Exam 2: Gustafson Lectures: Anticonvulsants and Chemo Flashcards
What is the drug of choice for treatment of seizure disorders in cats and dogs?
Phenobarbitol
diazepam if active
What is the drug of choice for anticonvulsants? What is a close second?
Diazepam (valium), Phenobarbital ext up but give IM which will make it reach brain slower.
Which drug is a well known inducer of microsomal cytochrome P450 (CYP450) enzymes? What is a negative effect o this?
Phenobarbitol
It interacts with other drugs, shortens their half life, and may not make the work as well.
You dog is presenting as sedation, plyphasia, polydipsia, polyuria… you just remembered you started them on a new drug. Which drug has these adverse effects?
Phenobarbitol
Not common to see hepatic toxicosis but you can.
Which drugs are used as an add-on with phenobarbitol and bromide? (not usually a monotherapy use)
Gabapentin, Levetiracetam (Keppra)
Anticonvulsants
What is the goal of anticonvulsant therapy?
Anticonvulsant suppress seizure activity and do not cause unconsciousness. Their general mechanism of action is that they prevent initiation or spread of seizure focus, raise seizure threshold, and inhibit excitatory neural activity. They do this by supressing nerve conduction, stabilizing neurons (so that there are less action potentials), and potentiate the effects of the inhibitory neurotransmitter GABA.
Anticonvulsants
What is the drug of choice for stabilization therapy in veterinary medicine?
Diazepam, valium. Phenobarbtiol is a second but most commonly used in chronic cases. Bromide last maybe in combination with the first two.
Anticonvulsants
What are the mechanism of actions for the major drugs used in the treatment of seizures in veterinary medicine?
they bind to specific GABAa receptors and increase the efficacy of endogenous GABA on the GABAa receptors (same amt of GABA will have greater inhibitory effect when drug is bound)
Anticonvulsants
What are the potential adverse effects associated with the drugs primarily used to treat seizures in dogs?
Diazepam: tolerance (tachyphylaxis) during chronic treatment, sedation/ behavioral changes, hepatic toxicosis in cats during chronic oral treatment (Potentially from toxic metabolite), generally safer than barbiturates and difficult to fatally overdose.
Phenobarbital: Sedation, Polyphagia (increased eating), Polydipsia (increased thirst), Polyuria (increased urination), (These may subside over the first few weeks due to tolerance and increased hepatic metabolism). Induction of CYP450 enzymes, elevated hepatic enzymes like alkaline phosphatase both toxic and non-toxic, bilirubin, and serum levels are also increased. Elevated bilirubin and toxins can lower seizure thresholds, hepatocutaneous syndrome (superficial necrolytic dermatitis). monitor liver when giving.
Bromide: polyphagia (increased eating), behavior changes, sedation. Bromism (bromide toxicosis): CNS depression (sedation, weakness, ataxia), joint stiffness in rear limbs, coughing (cats)
Anticonvulsants
What is the primary drug used for maintenance therapy for seizures in veterinary medicine?
phenobarbitol
Anticonvulsants
What potential drug interactions exist for the drugs used to treat seizures in veterinary medicine?
For Phenobarbitol: digoxin, steroids, and chloramphenicol
Cancer Chemotherapy I
What is the “selective basis” for cancer chemotherapy?
Attempting to use drug therapy to kill mammalian cells that actually arose from the organism that you are trying to treat…. Selectivity is based on very small differences in cell growth, recovery potential and in relatively rare cases a driving mutation to which the cancer is addicted.
Cancer Chemotherapy I
Be able to define how chemotherapy is used clinically to treat cancer. For example, how does neoadjuvant therapy differ from adjuvant therapy?
- Induction – Initial treatment to bring about remission
- Consolidation – To kill remaining cancer cells (intensification or post-remission therapy)
- Maintenance – Enhance primary response and prevent relapse
- Salvage – Treatment after primary therapy fails
- Adjuvant – Treatment when there is no measurable disease to suppress secondary tumor formation. Generally thought of as treatment after surgical resection
- Neoadjuvant – Treatment prior to surgery to shrink or “pretreat” tumor
- Radio-sensitization – To enhance the response of ionizing radiation
- Palliation – Treatment to ease symptoms without curative intent
Cancer Chemotherapy I
What are the goals associated with cancer therapy and how does the treatment regimen coincide with this goal?
Cure – all cancer cells have been eradicated
Remission – clinical evidence of cancer has disappeared, BUT…microscopic foci likely remain
Palliation – treatment to reduce pain, improve function.
Therapeutic regimen must be consistent with the goal of treatment**
Cancer Chemotherapy I
Describe the basis of combination cancer chemotherapy and the characteristics of a favorable vs. unfavorable drug combination protocol.
The basis of combination chemotherapy is to treat with more intensive cycles of therapy without exacerbating normal tissue toxicity or recovery.
Thus combination protocols should:
Combine agents with complimentary activity
Combine agents without overlapping toxicity
Cancer Chemotherapy I
Be able to define MTD and DLT and what role they play in cancer drug dosing.
Dosing is based on the concept of Maximum Tolerated Dose (MTD): MTD is the dose that allows for the highest exposure with acceptable toxicity
DLT: Dose Limiting Toxicity: General DLT Criteria
≥ Grade 3 non-heme toxicity
Grade 4 neutropenia lasting longer than 5 days (<500/𝜇L)
Grade 4 thrombocytopenia (<25,000/𝜇L)
Cancer Chemotherapy I
Be able to describe the measures by which cancer chemotherapy response is reported (CR, PR, SD and PD).
Complete Remission (CR): complete disappearance of tumor and symptoms of disease 😀
Partial Remission (PR): ↓ volume by ≥ 50% or max diam. ≥ 30% 🙂
Stable Disease (SD): No increase or decrease (or ↑ < 20% in diam) 😐
Progressive Disease (PD): ↑ volume >25%; ↑ diam >20%; new lesions ☹️
Cancer Chemotherapy I
What are the general mechanisms by which tumor cells become resistant to cancer chemotherapeutic agents.
Can be drug/mechanism dependent or through a multi-drug mechanism
decreased uptake:
Diseased GI tract with oral dosing
Reduced cellular uptake of drug by transporters
decreased biotransformation/ activation:
cytoxan must be metabolized to an active form
increased inactivation:
Glutathione
Dihydropirimidine dehydrogenase (DPD) and 5-FU
Cancer Chemotherapy II
How do glucocorticoids kill cancer cells?
Direct lytic effect on malignant cells in lymphoid malignancies, leukemia, myeloma.
Ability to induce apoptosis dependent upon balance of pro- and anti-apoptotic proteins.
Cancer Chemotherapy II
What is the mechanism of action of alkylating agents and what side effects do all alkylating agents generally have in common?
Mechanism of action involves covalently binding to cellular macromolecules; Binding can be monofunctional (DNA lesion) or bifunctional (cross-link)
As a class they share a common cellular target: cross link DNA, cell cycle non-specific, Inhibit DNA synthesis through damage to the nucleic acid template
BAG of side effects (Bone marrow suppression, Alopecia, and Gastrointestinal)
Cancer Chemotherapy II
what are the characteristics that differentiate cyclophosphamide from other alkylating agents? (include aspects of metabolism as well as any unique side effects)
Cyclophosphamide can be given IV or oral - it is a prodrug that requires metabolic activation: MUST BE METABOLIZED BY THE LIVER. Sterile hemorrhagic cystitis (SHC) is caused by acrolein damaging bladder tissue when excreted in the urine, 10% of dogs get SHC when treated with CP. Use of furosemide dilutes and increases clearance of acrolein in the bladder, Mesna collects in the bladder and “captures” the acrolein.
Cancer Chemotherapy II
What drug can cause sterile hemorrhagic cystitis (SHC) and what treatments can limit the occurrence of SHC and by what mechanism(s)?
Cyclophosphamide can be given IV or oral - it is a prodrug that requires metabolic activation: MUST BE METABOLIZED BY THE LIVER. Sterile hemorrhagic cystitis (SHC) is caused by acrolein damaging bladder tissue when excreted in the urine, 10% of dogs get SHC when treated with CP. Use of furosemide dilutes and increases clearance of acrolein in the bladder,Mesna collects in the bladder and “captures” the acrolein.
collects in the bladder and “captures” the acrolein.
Cancer Chemotherapy II
What is the general mechanism of action of antimetabolite cancer chemotherapy drugs? And what is the target(s) for the specific agents (methotrexate, cytosine arabinoside, gemcitabine and 5-fluorouracil)?
This class of drugs interferes with cellular metabolism associated with making the building blocks of DNA and interfering with DNA and RNA synthesis
Methotrexate: Folate analog that inhibits dihydrofolate reductase
Cytosine Arabinoside, Ara-C, Cytarabine: Phosphorylated in cells to arabinosylcytosine triphosphate (ara-CTP)
Gemcitabine: dFdCTP inhibits DNA polymerase
5-Fluorouracil: FdUMP inhibits thymidylate synthase depleting thymidine pools
Cancer Chemotherapy II
What are the potential mechanisms of action by which doxorubicin (WIDELY USED) can kill tumor cells?
- Inhibition of RNA and DNA polymerases
- Topoisomerase II inhibition
- Alkylation of DNA
- Reactive oxygen generation
- Perturbation of cellular Ca2+ homeostasis
- Inhibition of thioredoxin reductase
- Interaction with plasma membrane components
