it has the window
- May or may not be effective, but it's the only option
99
***Contraindication of melarsomine
- Contraindicated in dogs with Class 4 (very severe) heartworm disease
- NOT indicated for cats
100
Melarsomine route*******
- A lot of recommendations about where and how to administer
- The drug must be administered ONLY in the lumbar area in the muscles
- DO NOT use in any other muscle group. DO NOT USE IV
- Care should be taken to avoid superficial injection or leakage
- You must be careful - should not be any subcutaneous leak of the injection --> can lead to abscesses
- change the side between injections
101
Melarsomine monitoring
- Should be monitored during treatment and for up to 24 hours after the last injection
- at least 8 hours
102
Goal of melarsomine
- Elimination of ALL adult heartworms with minimal post treatment complications
103
Emodepside mechanism of action***
- Binds to a GPCR (latrophilin like receptor) and via secondary messenger systems releases an inhibitory neuropeptide (possibly GABA) that causes a flaccid paralysis
104
Spectrum of activity for emodepside
- Broad nematodal activity** against both larval and adult forms (including those that havae developed resistance to other antinematodal drugs)
- Has activity against tapeworms (Dipylidium caninum, Taenia taeniaformis, Ancylostoma tubaeforme)
105
Margin of safety of emodepside
- High margin of safety
106
Emodepside pecies
- Cats and dogs
107
Cat formulation of emodepside***
- Currently approved only for cats as a spot-on formulation (Profender)
- Contraindicated in kittens under 2 months of age
108
Dog formulation of emodepside
- Have an oral formulation that is tolerated very well
- In IVERMECTIN-sensitive collies the therapeutic margin of emodepside is significantly lower. Treatment at 2x the therapeutic dose can cause symptoms such as discomfort and uncertain gait
- Might have to be due with p-glycoprotein export so it concentrates in the brain
109
Important cestodes
- Anoplocephala perfoliata (causes erosions around the ileocecal valve predisposing to intussusception)
- Dogs (Echinococcus)
110
Choices for anticestodes**
- Pyrantel
- Morantel
- Praziquantel
- Epsiprantel
111
MOA for praziquantel and epsiprantel***
1. Damage integument of the parasites which generates gaps and allows molecules to enter and exist
2. Causes muscular contraction and paralysis by interfering with calcium homeostasis
- May not kill them right away but eliminates in the feces
112
Praziquantel spectrum***
- Adult stages of all species of tapeworms of farm and companion animals
- Has shown 100% activity against E. granulosus in dogs and is considered the treatment of choice*****
- Some activity against trematodes
113
Epsiprantel spectrum of activity
- Labeled for treatment of common tapeworms in dogs and cats
114
Praziquantel toxicity
- In general quite safe
- GI toxicity can occur with high doses
- Has been used safely in pregnant animals
115
Epsiprantel toxicity
- In general quite safe
- Might be even safer than praziquantel
- GI toxicity (vomiting) can occur with large overdoses (40x in cats); no signs of toxicity with 36x dose in dogs
116
Antitrematode drugs
1. Clorsulon
2. Triclabendazole
3. Praziquantel
117
Main drugs for treating Fasciola
1. Clorsulon
| 2. Triclabendazole
118
Clorsulon MOA***
- Competitively disrupts glycolysis after its ingestion by the fluke
- Disrupts synthesis of glucose
- Affects metabolism of glucose
119
***Spectrum of Clorsulon
- Adult*** liver flukes in cattle, sheep, and goat; some other flukes
120
Margin of safety of clorsulon
- WIDE MARGIN of safety
121
Mechanism of action of Triclabendazole
- Prevents polymerization of beta-tubulin
- Parasite has problems moving and taking in nutrients
- May involve binding to tubulin, but at different site than other benzimidazoles
122
Triclabendazole spectrum****
- Adult liver flukes AND immatures to 1-week-old flukes
- Clorsulon only against adults
- Significant because it is effective against migratory stages of the parasite that cause tissue damage****
- Also has greatest antitrematodal activity of all benzimidazoles******
- This is the best one you can choose
- In dogs, fenbendazole may be the best choice
123
Albendazole spectrum
- Active against liver flukes older than 12 weeks
124
Safety of triclabendazole
- Wide margin of safety
| - In general benzimidazoles are contraindicated against pregnant cattle; same contraindication for triclabendazole
125
Triclabendazole route
- Orally
126
Triclabendazole species***
- Cattle, sheep, and goats
- Keep withdrawal times in mind (about 2 months)
- For macrocyclic lactones, they require a longer withdrawal time
127
Clinical use of triclabendazole***
- For treatment of liver flukes - both acute and chronic because it is effective against mature and immature stages (advantage over many other flukicidal drugs)
128
Macrocyclic lactones overview
- Used in livestock, companion animal , wildlife, and humans and are available as injectable, pour-on (cattle), and oral formulations
129
Why are MLs do desirable?
- High potency
- High lipophilicity (stay in tissues for a long time)
- High therapeutic index
- Persistence in tissues
130
High potency meaning
- small amount of drugs have a really big effect
131
Examples of MLs
- Ivermectin
- Selamectin
- Moxidectin
- Doramectin
- Milbemycins
132
What defines an ML?
- 16 member macrocyclic lactone ring structure and are derived from the fermentation products of various strains of Streptomycete
133
What channels do MLs impact?***
- Glutamate-gated chloride channels
134
What is the MOA of MLs?****
1. Glutamate-gated chloride channels
2. (MLs bind to the channels which) Increases chloride conductance across cell membranes, leading to hyperpolarization
3. Paralyses two things with flaccid paralysis:
A. Paralyzes pharyngeal pump (alters nutrient ingestion)
B. Also paralyzes somatic musculature (alters parasite to remain at the site of predilection)
135
Spectrum of activity of MLs***
- Insects (some lice)
- Nematodes
- Ectoparasites (Often used for treating various mite infections in dogs including otodectes, sarcoptes, demodex)
- HW disease prevention: Microfilaria are very sensitive and doses required for prevention of HW disease are very low and not a problem for dogs sensitive to avermectin; this has to do with potency
136
What do MLs not work against (which is why they aren't considered broad spectrum)?***
- Most cestodes and trematodes
137
Variable susceptibility of helminth larvae to MLs***
- In horses, encysted and developmentally arrested (hypobiotic) cyathostome larvae are the most resistant
- In contrast, all stages of susceptible helminths in cattle - including hypobiotic larvae - are sensitive**
138
Primary toxicity of MLs****
- Neurotoxicity
| - Can occur in all mammals, but toxicity is a matter of dose
139
What is the reason behind the selective toxicity of MLs?******
- Mammalian GABA gated channels are located primarily in the CNS, and these drugs (in most animals) do not cross the blood brain barrier*******
- Several dog breeds suffer neurotoxicity from macrolides at doses much lower than most dogs - these dogs are "avermectin sensitive"
140
***ML Drugs that we are concerned with the most for MDR1
1. Ivermectin
2. Doramectin
3. Abamectin
141
***ML Drugs that we should be cautious with but aren't as big of a deal with MDR1
1. Milbemycin
2. Moxidectin
3. Selamectin
142
Primary clinical signs with MLs***
- These drugs increase GABA release; therefore, clinical signs are predictable and neurologic (CNS)
- Muscle tremors, mydriasis, hypersalivation, ataxia, depression
- Severe toxicoses can result in coma, respiratory depression, and death (may need critical care for 10 days)
143
What are the first signs you usually see with ML toxicity?
- Mydriasis
| - Hypersalivation
144
What are other adverse affects associated with MLs that are associated with the death of pathogenic and/or incidental parasitic species?
- Hind limb paralysis in cattle treated during spinal cord migratory phase of Hypoderma bovis
- SC edema and pruritus in horses with heavy infestations of Onchocerca cervicalis (uncommon)
145
Can susceptible dogs that ingest feces of cows or horses treated with MLs show signs?****
- Yes!
- Active drug eliminated in feces
- Dogs ingesting feces of sheep and horses recently dosed with MLs have developed toxicity
- This class of anthelmintic is extremely potent compared to other classes of parasiticides
146
Minimum age for MLs treatment?****
- Do not administer to animals less than 6 weeks of age - immature BBB****
147
Clinical use of MLs in ruminants
- Ruminants - SC, oral, and topical formulations available for GI nematodes, lungworms, arthropod parasites (mites, Hypoderma bovis, Oestrus ovis, lice, cattle ticks, and screwworm)
- Remember nematodes and ectoparasites in general
148
Withdrawal time length for MLs****
- Prolonged tissue residues exist
- WIthdrawal times are fairly long (1-4 months)
- Fairly lipophilic
149
Clinical use of MLs in horses
- Ivermectin and moxidectin available by either oral paste or gel formulations
- Both are effective against GI nematodes and lungworms
150
Clinical use of MLs in cats***
- Topical formulations available for treating ear mites in cats***
- Other treatments are extralabel (heartworms, demodectic mange, sarcoptic mange, GI nematodes)
151
Dogs and cats licensed MLs
- licensed macrocyclic lactones (oral, topical, injectable) are available for heartworm prevention in dogs and cats
