Exam 3 Flashcards
Mitosis; How long? Drugs that Target
o 1-7hrs
o Small % of cell cycle
Drugs
* Vinca alkaloids
* Taxols
G1 - 1st Gap Phase; What happens? Drugs that Target
o 7-170hrs
o RNA transcription
o Protein synthesis
Drugs
* L-Aspariginase (Elspar)
S-Phase; What happens? Drugs that Target
o 8-30hrs
o DNA synthesis in preparation for chromosomal duplication
o High metabolic rate
o High energy requirements
o Neoplastic cells have large nuclei
Drugs
* Antimetabolites
G2 - 2nd Gap Phase; What happens? Drugs that Target
o 1-4hrs
o pause prior to mitosis
o “checklist”
Drugs
* none
G0; What happens? Cells Involved
o Cells that are not actively cycling (replicating)
o Neurons, muscle cells do not re-enter cell cycle
o Hepatocytes normally do not re-enter cell cycle after maturity, but can
Fraction Cell Kill
o Chemo only kills fraction of cells not number of cells
o Very hard to completely eliminate (fraction of a fraction of a fraction)
Reasons for Chemo Failure
Dose limited by toxicity to patient
Drug resistance
* Failure to reach target
* Inactivation of drug
* Altered target
* Failure to undergo apoptosis
Response to Chemo
Complete
* Resolution of clinically apparent disease for at least 1mo
Partial
* Reduction of measurable tumor dimensions by at least 50% for 1 mo
Stable
* No change
* OR
* < 50% reduction in tumor dimensions
Progressive
* Growth of lesion
* OR
* appearance of new lesions
Resistance Criteria Based on 1 Dimension
Complete response:
o tumor no longer detectable,
Partial response:
o greater than 30% decrease in longest dimension of all target lesions
Stable disease:
o less than 30% decrease in the longest dimension of all target lesions, or less than 20% of tumor growth.
Progressive disease:
o greater than 20% increase in longest dimension was observed.
Biological response
o complete responders + Partial response + Stable disease
Chemo Dosing Based on Body Surface Area Vs Weight
Body Surface Area correlates w/
* Cardiac output
* Glomerular filtration rate
* Basal metabolic rate
Weight
* better for bone marrow stem cell turnover
Common Toxicities from Chemo Drugs
o BAGI
Bone marrow
* RBCs ->
* Neutrophils ->
* platelets
Alopecia
* Less common
GI
* Anorexia, nausea, V/D
* Premed w/ cisplatin to avoid nausea
* Lomustine at bed to allow sleep
* Doxorubicin for colitis associated nausea
Infertility
* Congenital malformations
Chemo Dosing & “cure” rate
o 20% dose reduction -> 50% reduction in cure rate
Chemo Safety Considerations
o Pregnant women should avoid
o Avoid contact w/ urine & feces 3 days post chemo
o PPE when prepping
Alkylating Agents for Chemo; MOA, Drugs, Use
MOA
* Interfere w/ DNA replication
* Form cross-bridges
* Mispairing
Drugs
* Cyclophosphamide
* Lomustine (can penetrate CNS)
* Chlorambucil
* Melphalan
Use
* Part of lymphoma treatment
* Mast cell tumors (lomustine)
* Histiocytic sarcoma (lomustine)
* Metronomic chemo
Cyclophosphamide, Lomustine, Chlorambucil Toxicities
Cyclophosphamide Toxicity
* BAG (worst at 7-14d)
* Sterile hemorrhagic cystitis
Lomustine Toxicity
* BAG
* Chronic neutropenia or thrombocytopenia
* Long-term hepatic, renal, & lung tox
Chlorambucil Toxicity
* BAG
* Used for pts that don’t tolerate Cyclophosphamide
* Rare animal still develops GI signs
Mitotic Inhibitors; Where from? MOA, Drugs, Use
o Initially from nature
MOA
* Bind microtubules ->
* interfere w/ cell division by interrupting the mitotic spindle
Drugs
* Vinca alkaloids (tubules don’t form): Vincristine (Oncovin®)
or Vinblastine
* Taxanes (tubules don’t break down): Paclitaxel
Use
* Component of lymphoma protocols (Vincristine)
* Vincristine alone: TVT
* Vinblastine-canine mast cell tumor, lymphoma
* Vinorelbine- concentrates in lung
* Injectable only
Vinca Alkaloids & Paclitaxel Toxicity
Vinca Alkaloids Toxicity
* BAG
* Peripheral neuropathy
* Dose must be reduced in MDR1 mutants
Paclitaxel Toxicity
* BAG
Antibiotics for Cancer; MOA, Drugs, Use
MOA
* Most from plants
* Many
* Interfere w/ DNA & RNA synthesis
* Intercalation into DNA
* Inhibition of topoisomerase
Drugs
* Doxorubicin (Adriamycin®)
* Mitoxantrone
* Bleomycin
Use
* Doxorubicin has high activity against a variety of tumors
* Newer analogues (Mitoxantrone) with less cardiotoxicity don’t seem to have same efficacy as doxorubicin
* Bleomycin is used for electrochemotherapy
Antibiotics for Cancer; Toxicity, Specific tox for Doxorubicin
- BAG
- Colitis
Doxorubicin
* Cumulative cardiac tox
* Possible renal damage in cats
* Severe tissue reaction if extravasated
* MDR1 substrate
Platinum Compounds; MOA, Drugs, Use
MOA
* Lab created
* Intra-strand cross-link DNA ->
* Interferes w/ RNA synthesis & DNA replication
Drugs
* Cisplatin
* Carboplatin
Use
* Osteosarcoma (Cisplatin is agent of choice but replaced by Carboplatin due decreased)
* Carcinomas- anal sac tumors, squamous cell carcinomas, nasal carcinomas
* Intralesional in equine sarcoids
Platinum Compounds; Toxicity, Specific Tox for Cisplatin
- BAG
- Carboplatin much safer in cats than Cisplatin
Cisplatin Toxicity
* Emetogenic
* Nephrotoxic
* Ototoxic
* Fatal pulmonary edema in cats
Antimetabolites for Cancer; MOA, Drugs, Use
MOA
* Man made
* Interfere with purine and pyrimidine synthesis and incorporation into DNA
Drugs & Use
* Methotrexate - older UW-Madison protocol for lymphoma
* 5-fluorouracil – carcinomas
* Azathioprine – immune mediated dz
* Cytosine arabinoside - Canine non-infectious encephalitis, Acute leukemia, Lymphoma in horses
Antimetabolites for Cancer; Specific Drug Toxicities
Methotrexate
* BAG
* Drug interactions due to protein bound
5-fluorouacil
* BAG
* Central neurotoxicity
Azathioprine
* BAG
* Myelosuppression in cats
Cytosine arabinoside
* BAG
L-asparaginase Enzyme; MOA, Toxicity, Use
MOA
* Inhibits protein synthesis
Toxicity
* Allergic reactions
* Pancreatitis
* Vomiting
Use
* Lymphoma
* Tumors in CNS
* NO IV
NSAIDs for Cancer; MOA, Drugs, Toxicity, Use
MOA
* COX-2 overexpressed in many tumors
* Enhance apoptosis
* Decrease tumor invasiveness
* Block angiogenesis
* Increase immune response by suppressing T-regulatory cells
Drugs
* Piroxicam
Toxicity
* GI ulceration (can add misoprostol)
* Renal (keep patients hydrated)
* Platelet dysfunction, bleeding
Use
* Transitional cell carcinoma
* Palliation of other tumors w/ metronomic chemotherapy
Tyrosine Kinase Inhibitors; MOA, Drugs, Adverse Effects, Uses
MOA
* Inhibit cell signaling
Drugs
* Toceranib Phosphate
* Masitinib (unavailable)
Adverse Effects
* Neutropenia
* GI ulceration (avoid NSAIDs)
* Protein-losing nephropathy
* Vasculitis
Uses
* Mast Cell tumors
* Neuroendocrine tumors
* Anything for which we have no treatment
Canine Melenoma Vx; MOA, Drugs, Adverse Effects, Uses
MOA
* DNA Vx ->
* Human tyrosinase taken up & processed by host cells ->
* Immune response triggered against tyrosinase on melanoma cells
Drug
* Oncept
Use
* Stage II or III melanoma in conjunction with standard tx for local disease
Adverse Effects
* Injection site pain
* Fever
* Hypersensitivity (rare)
* Localized vitiligo
Metronomic Chemo
o Low doses of a chemotherapy drug daily
o Tends to be alkylating agents because they can be given orally
o May have antiangiogenic effects
o May positively affect immune cells
Managing Adverse Effects of Chemo
o Maropitant for nausea
o Metronidazole for bacterial overgrowth Ds
o Morphine for pain
o Metamucil in diet to help w/ Ds
o Famotidine & Omeprazol to prevent ulcers in mast cell patients
Seizures; Most common cause, Pathophysiology, When to Treat
Most common Cause
* Idiopathic/genetic epilepsy
Pathophysiology
* Excesive hypersynchronous electrical activity in the thalamocortex -> sudden transient event
* Glutamate depolarizes -> excitation
* GABA hyperpolarizes -> inhibition
When to Treat
* >2 seizures in 6 months
* cluster seizures
* status epilepticus
* known structural brain dz
* prolonged/severe post-ictal period
* consider QOL of patient & owner
Phenobarbitol; MOA, Pros, Cons
MOA
* Bonds GABA receptor ->
* Hyperpolarization / inhibition
Pros
* Best efficacy
* Works in MANY species
* Inexpensive
* High bioavailability
Cons
* hepatic metabolism
* Q12 timing matters
* Takes 2wks to reach steady state
* Sedation
* Ataxia
* PU/PD
* Over time need high & higher dose -> Hepatotoxicity
* Withdrawal seizures
* MANY side effects
Potassium Bromide; MOA, Pros, Cons
MOA
* Mimics Cl ->
* Hyperpolarizes / inhibits
Pros
* Good efficacy
* Inexpensive
* SID dosing
Cons
* Need to monitor salt intake
* Very slow clearance
* Renal excretion
* Contraindicated in cats
* Sedation
* Ataxia
* PU/PD
* Polyphagia
* OTHER
Levetiracetam (Keppra); MOA, Pros, Cons
MOA
* Binds synaptic vesicle protein ->
* Prevent neurotransmitter release
Pros
* Rapid oral absorption
* Little hepatic metabolism
* Fewer side effects
Cons
* Should use w/ other drugs
* Variable efficacy & tolerance
* Sedation
* Ataxia
* Behavior changes (aggression)
Zonisamide; MOA, Pros, Cons
MOA
* Blocks voltage gated Na channels ->
* Hyperpolarizes
Pros
* Few
Cons
* Should use w/ other drugs
* Variable efficacy & tolerance
* Hepatic metabolism
* Sedation
* Ataxia
* VERY MANY
* Don’t use
Method for Using Multiple Seizure Drugs
o Start with 1st line drug
o Slowly titrate to effect
o Once maxed out, THEN reach for 2nd drug
o Once maxed out, THEN reach for 3rd, etc
o If >1 anticonvulsant, consider referral
o Make sure to look up drug interactions
Treating Seizures in Emergency; Drugs, MOA, Things to know, Adverse Effects
Benzodiazepines – Diazepam or Midazolam
MOA
* Binds to GABA receptor
Things to know
* Binds to plastic
* Light sensitive
* Intranasal faster than IV
* Rapid distribution to CNS
* Metabolized by liver
* Short half life -> need frequent bolus or CRI
Adverse Effects
* Sedation
* Paradoxical excitation (rare)
Drugs to Use at Home in Emergency Seizure
- Rectal diazepam
- Intranasal midazolam
Buspirone; MOA, Use Adverse Effects
MOA
* Partial serotonin agoinist
Use
* Stress-related urine marking in cats
* Generalized anxiety
Adverse Effects
* Increased affection
* +/- aggression
* hypotension when on diuretics
Trazadone; MOA, Use Adverse Effects
MOA
* Serotonin antagonist and reuptake inhibitor
Use
* Anxiety/phobias
* Facilitate post-op confinement in dogs
* Facilitate transport & exam anxiety in cats
* Need less propofol
* Calming to horses
Adverse Effects
* Sedation
* Ataxia
* GI effects (nausea, V+/D+)
* Disinhibition (aggression, tachycardia, anxiety)
* Priapism
* Pupil dilation (careful w/ glaucoma)
* Can cause serotonin syndrome when given w/ other drugs
Alprazolam; MOA, Use Adverse Effects
MOA
* Benzodiazepine -> GABA agonist
Use
* Acute anxiety induced by loud noise stimuli
* Preferred for storms, fireworks
* Fast acting; given 30-60min prior to trigger
Adverse Effects
* Don’t use w/ carbonic anhydrase inhibitors
* Antacids reduce PO absorption
* Sedation
* Increased appetite
* Decreased learning
* Paradoxical excitement
Dexmedetomidine; MOA, Use Adverse Effects, Similar Drugs
MOA
* Oromucosal gel
* Alpha-2 agonist
* 30-60 mins prior to stimuli
Use
* Noise phobia
Adverse Effects
* GI
* Periorbital edema
* Sedation
* Bradycardia
Similar
* Clonidine off-label
Clomipramine; MOA, Use Adverse Effects
MOA
* Blocks pumps involved in reuptake of serotonin (5-HT) and norepinephrine (NE) ->
* Increase Conc of 5-HT & NE in synapse
Use
* Separation anxiety in dogs
* Steryotopies
* Noise phobia
* Urine spraying in cats
* Feather picking in birds
Adverse Effects
* decreased PO bioavailability (improved when given with food )
* Urine/fecal retention
* Cats more sensitive to adverse effects
* Sedation
* GI signs
* Increased Liver values
* Anticholinergic effects (dry mouth, tachycardia, etc)
* Testicular hypoplasia risk in breeding dogs (at high doses)
* Can decrease total and free T4
* Overdose: mydriasis, seizures, arrhythmias, death
* Metabolized by Cyp450
Fluoxetine; MOA, Use Adverse Effects
MOA
* Blocks pumps involved in reuptake of serotonin (5-HT) ->
* Increase Conc of 5-HT in synapse
Use
* Separation anxiety on dogs (licensed)
* Aggression in dogs & cats
* Compulsive disorders in dogs & cats
* Inappropriate urination in dogs & cats
* Overgrooming in cats
* Movement disorders (Scotties)
Adverse Effects
* Lethargy
* GI signs
* Restlessness/anxiety
* Tremors (+/- seizures?)
* Panting, hypersalivation
* Behavior changes (esp cats)
* increased blood glucose (caution in diabetes)
* MANY drug interactions
Selegiline MOA, Use Adverse Effects
MOA
* Selegiline inhibits MAO-B ->
* Inhibits dopamine reuptake & stimulates dopamine production
* Dopamine breakdown results in free radicals ->
* Selegiline reduces breakdown & free radicals
Use
* Canine cognitive dysfunction (licensed)
* Hyperadrenocorticism
* Chronic anxiety
* Social/noise phobia
* Feline cognitive dysfuntion
Adverse Effects
* Aggression
* GI signs
* Restlessness/disorientation
* Repetitive movements, tremors
* Lethargy
* Salivation
* Deafness
* Pruritus
* MANY drug interactions
Serotonine Syndrome
o Excessive serotonin results in ->
o Hypertension
o Tremors/Seizures
o Ataxia
o Blindness, mydriasis
o Hyperesthesia (nonspecific vs abdominal)
o GI signs
o Hyperthermia
o Coma, death
Urinary Retention; Causes, Drugs to relax sphincter, drugs for detrusor contraction
Causes
* UMN bladder (spinal cord injury)
* Obstruction (stones, flutd, etc)
Drugs to relax sphincter
* Prazosin/Tamsulosin preferred (selective a-antagonists)
* Acepromazine (non-selective)
* Diazepam
Drugs for Detrusor Contraction
* Bethanechol (muscarinic agonist)
Urinary Incontinence; Causes, Drugs to constrict sphincter, drugs for detrusor relaxation
Causes
* LMN bladder (spinal cord or nerve injury)
* Urethal sphincter mechanism incompetence
Drugs to Constrict Sphincter
* Phenylpropanolamine (a-agonist)
* Estrogens (increase sensitivity of alpha receptors)
Drugs to Relax Detrusor
* Propantheline (muscarinic antagonist)
Pyrimethamine; MOA, Use, Adverse Effects
MOA
* Inhibits dihydrofolate reductases ->
* Interferes w/ folic acid synthesis necessary fro DNA & RNA synthesis
Use
* Toxo in dogs & cats
* Neospora in dogs
* EPM in horses
Adverse Effects
* Bone marrow suppression
Amprolium; MOA, Use, Adverse Effects
MOA
* Analog of thiamine ->
* Competes w/ thiamine uptake in protozoal organisms
Use
* Preventative for coccidian
* Used in drinking water for poultry & cows
Adverse Effects
* Thiamine deficiency ->
* Polioencephalomalacia or polyneuritis
Clindamycin; MOA, Use, Adverse Effects
MOA
* Long‐term exposure to low concentrations of clindamycin reduces level of replication of T. gondii
* Affects the protein synthesis of free parasites
* Impairs the ability of tachyzoites to infect host cells
Use
* Treatment of choice for toxo
Adverse Effects
* Unexplained death in cats w/ pulmonary toxo
* Must use higher does than for anaerobic infections
Metronidazole; MOA, Use, Adverse Effects
MOA
* Intermediate metabolites affect DNA
* Alter essential metabolic pathways critical for protozoa survival
Use
* first‐line agent for treating giardiasis
* Effective against trichomonas (banned in cows)
Adverse Effects
* Dose-dependent vestibular toxicity in cats
Ponazuril & Diclazuril; MOA, Use, Adverse Effects
MOA
* May act on the apicoplast of protozoal organisms
Use
* FDA approved for EPM in horses (need longer than stated)
Adverse Effects
* Blisters on nose & mouth (uncommon)
Benzimidazoles; Drugs, MOA, Use, Adverse Effects
Drugs
* Albendazole
* Fenbendazole
* thiabendazole (ineffective against cestodes and trematodes)
* febantel (pro‐drug of fenbendazole)
MOA
* Binds parasite free beta-tubulin ->
* Inhibits cell division, motility, transport
* Also decreases energy production
Use
* Hookworms
* Whipworms
* Tapeworms
* Giardia
* Fungi
* Mites
* Large & small strongyles
* pinworms
Adverse Effects
* Very safe
* All may cause teratogenic effects (no pregnant animals!)
* Albendazole may cause:
* weightloss, neutropenia, mental dullness in cats
* bone marrow suppression & liver tox in dogs
Levamisole; MOA, Use, Adverse Effects
MOA
* Agonist at nicotinic acetylcholine receptors on nematode muscle cells ->
* spastic paralysis
Use
* GI & lung NEMATODES
Adverse Effects
* MOST toxic antithelmintic
* Muscarinic & nicotinic effects
* No antidote
* “SLUD”,
* respiratory distress, asphyxia
* CNS depression
* bradycardia,
Pyrantel & Morantel; MOA, Use, Adverse Effects
MOA
* Agonist at nicotinic acetylcholine receptors on nematode muscle cells ->
* spastic paralysis
Use
* GI nematodes
* Tapeworms in horses (at high dose)
Adverse Effects
* VERY safe
* Not recommended to use concurrently with other cholinergic agonists (levamisole, others) or antagonists (piperazine, others)
Piperazine; MOA, Use, Adverse Effects
MOA
* GABA agonist
* Cholinergic antagonist ->
* Flaccid paralysis in some nematodes
Use
* Ascarids
* Used to be used for heartworm preventative
Adverse Effects
* VERY safe
* CNS depression
Melarsomine; MOA, Use, Adverse Effects, Antidote
MOA
* May affect glycolysis
Use
* Adult & 4-mo old heartworms
* Regimen of 2 injections + 2 injections 4 months later
Adverse Effects
* Very low margin of safety
* Liver toxicity
* Nephrotoxicity
* Thromboembolic pneumonia
* Contraindicated in vena caval syndrome
* Not indicated for cats
Antidote
* Dimercapol
Emodepside; MOA, Use, Adverse Effects
MOA
* Binds to latrophilin like receptor->
* releases an inhibitory neuropeptide (GABA) ->
* flaccid paralysis
Use
* Broad nematodal activity
* Tapeworms
* Spot-on for cats
* PO for dogs
Adverse Effects
* VERY safe
* Less safe for MDR1 mutants
Praziquantel & Epsiprantel; MOA, Use, Adverse Effects
MOA
* Interfere w/ Ca homeostasis ->
* Damage tegument
* Cause muscular contraction & paralysis
Use
* Praziquantel – drug of choice for E. granulosus (can use in ag)
* Epsiprantel – tapeworms in dogs & cats
Adverse Effects
* Vomiting w/ high doses
Clorsulon; MOA, Use, Adverse Effects
MOA
* disrupts glycolysis after ingested by fluke
Use
* Adult liver flukes in ag
Adverse Effects
* VERY safe
Triclabendazole; MOA, Use, Adverse Effects
MOA
* May bind to tubulin at different site than Benzimidazoles
Use
* Adult & up to 1wk old liver flukes (migratory stages)
* Greatest activity against liver flukes of all meds
Adverse Effects
* VERY safe
Macrocyclic Lactones; Drugs, Desirable Characteristics
Drugs
* Ivermectin
* Moxidectin
* Anything with –ectin
* Milbemycin
Desirable characteristics
* high potency
* high lipophilicity
* high therapeutic index
* prolonged persistence in tissues
Macrocyclic Lactones; MOA, Use, Adverse Effects
MOA
* Interfere w/ glutamate-gate chloride channels ->
* Hyperpolarization of cell membranes ->
* Paralysis ->
* Alters nutrient ingestion & makes parasite remain at site of predilection
Use
* Insects
* Some lice
* Mites
* Some helminthes of horses
* All helminthes of cows
* Heartworm prevention
* Nematodes
Adverse effects
* Neurotoxicity
* Avermectin sensitive
* Tox from eating poo
* Contraindicated in animals <6wks old
