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VETM 443 Pharmacology > CNS Pharmacology > Flashcards

CNS Pharmacology Flashcards

1
Q

What method of action potential transmission is mainly used in the CNS

A

chemical (vs. electrical)

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2
Q

How does neuron input impact its effect

A

neurons have hundreds of inputs

can be excitatory or inhibitory by changing RMP
- cumulative effect determines response

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3
Q

List 4 categories of neurotransmitter and some examples of each

A

Ach

biogenic amines
- norepi/dopamine = excite or inhibit
- serotonin = inhibit
- histamine = excite

amino acids
- GABA = inhibitory
- glutamate = excite
- glycine = inhibit

neuropeptides
- substance P
- endogenous opiates (enkephalins/endorphine/dynorphine)

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4
Q

What is the mechanism of excitatory and inhibitor neurotransmitters respectively

A

excite
- increase likelihood of depolarization
- linked to Na channel

inhibit
- reduce likelihood of depol
- linked to Cl channel

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5
Q

What are the main excitatory and inhibitory neurotransmitters in CNS

A

inhibit = GABA

excite = glutamate

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6
Q

What is the main mechanisms that CNS drugs use

A

receptor interactions

direct interaction = agonist or antagonist

indirect interaction = changing concentration of neurotransmitter

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7
Q

How selective are CNS drugs

A

only relatively selective

multiple modes of action and a range of effects
- effects can be dose dependent

species differences

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8
Q

How does the body’s response to CNS drugs impact how you use them

A

CNS is plastic, meaning its response can change over time
- it wants to maintain homeostasis
- initial and delayed responses can impact clinical effect

must be patient and wait for the maximal effect to occur

taper drugs that effect the CNS when stopping

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9
Q

What are the pharmacokinetics of CNS drugs

A

lipophilic -cross CNS

usually have an active metabolite that has a longer half life than the pro-drug

will need longer time to reach steady state

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10
Q

List 5 type of CNS drugs

A

anesthetics
- reduce consciousness

analgesics

tranquilizer/sedative
- tranquilizer = calming without lots of general CNS depression
- sedative = calming with CNS depression/reduced awareness

antidepressant/antianxiety

antiepileptic

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11
Q

What is a seizure and what causes them?

A

abnormal hypersynchronous discharge of group of neurons in cerebral cortex
- generalized or focal

due to brain injury/dz or metabolic disease or idiopathic (epilepsy)

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12
Q

What are the 4 goals we are trying to achieve with anti-epileptic drugs

A

balance reduced seizures with quality of life
- full prevention of seizures usually not possible

reduce number/frequency/severity

mitigate/limit adverse effects

increase QoL of patient and owner

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13
Q

List 6 anti-epileptic drugs commonly used

A

phenobarbitol

potassium bromide

diazepam or midazolam

levetiracetam

zonisamide

gabapentin

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14
Q

What criteria indicate the need for anti-epileptic drugs

A

a longer history of seizure - because having seizures will predispose to more
- >2 in 6 months
- status epilepticus (v long) or cluster seizures (many)

severe post seizure (post-ictal) signs
- behaviour change
- blind

increasing frequency/severity

can start when trying to manage/find underlying cause

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15
Q

Which anti-epileptic drug is noted by the ACVIM consensus seizure management statement to be primarily used as a monotherapy

A

phenobarbitol

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16
Q

List 4 mechanisms of actions of anti-epileptic drugs

A

GABA activated Cl conductance

Ca channel currents

Na channel conductance

modulate neurotransmitter release through protein binding

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17
Q

What is the mechanism of action of levetiracetam

A

not fully understood

may modulate neurotransmitter release via protein binding to presynaptic vesicle (inhibit release)

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18
Q

What is the mechanism of action of zonisamide

A

not fully understood

reduced Na channel conductance
- antagonize Na and Ca channel (reduce neurotransmitter release)

has effects on GABA/glutamate neurotransmission

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19
Q

Which anti-epileptic drugs act on GABA activated Cl conductance

A

phenobarbital
- also will reduce Ca channel current

K or Na bromide

diazepam

midazolam

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20
Q

Explain how GABA receptors are used for seizure management

A

GABAa receptor is a ligand gated Cl channel
- allows Cl influx into post synaptic neuron resulting in hyperpolarization
- many subunits = structural diversity = different responsiveness to GABA

GABAb receptor is a G coupled receptor reduces the influx of Ca into the presynaptic neuron = prevent release of neurotransmitters

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21
Q

What is the mechanism of action of phenobarbital

A

barbituate

act on GABAa (main, hyperpolarize) and GABAb

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22
Q

How is phenobarbital distributed

A

moderately lipophilic
- cross BBB
- slower than benzodiazepine

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23
Q

How is phenobarbital metabolized

A

CYP450 in liver

also induce expression of CYP450
- the initial effective dose will change because CYP450 is upregulated - need to modify

lots of variation in serum concentration + variable half life (48h)
- monitor required

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24
Q

How often is phenobarbital given in dogs and cats

A

dog = BID

cat = SID

25
Q

What are the 4 types/levels of adverse effects

A

type
1 = predictable/dose related
2 = unpredictable/ +/-life threatening
3 = cumulative/ +/-life threatening
4 = delayed/life threatening via carcinogen or teratogen

26
Q

What are the adverse effects of phenobarbital

A

type 1
- behaviour change (sedation/hyperexcitability)
- liver enzymes

type 2
- IMHA
- neutropenia
- acute hepatotoxicity

type 3
- polydipsia/polyphagia/polyuria
- hepatotoxicity
- reduced serum T4

type 4 - none

27
Q

What are important drug interactions associated with phenobarbital

A

drugs that inhibit CYP450 can cause phenobarbital toxicity
- ketoconzole
- chloramphenicol
-cimetidine

increasing expression of CYP450 by phenobarb can change metabolism of other drugs

28
Q

How should you monitor phenobarbital administration? What should you look for?

A

monitor 5-6 half lives after starting tx
- 10-12d post start

again after 6 weeks
- reach clearance steady state

then every 6 months (CBC/Chem) - liver function
- if >2 seizures = recheck

use bichem to monitor liver function
- some elevation is normal
- if ALP or ALT over 4 or 5x upper limit or if any elevation of GGT = adjust dose

29
Q

What is the mechanism of potassium bromide

A

GABA Cl channels = hyperpolarize

30
Q

What is potassium bromide mainly used as

A

monotx or as an add on tx for seizures

31
Q

How is potassium bromide distributed, metabolized and excreted

A

long half life
- dog = 15d
- cat = 10d
- slow to reach steady state
- usually use loading dose

renal clear
- no liver metabolism
- it is a salt (higher salt diet will increase its excretion in kidney)

32
Q

What are the adverse effects associated with potassium bromide

A

type 1
- lethargy
- mild ataxia
- polydipsia/polyphagia

type 2
- gastric irritation
- pancreatitis

type 3
- pelvic limb ataxia and paresis
- behavioural changes

no type 4

33
Q

How is potassium bromide administration monitored (frequency/what to look for)

A

steady state reached in 3 months

recheck at 1 and 3 months after starting then annually
- unless evidence of toxicity or reduced efficacy

use fasted sample, 2hr after last dose (because of the long half life)

It is impacted by renal clearance so patients with kidney disease may need a higher dose

If using with phenobarbital - use lower dose

34
Q

What is levetiracetam used for? What is another name for it?

A

keppra

add on tx in dogs
- some evidence for monotx in dogs/cats
- can use with midazolam or diazepam for status epilepticus

35
Q

How is levetiracetam metabolized and excreted

A

short half life with a short onset of effects

renal excretion with some tubular reabsorption
- low liver metabolism

dogs can become refractory to it
- will stop working over time

36
Q

What are the adverse effects associated with levetiracetam

A

very safe - wide range of therapeutic doses
- drug monitoring not necessary

lethargy most common
- sometimes behavioural change

sometimes
- vomit
- sedation
- ataxia
- hyperactivity

less commonly
- anorexia/polyphagia/polydipsia
- aggression/attention seeking

37
Q

What is zonisamide used for

A

monotherapy or add on

not a lot of evidence in cats

38
Q

How is zonisamide metabolized and excreted

A

half life
- dog = 15h
- cat = 33h

20% metabolized in liver
80% excretion in kidney

39
Q

What are the adverse effects associated with zonisamide

A

teratogen
reduce T4
sedation, inappetance, ataxia

not for pregnant

wear gloves when administering

40
Q

How is the dose of zonisamide affected by other drugs

A

if giving with phenobarbital you need a higher dose of zonisamide because it is a CYP3a substrate

41
Q

How is zonisamide administration monitored

A

1-2 weeks after starting to evaluate the troughs

recheck when seizure frequency changes

42
Q

What important aspect of client education is important when administering zonisamide

A

teratogenic

need to wear gloves and wash hands after administering

43
Q

What type of drug is used to manage status epilepticus

A

benzodiazepines

44
Q

What are 5 uses for benzodiazepines

A

anti-epileptic
sedative
muscle relaxant
behaviour modifier
appetite stimulant

45
Q

What is one feature of benzodiazepines that impact its efficacy

A

it is very lipophilic

46
Q

What are 2 types of benzodiazepines used to manage status epilepticus

A

diazepam

midazolam

47
Q

What is the route of administration of diazepam

A

IV
per rectum
intra nasal

48
Q

What is diazepam used for

A

acute seizures and status epilepticus
- as an emergency seizure tx (owner can give per rectum during seizure)

not for long term use in dogs

49
Q

What is the route of adminstration of midazolam

A

IM and intranasal mainly

also IV and per rectum

50
Q

What are the cons when using diazepam

A

cats = can cause liver necrosis when given PO

very short half life (15m - 3h)
- very frequent administration
- tolerance can develop if used chronically
- abuse potential (owners)

51
Q

What is the mechanism of action of diazepam

A

binds GABAa receptor = hyperpolarize

it is metabolized in the liver to form active metabolites

52
Q

What is the brand name for diazepam

A

valium

53
Q

What is the brand name of midazolam

A

versed

54
Q

How does midazolam compare to diazepam

A

midazolam is 3x more potent, faster onset, shorter duration vs diazepam

55
Q

How is midazolam metabolized

A

in liver to active metabolites

poor bioavailability resulting in increased time to onset when given IM (increase dose)

56
Q

What is intranasal administration of midazolam indicated

A

for status epilepticus

it has a faster onset than per rectum (comparable to IV)

57
Q

What are 3 standard treatments + routes of administration of anti-epileptics for status epilepticus

A

IV diazepam (but may be unfeasible)

IV or IM midazolam

per rectum diazepam

58
Q

Define status epilepticus

A

seizure longer than 5-10 mins

59
Q

What are the 4 stages of status epilepticus

A
  1. impending
    - neurotransmitter imbalance
    - use 1st line tx
  2. established
    - reduced GABAa receptors
    - 1st line tx less effective, use 2nd line tx
  3. refractory
    - excite and inhibitory neurotransmitters released
    - BBB drug transporters upregulated
    - 1st and 2nd line tx not effective, use 3rd line
  4. super-refractory
    - gene expression change
    - non responsive to tx

VETM 443 Pharmacology (11 decks)

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