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Exam 3 Flashcards

1
Q

Mitosis; How long? Drugs that Target

A

o 1-7hrs
o Small % of cell cycle

Drugs
* Vinca alkaloids
* Taxols

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2
Q

G1 - 1st Gap Phase; What happens? Drugs that Target

A

o 7-170hrs
o RNA transcription
o Protein synthesis

Drugs
* L-Aspariginase (Elspar)

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3
Q

S-Phase; What happens? Drugs that Target

A

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

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4
Q

G2 - 2nd Gap Phase; What happens? Drugs that Target

A

o 1-4hrs
o pause prior to mitosis
o “checklist”
Drugs
* none

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5
Q

G0; What happens? Cells Involved

A

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

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6
Q

Fraction Cell Kill

A

o Chemo only kills fraction of cells not number of cells
o Very hard to completely eliminate (fraction of a fraction of a fraction)

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7
Q

Reasons for Chemo Failure

A

Dose limited by toxicity to patient

Drug resistance
* Failure to reach target
* Inactivation of drug
* Altered target
* Failure to undergo apoptosis

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8
Q

Response to Chemo

A

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

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9
Q

Resistance Criteria Based on 1 Dimension

A

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

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10
Q

Chemo Dosing Based on Body Surface Area Vs Weight

A

Body Surface Area correlates w/
* Cardiac output

* Glomerular filtration rate

* Basal metabolic rate

Weight
* better for bone marrow stem cell turnover

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11
Q

Common Toxicities from Chemo Drugs

A

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

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12
Q

Chemo Dosing & “cure” rate

A

o 20% dose reduction -> 50% reduction in cure rate

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13
Q

Chemo Safety Considerations

A

o Pregnant women should avoid
o Avoid contact w/ urine & feces 3 days post chemo
o PPE when prepping

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14
Q

Alkylating Agents for Chemo; MOA, Drugs, Use

A

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

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15
Q

Cyclophosphamide, Lomustine, Chlorambucil Toxicities

A

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

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16
Q

Mitotic Inhibitors; Where from? MOA, Drugs, Use

A

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

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17
Q

Vinca Alkaloids & Paclitaxel Toxicity

A

Vinca Alkaloids Toxicity
* BAG
* Peripheral neuropathy
* Dose must be reduced in MDR1 mutants

Paclitaxel Toxicity
* BAG

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18
Q

Antibiotics for Cancer; MOA, Drugs, Use

A

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

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19
Q

Antibiotics for Cancer; Toxicity, Specific tox for Doxorubicin

A
  • BAG
  • Colitis

Doxorubicin
* Cumulative cardiac tox
* Possible renal damage in cats
* Severe tissue reaction if extravasated
* MDR1 substrate

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20
Q

Platinum Compounds; MOA, Drugs, Use

A

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

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21
Q

Platinum Compounds; Toxicity, Specific Tox for Cisplatin

A
  • BAG
  • Carboplatin much safer in cats than Cisplatin

Cisplatin Toxicity
* Emetogenic
* Nephrotoxic
* Ototoxic
* Fatal pulmonary edema in cats

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22
Q

Antimetabolites for Cancer; MOA, Drugs, Use

A

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

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23
Q

Antimetabolites for Cancer; Specific Drug Toxicities

A

Methotrexate
* BAG
* Drug interactions due to protein bound

5-fluorouacil
* BAG
* Central neurotoxicity

Azathioprine
* BAG
* Myelosuppression in cats

Cytosine arabinoside
* BAG

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24
Q

L-asparaginase Enzyme; MOA, Toxicity, Use

A

MOA
* Inhibits protein synthesis

Toxicity
* Allergic reactions
* Pancreatitis
* Vomiting

Use
* Lymphoma
* Tumors in CNS
* NO IV

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25
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
26
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
27
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
28
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
29
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
30
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
31
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
32
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
33
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)
34
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
35
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
36
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)
37
Drugs to Use at Home in Emergency Seizure
* Rectal diazepam * Intranasal midazolam
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
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)
47
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)
48
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
49
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
50
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
51
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
52
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)
53
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
54
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,
55
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)
56
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
57
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
58
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
59
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
60
Clorsulon; MOA, Use, Adverse Effects
MOA * disrupts glycolysis after ingested by fluke Use * Adult liver flukes in ag Adverse Effects * VERY safe
61
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
62
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
63
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

Clin Pharm (8 decks)

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