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Flashcards in Principles of neuropharmacology Deck (54):
1

How is a brain capillary different to a general capillary?

- pericytes
- more mitochondria (for active transport)
- astrocytes

2

Which drugs enter the brain?

the more lipophilic the drug, the better the penetration (e.g. diazepam is very lipophlic)

3

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

4

Outline phenobarbital (PB) and phenytoin uptake into the brain

- quite lipophilic but not as much penetration to brain as would be expected

5

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

6

Define AED

anti-epileptic drug

7

Why are collies sensitive to ivermectin?

They lack the PGP molecule to pump ivermectin out of brain cells --> seizure activity when administered this.

8

Are the neural impulses in all seizures hypersynchronous?

Yes - it means all neurons are firing at the same time

9

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?

10

How many seizure dogs respond to AED?

2/3

11

How do AEDs affect epilepsy?

suppress seizures, don't actually tx the epilepsy

12

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)

13

Considerations for starting seizure tx

- monotherapy
- seizure frequency may influence choice of AED
- monitor plasma levels
- owner compliance

14

What is the best aim of seizure tx?

to increase inhibition in the brain (as there are no advantages to blocking excitation route)

15

Tx - refractory epilepsy

Ketamine (NMDA antagonist)

16

Mode of action - barbiturate

increases the duration of chloride ion channel opening at the GABA-A-R. This increases the efficacy of GABA.

17

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.

18

Tx for a seizure of 2 hours duration

give diazepam and phenobarbitone at the same time

19

Tx for a seizure of

Give 2 doses diazepam and then give phenobarbitone. (barbiturates need no/less GABA to act than benzodiazepines)

20

PB- half life

24- 40 hours

21

PB - time to steady state

10-14 days

22

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

23

Metabolism - PB

liver

24

Administration - PB

- loading dose if indicated.
- adjust dose if seizure frequency is equal or increased after 30 days
- increment of 5 m, icrog/ml

25

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

26

Calculate oral daily dose for mg PB

= (desired concentration/ actual concentration) * total mg PB per day

27

KBr - half-life as an AED

15-20 days

28

KBr - time to steady state

100-200 days

29

Side effects - KBr AED

sedation, weakness, PU, PD, GIT irritation (V and D), (pancreatitis)

30

Outline bromide toxicity

RARE
- severe ataxia, sedation, somnolence, skin reactions
- dogs with renal insufficiency
* ACTION: I.V. saline to enhance renal excretion

31

Why do you get a pseudohyperchloraemia with KBr?

biochem test can't distinguish Cl- from Br- so counted as one and the same.

32

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.

33

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

34

Half- life PB

2 hours

35

Time to steady state - PB

1-2 days

36

side effects - PB

sedation, polphagia, hyperactivity

37

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

38

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

39

Signs of refractory epilepsy / non-responder

- seizure frequency reduction of less than 50%
- 20-30% poorly responsive with combination of PB and KBr

40

First choice AED in cats

Phenobarbital

41

PB - side effects - cats

polyphagia, BM suppression, cutaneous hypersenstivity

42

2nd choice AED in cats

diazepam

43

Side effects - diazepam in cats

- (acute) hepatotoxicosis (important to evaluate liver enzymes 5- 7 days after initiation). Can progress to fulminant hepatic necrosis.

44

Outlien KBr in cats as an AED

contraindicated as --> bronchial asthma

45

Name 2 other AEDs in cats

- levetiracetam
- gabapentin

46

What type of damage does status epilepticus cause?

- primary
- secondary / complications (may be more important)

47

Problems experienced with seizure of 30 minutes duration

- arterial hypertension
- increased cerebral BF
- hypoxaemia
- hypercarbaemia
- hyperglycaemia
- lactic acidosis

48

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

49

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)

50

What causes multiple organ failure

- energy depletion
- circulatory collapse
- organ hypoperfusion

51

3 tx goals for seizure

- stop the seizures
- protect the brain
- think about the future

52

What should you monitor with seizures?

- HR
- BP
- O2
- electrolytes/ fluid balance
- body temperature

53

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

54

Ddx - underlying disease --> seizures

- HYPOGLYCAEMIA/ ELECTROLYTE IMBALANCE: correct
- POSSIBLE TOXICITY? diuresis, decontaminate
- SUSPECT INTRACRANIAL CAUSE: advanced imaging, CSF analysis
- REFERRAL?