7 Clinical Pharmacology for Neurologic Diseases

Anticonvulsant

Phenobarbital, bromide, zonisamide, levetiracetam, topiramate, diazepam, clonazepam, and clonazepate are all examples of drugs that do what?

Change in conformation --> entrance of Cl = hyperpolarizes membrane (farther away from action potential threshold)

What happens in medications that bind GABA-A receptors?

GABA-A receptor

Benzodiazepines and Barbiturates bind where?

Diazepam

What is the "prototypical benzo", highly lipid soluble and a schedule IV drug?

Diazepam

This medication depresses the subcortical regions of the brain, enhances release and binding of GABA, and diminishes release of AcH

This means it readily passes the blood brain barrier and has a rapid onset

Diazepam is highly lipid soluble. What does this mean?

Diazepam

Which medication is NOT recommended in cats due to hepatic failure if used orally?

1. irritating IM and SQ

2. binds to plastic (so keeping it in a syringe makes it rapidly degrade)

What is the problem with Diazepam injectable?

IV

What route of administration is best for Diazepam in emergency situations?

Midazolam

Which benzo is water soluble normally, but LIPID soluble at body pH?

Anesthetic and anti-seizure

What are the main indications for Midazolam?

Phenobarbital

Which medication increases neuronal post synaptic responsiveness to GABA?

10-14 days

How long does it take for Phenobarbital to reach a steady, therapeutic state?

Liver (Cytochrome P450)

Where does metabolism occur for Phenobarbital?

You have to avoid tubes with additives = artificially low phenobarb levels with additives like silicone

Why do you have to be careful when taking blood to measure Phenobarbital levels?

Phenobarbital

15-35 micrograms/mL is the therapeutic serum level for what medication?

FALSE: NEVER ABRUPTLY DISCONTINUE

TRUE OR FALSE: Most anticonvulsants like phenobarbital can be discontinued abruptly with minimal side effects.

Increase by 25%, raising to 50%, 75%, and eventually 100% every 1-2 weeks.

When increasing the dose, you want the night dose to be higher, or both of the doses to be even.

FOR EXAMPLE: you have a 32 mg tab you're giving in morning and at night for a total of 64 mg. So, if you're increasing by 25% initially = 64 x 0.25 = 16 roughly. Which means a 25% increase of the initial dose is 80 mg over the course of the day. But, if the tabs come in 32 mg, you will still be giving a 32 mg tab in the morning, and then 1.5 tabs in the evening to reach the 80 mg total.

How can you change the dose of phenobarbital?

Potassium bromide

What is the second line anticonvulsant?

Bromide

Which medication competes with Cl at the GABA ion channel to hyperpolarize the cell?

Bromide

This medication reaches steady state after 3-4 MONTHS, and the halflife itself is long at 25 days

Cl = sea water, saline water swimming pool

What element can interfere with Bromide medication? Where would this be a problem, because the body would rather accept this element over Bromide?

Zonisamide

What is the 3rd choice anticonvulsant?

Blocks Na channel and type T Ca channel

What is the MOA of Zonisamide?

Zonisamide

Which medication has no effect on GABA, instead it blocks Na channels, T-type Ca channels, and inhibits presynaptic glutamate to suppress hypersynchronization?

Zonisamide

What anticonvulsant can you treat cats with once daily?

Mostly kidneys, 20% liver

Where is Zonisamide metabolism?

Zonisamide and Levetiracetam

Phenobarbital may cause overmetabolism/increased clearance of which drugs?

Levetiracetam

This anticonvulsant binds to synaptic vesicle protein SV2A, regulating vesicle exocytosis to prevent hypersynchronization (reducing the spread of seizure activity)

It isn't heavily metabolized and most is renally excreted unchanged

What should you know about Levetiracetam metabolism?

Topiramate and Phenobarbital

What two anticonvulsants are considered "broad spectrum"?

Topiramate

This medication works on Voltage gates Na and Ca channels, GABA-A receptor, AMPA receptor, and carbonic anhydrase isoenzymes

a. Voltage gated Na channels

b. Voltage gated Ca channels

d. GABA-A receptor

e. AMPA receptor

f. Carbonic anhydrase isoenzymes

Select the MOA for Topiramate:

a. Voltage gated Na channels

b. Voltage gated Ca channels

c. inhibits presynaptic glutamate

d. GABA-A receptor

e. AMPA receptor

f. Carbonic anhydrase isoenzymes

Zonisamide

note: it doesn't seem like Levetiracetam does either?

Which anticonvulsant does NOT work on GABA-A receptor?

BOTH renal and hepatic

How is Topiramate metabolized?

Gabapentin, Pregablin, Felbamate, Imepitoin

Name 4 other possible anticonvulsants BESIDES the usual (midazolam, diazepam, phenobarbital, bromide, zonisamide, topiramate, levetiracetam):

They are VERY WEAK anticonvulsants

Both Gabapentin and Pregablin work on alpha 2 delta subunits of Ca channels to prevent excitation. Why aren't they commonly used as anticonvulsants?

It works really well as an anticonvulsant, but it ABSOLUTELY causes liver failure

Felbamate inhibits NMDA excitatory transmission. Why is it not commonly used as an anticonvulsant?

Imepitoin

This imidazolone is a low affinity PARTIAL agonist at the benzodiazepine site, though it is only 10-20% as strong as diazepam

Control vestibular disease

Meclizine, diazepam, maropitant, and ondansetron are examples of drugs that do what?

Antihistamine (H1) blocker

What is the MOA of meclizine (dramamine)?

Meclizine (dramamine)

This central anticholingergic depresses vestibular stimulation using antihistamine (H1) blockers for disequilibrium and motion sickness

Meclizine

There is a lack of blood brain barrier in the 4th ventricle under the cerebellum. Which drug takes advantage of this and acts here?

Diazepam

This medication treats central AND peripheral disease.

Central like vascular problems and metronidazole toxicity thru GABA-minergic receptors in the cerebellum.

Peripheral like otitis media/interna thru general suppression of *normal* vestibular function

Substance P

This chemical is found in significant concentrations in the nuclei comprising the emetic center and is considered the key neurotransmitter involved in emesis

Substance P

Inhibiting WHICH chemical inhibits vomiting?

Inhibits Substance P

What does Maropitant (Cerenia) inhibit? What is the MOA?

It is an analgesic, anti anxiety, and anti inflammatory medication

Besides inhibiting vomiting, what else does Maropitant do when it suppresses Substance P?

CYP450 isoform

How is maropitant metabolized?

Ondansetron (Zofran)

This medication reduces nausea and vomiting thru selective serotonin 5HT3 receptor antagonism at the vagus nerve

Selective Serotonin 5HT3 antagonist at vagus nerve

What is the MOA of ondansetron?

Immunosuppression

Cytarabine, Leflunomide, Lomustine, and Cyclosporine are examples of drugs that do what?

Cytarabine

This medication is often used to treat Leukemias and Lymphomas as an antimetabolite drug (a type of chemotherapy). It is a nucleoside analogue

S-phase interference (interferes with DNA synthesis)

What is the MOA of cytarabine?

Cytarabine

Which medication interferes with S-phase DNA replication by mimicking deoxycytidine (a nucleoside) and by being a weak inhibitor of DNA polymerase?

1. inflammatory autoimmune CNS disease

2. steroid responsive meningitis (SRMA?)

3. lymphoma

What are the main indications for Cytarabine in vet medicine?

Injectable as a CRI over 48 hours

How do you give cytarabine chemotherapy?

Leflunomide

This immune modifier is used to treat immune mediated polyarthritis in dogs. It is considered a "prodrug", where the active version is called teriflunomide

note: "prodrug" is a biologically inactive compound that is converted into an active drug within the body through metabolic processes

Affects at level of mitochondria

WHERE does leflunomide mainly effect to stop DNA and RNA synthesis?

Leflunomide

This medication stops mitochondrial enzyme, which means uridine monophosphate cannot be made, which means G1 cannot progress into S phase, which in turns stops DNA and RNA synthesis

B and T lymphocytes

Leflunomide *inhibits reproduction of rapidly dividing cells*. Give some examples

Leflunomide

This medication *inhibits reproduction of rapidly dividing cells*, suppresses Ig production, inflammatory cytokines, AND reduces leukocyte adhesion and diapedesis (neutrophils slowing and rolling to get into tissues)

Lomustine

This immune modifier is highly lipid soluble that targets cell cycle non-specific alkylating agents to damage the nucleus resulting in breakage during replication = apoptosis

Lomustine

Which medication do you use for inflammatory brain disease and lymphoma or glial neolasia?

1. inflammatory brain disease

2. lymphoma or glial neoplasia

What are the indications for lomustine?

Lomustine

This immune modifier has side effects like bone marrow suppression, GI (diarrhea, vomiting), and hepatopathy issues

Cyclosporine

This immune modifiers MAIN USE is to reduce transplant rejection and treat autoimmune diseases

Cyclosporine

This immune modifier has an MOA of inhibiting calcineurin, which results in reduction of cytokine IL 2 production by the T cells

Modified and NON modified

*VET MED NEEDS MODIFIED*

What are the two different versions of Cyclosporine?

Cyclosporine

This medications adverse side effects include nausea, gingival hyperplasia, infection and potentially lymphoma

a. bone marrow suppression

b. GI-diarrhea, vomiting

e. hepatopathy

Select the side effects for Lomustine:

a. bone marrow suppression

b. GI-diarrhea, vomiting

c. gingival hyperplasia

d. nausea

e. hepatopathy

f. infection

c. gingival hyperplasia

d. nausea

f. infection

Select the side effects for Cyclosporine:

a. bone marrow suppression

b. GI-diarrhea, vomiting

c. gingival hyperplasia

d. nausea

e. hepatopathy

f. infection

Pentobarbital

What is the short acting barbiturate that is commonly used for euthanasia and has nasty cardio/respiratory depression side effects?