CNS Pharmacology Flashcards
What method of action potential transmission is mainly used in the CNS
chemical (vs. electrical)
How does neuron input impact its effect
neurons have hundreds of inputs
can be excitatory or inhibitory by changing RMP
- cumulative effect determines response
List 4 categories of neurotransmitter and some examples of each
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)
What is the mechanism of excitatory and inhibitor neurotransmitters respectively
excite
- increase likelihood of depolarization
- linked to Na channel
inhibit
- reduce likelihood of depol
- linked to Cl channel
What are the main excitatory and inhibitory neurotransmitters in CNS
inhibit = GABA
excite = glutamate
What is the main mechanisms that CNS drugs use
receptor interactions
direct interaction = agonist or antagonist
indirect interaction = changing concentration of neurotransmitter
How selective are CNS drugs
only relatively selective
multiple modes of action and a range of effects
- effects can be dose dependent
species differences
How does the body’s response to CNS drugs impact how you use them
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
What are the pharmacokinetics of CNS drugs
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
List 5 type of CNS drugs
anesthetics
- reduce consciousness
analgesics
tranquilizer/sedative
- tranquilizer = calming without lots of general CNS depression
- sedative = calming with CNS depression/reduced awareness
antidepressant/antianxiety
antiepileptic
What is a seizure and what causes them?
abnormal hypersynchronous discharge of group of neurons in cerebral cortex
- generalized or focal
due to brain injury/dz or metabolic disease or idiopathic (epilepsy)
What are the 4 goals we are trying to achieve with anti-epileptic drugs
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
List 6 anti-epileptic drugs commonly used
phenobarbitol
potassium bromide
diazepam or midazolam
levetiracetam
zonisamide
gabapentin
What criteria indicate the need for anti-epileptic drugs
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
Which anti-epileptic drug is noted by the ACVIM consensus seizure management statement to be primarily used as a monotherapy
phenobarbitol
List 4 mechanisms of actions of anti-epileptic drugs
GABA activated Cl conductance
Ca channel currents
Na channel conductance
modulate neurotransmitter release through protein binding
What is the mechanism of action of levetiracetam
not fully understood
may modulate neurotransmitter release via protein binding to presynaptic vesicle (inhibit release)
What is the mechanism of action of zonisamide
not fully understood
reduced Na channel conductance
- antagonize Na and Ca channel (reduce neurotransmitter release)
has effects on GABA/glutamate neurotransmission
Which anti-epileptic drugs act on GABA activated Cl conductance
phenobarbital
- also will reduce Ca channel current
K or Na bromide
diazepam
midazolam
Explain how GABA receptors are used for seizure management
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
What is the mechanism of action of phenobarbital
barbituate
act on GABAa (main, hyperpolarize) and GABAb
How is phenobarbital distributed
moderately lipophilic
- cross BBB
- slower than benzodiazepine
How is phenobarbital metabolized
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
How often is phenobarbital given in dogs and cats
dog = BID
cat = SID
What are the 4 types/levels of adverse effects
type
1 = predictable/dose related
2 = unpredictable/ +/-life threatening
3 = cumulative/ +/-life threatening
4 = delayed/life threatening via carcinogen or teratogen
What are the adverse effects of phenobarbital
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
What are important drug interactions associated with phenobarbital
drugs that inhibit CYP450 can cause phenobarbital toxicity
- ketoconzole
- chloramphenicol
-cimetidine
increasing expression of CYP450 by phenobarb can change metabolism of other drugs
How should you monitor phenobarbital administration? What should you look for?
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
What is the mechanism of potassium bromide
GABA Cl channels = hyperpolarize
What is potassium bromide mainly used as
monotx or as an add on tx for seizures
How is potassium bromide distributed, metabolized and excreted
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)
What are the adverse effects associated with potassium bromide
type 1
- lethargy
- mild ataxia
- polydipsia/polyphagia
type 2
- gastric irritation
- pancreatitis
type 3
- pelvic limb ataxia and paresis
- behavioural changes
no type 4
How is potassium bromide administration monitored (frequency/what to look for)
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
What is levetiracetam used for? What is another name for it?
keppra
add on tx in dogs
- some evidence for monotx in dogs/cats
- can use with midazolam or diazepam for status epilepticus
How is levetiracetam metabolized and excreted
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
What are the adverse effects associated with levetiracetam
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
What is zonisamide used for
monotherapy or add on
not a lot of evidence in cats
How is zonisamide metabolized and excreted
half life
- dog = 15h
- cat = 33h
20% metabolized in liver
80% excretion in kidney
What are the adverse effects associated with zonisamide
teratogen
reduce T4
sedation, inappetance, ataxia
not for pregnant
wear gloves when administering
How is the dose of zonisamide affected by other drugs
if giving with phenobarbital you need a higher dose of zonisamide because it is a CYP3a substrate
How is zonisamide administration monitored
1-2 weeks after starting to evaluate the troughs
recheck when seizure frequency changes
What important aspect of client education is important when administering zonisamide
teratogenic
need to wear gloves and wash hands after administering
What type of drug is used to manage status epilepticus
benzodiazepines
What are 5 uses for benzodiazepines
anti-epileptic
sedative
muscle relaxant
behaviour modifier
appetite stimulant
What is one feature of benzodiazepines that impact its efficacy
it is very lipophilic
What are 2 types of benzodiazepines used to manage status epilepticus
diazepam
midazolam
What is the route of administration of diazepam
IV
per rectum
intra nasal
What is diazepam used for
acute seizures and status epilepticus
- as an emergency seizure tx (owner can give per rectum during seizure)
not for long term use in dogs
What is the route of adminstration of midazolam
IM and intranasal mainly
also IV and per rectum
What are the cons when using diazepam
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)
What is the mechanism of action of diazepam
binds GABAa receptor = hyperpolarize
it is metabolized in the liver to form active metabolites
What is the brand name for diazepam
valium
What is the brand name of midazolam
versed
How does midazolam compare to diazepam
midazolam is 3x more potent, faster onset, shorter duration vs diazepam
How is midazolam metabolized
in liver to active metabolites
poor bioavailability resulting in increased time to onset when given IM (increase dose)
What is intranasal administration of midazolam indicated
for status epilepticus
it has a faster onset than per rectum (comparable to IV)
What are 3 standard treatments + routes of administration of anti-epileptics for status epilepticus
IV diazepam (but may be unfeasible)
IV or IM midazolam
per rectum diazepam
Define status epilepticus
seizure longer than 5-10 mins
What are the 4 stages of status epilepticus
- impending
- neurotransmitter imbalance
- use 1st line tx - established
- reduced GABAa receptors
- 1st line tx less effective, use 2nd line tx - refractory
- excite and inhibitory neurotransmitters released
- BBB drug transporters upregulated
- 1st and 2nd line tx not effective, use 3rd line - super-refractory
- gene expression change
- non responsive to tx
