Principles of neuropharmacology Flashcards
How is a brain capillary different to a general capillary?
- pericytes
- more mitochondria (for active transport)
- astrocytes
Which drugs enter the brain?
the more lipophilic the drug, the better the penetration (e.g. diazepam is very lipophlic)
Outline glucose and L-DOPA uptake into the brain
Much more reaches the brain than would be expected with their level of lipophilicty due to active transport
Outline phenobarbital (PB) and phenytoin uptake into the brain
- quite lipophilic but not as much penetration to brain as would be expected
What is PGP?
- p-glycoprotein
- an efflux pump that pumps foreign material out of cells
- expressed in BBB
- overexpressed in epileptic focus therefore decreased anti-epileptic drug action
Define AED
anti-epileptic drug
Why are collies sensitive to ivermectin?
They lack the PGP molecule to pump ivermectin out of brain cells –> seizure activity when administered this.
Are the neural impulses in all seizures hypersynchronous?
Yes - it means all neurons are firing at the same time
When to treat seizures?
- status epilepticus or animals with cluster seizures
- severe postictal signs
- when severity or frequency increases
? one seizure every 6 weeks?
? 2 or more isolated seizures within 6 months?
How many seizure dogs respond to AED?
2/3
How do AEDs affect epilepsy?
suppress seizures, don’t actually tx the epilepsy
Why encourage an owner to chart seizure frequency?
to give them something to do by de-emtoionalising the situation. You can give diazepam to owners to put in rectally (this is done in humans too)
Considerations for starting seizure tx
- monotherapy
- seizure frequency may influence choice of AED
- monitor plasma levels
- owner compliance
What is the best aim of seizure tx?
to increase inhibition in the brain (as there are no advantages to blocking excitation route)
Tx - refractory epilepsy
Ketamine (NMDA antagonist)
Mode of action - barbiturate
increases the duration of chloride ion channel opening at the GABA-A-R. This increases the efficacy of GABA.
Mode of action - benzodizepines
Increase the frequency of chloride ion channel opening at the GABA-A-R. This increases the potency of GABA. Diazepam may nt work with long seizures because GABA may already be depleted.
Tx for a seizure of 2 hours duration
give diazepam and phenobarbitone at the same time
Tx for a seizure of
Give 2 doses diazepam and then give phenobarbitone. (barbiturates need no/less GABA to act than benzodiazepines)
PB- half life
24- 40 hours
PB - time to steady state
10-14 days
Side effects - PB
sedation, PD, polyphagia, hepatotoxicity
- TT4 and fT4 reduction, no effect on ACTH stimulation test
- hepatotoxicity
- routine biochem +/- bile acid stim. q6-12 months
- may reduce elimination half-life with chronic life
RARE, BUT SEVERE (idiocyncratic reactions):
- behavioural alterations
- immune-mediated neutropaenia, thrombocytopaenia, anaemia
- superficial necrolytic dermatitis (SND)
- idiosyncratic hepatotoxic reactions
*ACTION: stop immediately, load with alternative AED (KBr)
- withdrawal seizures due to drug dependence
Metabolism - PB
liver
Administration - PB
- loading dose if indicated.
- adjust dose if seizure frequency is equal or increased after 30 days
- increment of 5 m, icrog/ml
How does PB affect metabolic clearance in liver?
increases metabolic clearance in liver so lower 1/2 life of itself and other drugs. also increases ALT and other enzymes due to generalised increased liver activity
Calculate oral daily dose for mg PB
= (desired concentration/ actual concentration) * total mg PB per day
KBr - half-life as an AED
15-20 days
KBr - time to steady state
100-200 days
Side effects - KBr AED
sedation, weakness, PU, PD, GIT irritation (V and D), (pancreatitis)
Outline bromide toxicity
RARE
- severe ataxia, sedation, somnolence, skin reactions
- dogs with renal insufficiency
- ACTION: I.V. saline to enhance renal excretion
Why do you get a pseudohyperchloraemia with KBr?
biochem test can’t distinguish Cl- from Br- so counted as one and the same.
What is imepitoin? How does it compare with diazepam?
- a partial benzodiazepine agonist
- it is 1000x less potent than diazepam (both benzodiazepines) but patient is less dependent on imepitoin so no withdrawal seizures if tx stopped unlike diazepam.
Use -imepetoin
- first like tx for dogs with newly diagnsoed idiopathic epilepsy
- relatively good side effect profile so can be considered is ‘less severe’ epilepsy cases sooner
- dogs with severe side effects on PB or other anti-convulsants
- alternative for dogs with unsatisfying seizure control on PB or other anti-convulsant drugs
- NOT for dogs with acute seizures (cluster seizures / status epilepticus) OR in cats
Half- life PB
2 hours
Time to steady state - PB
1-2 days
side effects - PB
sedation, polphagia, hyperactivity
Reasons for AED tx failure
- incorrect diagnosis (-> perform MRI)
- incorrect choice AED
- incorrect dosage
- low AED levels
- newly developed disease (liver, kidney, pancreas)
- change in BWt
- patient tolerance to drug
- monotherapy is insufficient
- refractory seizures
- poor compliance
Actions in case of tx failure
- monitor drug levels - adjust dose
- if still failure - adjust more
- if still failure - add anticonvulsant
- if still failure - monitor drug levels - adjust dose
- if still failure - consider new drug
- keep in touch with a neurologist
Signs of refractory epilepsy / non-responder
- seizure frequency reduction of less than 50%
- 20-30% poorly responsive with combination of PB and KBr
First choice AED in cats
Phenobarbital
PB - side effects - cats
polyphagia, BM suppression, cutaneous hypersenstivity
2nd choice AED in cats
diazepam
Side effects - diazepam in cats
- (acute) hepatotoxicosis (important to evaluate liver enzymes 5- 7 days after initiation). Can progress to fulminant hepatic necrosis.
Outlien KBr in cats as an AED
contraindicated as –> bronchial asthma
Name 2 other AEDs in cats
- levetiracetam
- gabapentin
What type of damage does status epilepticus cause?
- primary
- secondary / complications (may be more important)
Problems experienced with seizure of 30 minutes duration
- arterial hypertension
- increased cerebral BF
- hypoxaemia
- hypercarbaemia
- hyperglycaemia
- lactic acidosis
Problems experienced with seizure > 30 minutes duration
- continuous mm contraction
- hyperthermia (–> brain damage)
- acidosis (–> mm failure)
- myolysis (myoglobinuria, hyperkalaemia, cause renal failure)
- hypoglycaemia (energy deposition)
- hypotension
- cardiac arrhythmias
What does the initial AED tx (e.g. diazepam, PB) do?
- decreases HR
- increases RR
- decreases BP
- the animal is then hypoxic and hypotensive so never forget to also treat with these 3 things: oxygen, cool down, fluids)
What causes multiple organ failure
- energy depletion
- circulatory collapse
- organ hypoperfusion
3 tx goals for seizure
- stop the seizures
- protect the brain
- think about the future
What should you monitor with seizures?
- HR
- BP
- O2
- electrolytes/ fluid balance
- body temperature
How can you minimise seizure complications?
- MINIMIMISE BRAIN INJURY:
- tx hypotension (volume expansion, fluid balance)
- tx hypoxaemia (O2 supplementation)
- MINIMISE HYPERTHERMIA (critical to reducing damage)
- MINIMISE RENAL IMPAIRMENT
Ddx - underlying disease –> seizures
- HYPOGLYCAEMIA/ ELECTROLYTE IMBALANCE: correct
- POSSIBLE TOXICITY? diuresis, decontaminate
- SUSPECT INTRACRANIAL CAUSE: advanced imaging, CSF analysis
- REFERRAL?
