Priniples Neuropharmacology Flashcards
How do blood vesselsi n the BBB differ to normal capillaries?
- less fenestrations, pericytes, tight junctions, lots of mitochondria to facilitate active rtansport , layer of astrocytes as 2nd lineo f defence
Which drugs are most lipophilic and which are least on the S curve of lcoal brain uptake? Which drugs do not fit the trend?
- natrium
- morphine
- heroin
- nikotin
- ethaanol
- diazepam (most lipophilic, so most CNS specific)
> Glucose and L-Dopa are not lipophilic but ae actively uptaen into the brain so present in n^ than expected concentrations
> Phenobarbitol and phenytoin don’t get into the brain as much as they should for how lipophilic they are as PGP actively pumps out.
What is the role of PGP and what occours when it is over/under expressed?
mediates transembrane rtansport of lipophilic drugs
- if overexpressed -> pharmacoresistant epilepsy (humans)
- also over expressed at site of epileptic focus -> v AED concentration (antiepileptic drug)
- under expressed in collies -> ivermectin sensitivity as cannot be pumped back out of cells
Define seizures
- clinical sign (not disease)
- transient and involuntary change in behaviour or neurological status d/t abnoral activity of populations of CNS neurons
- hypersynchronous firing of neurons
- seizures named following clinical signs
What is seen in association with epilepsy in dogs? humans?
- dogs: behavioural probles eg. anxiety
- people: depression
When should seizure tx be initiated?
- status epilepticus
- cluster seizures
- severe postictal signs
- progessive (^severity or frequency)
? seizure/6months
? 2+ isolated seizures within 6 months - whatever owner will tolerate!
What is involved in client education regarding epilepsy?
- life-time commitment
- tx doesnt cure disease, just minimises signs
- chart for seizure frequency (de-emotionalise the experience, objecify records)
- rectal diazepam - give them something to do! ?efficacy as how much actually gets in?
- side effects of drugs
- 2/3 dogs respond to AED, some dont
- epilepsy app from rvc
How should tx be started?
- monotherapy (dont polypharm initially)
- seizure freq influences choice of AED
- monitor plasma levels of drug
- ensure owner compliance!
Which drugs act on the excitatory nerve terminal?
> Carbamazine, phenytoin (see slide for others)
- presynaptic neuron use dependent Na channel: dampens excitation so only normal excitaion gets through.
- less effective than targetting GABA
Ketamine (see slide for others)
- postsynaptic neuron NMDA receptor
- good for refractory status epilepticus
Which drugs affect the inhibitory nerve terminal? How do their ctions differ?
> benzodiazepines
- need GABA so will not work if GABA depleted
- ^ frequency of chloride ion channel opening at GABAa- R
- ^ potency of GABA
- very rapid onset of action
phenobarbital
- ^ duration of chloride channel opening
- ^ efficacy of GABA
- can work with no GABA present if needed - bind different subunits to benzos
- slower onset of action ~20mins
When is phenobarb indicated?
- sezing ~2hrs
- refractory to diazepam
- ALWAYS give diazepam first or at the same tiem as faster onset
Mode of action of phenobarbitone?
look up!!
Give a novel anti-epileptic drug. What is it’s mode of action?
partial agonist, modulates GABA channels
- 1000x less affinity than diazepam so can be stopped without dependance developing, and less opportunity for mis-use by owners
Outline dose, T1/2, therapeutic range and time to steady state of phenobarbital
- 2.5mg/kg BID
- 24-40hrs
- 15-35ug/ml
- 10-14d
How is Phenobarbital metabolised? Side effects?
liver
- sedation, PD, polyphagia, hepatotox (though should be ok if
Hhow regularly should you collect plasma levels when tx with phenobarbitone?
- 14, 45, 90, 180 and 360d
- then q6m
What is the loading dose of Phenobarbital if indicated?
12-24mg/kg total dose within 24hrs
- equal dose q30mins - 4hrs to effect (ie. no seizures)
when and how can phenobarbitol doses be altered?
- seizure freq equal or increased after 30
- monitor drug leves
- increment s of 5ug/ml
- oral daily dose of mg PB = (desired conc/actual conc) x total mg PB per day [LOOK UP]
Side effects of phenobarbitol
- TT4 and ft4 reduction
- no efffect on ACTH stim
> liver - ^ALP common
- hepatotox with serum conc >35ug/ml
- routine biochem +- BA stim q6-12 months may v elimination T1/2 with chronic use d/t cytochrome p450 system
> rare but severe (idiosyncratic reactions) - behviour change
- immune-mediated neutropenia, thrombocytonpenia and anaemia
- superficial necrolytic dermatitis
- hepatotoxic reactions (rapid ^ALT and abnormal BA)
- ACTION :stop drug immediately and load with another AED (KBr)
Is KBr a first line tx?
Can be, or add on
Dose, t1/2, tiem to steady state, therapeutic range, side effects and excretion of potassium bromide KBr?
- 30-40mg/kg SID
- 15-20d
- 100-200d
- 0.7-1.9mg/ml (2.3mg/ml?)
- sedation, weakness, PU, PD, GI irritation and pancreatitis
- renal
How regularly are plasma levels needed for KBr tx?
- 4 weeks, 8-12weeks
- then q6m
Loading dose of KBr if indicated?
600mg/kg equal doses over 6d + mainainence dose
What will be seen on biochem with KBr tx?
^ Cl as cannot distinguish from Br
Why is the time to steady state so long with KBr?
- Cl and Br recycled by body and rarely excreted
Howo is KBr dose adjustment carried out?
- full oral dose in mg/kg/day = (desired conc/actual conc) x current dose
What dietary effects may be sen with KBr?
- high chloride diet lowers serum conc
What must you be aware of with KBr Tx? Action?
- bromide toxicity (rare)
- severe ataxia, sedation, somnolence, skin reactions
- eg. dogs with renal insufficiency (v elimination)
> Action: iv saline to enhance renal excretion
When is imepitoin indicated?
- onsider 1st line tx for newy diagnosed idiopathic epilepsy (mild)
- good side effect profile so tx can be considered earlier for less severe epilepsy
- dogs with severe side effects on phenobarbitone or other anticonvulsants
- unsatisfactory seizure contol on phenobarb or other anticonvulsants
- NOT indicated ith acute (cluster or status epilepticus) seizures and NOT FOR CATS
Dose, T1/2, time to steady state, therapeutic range, side effects and metabolism of impitoin?
- 10-30mg/kg BID
- 2hrs
- 1-2d
- N/A
- sedation, polyphagia, hyperactivity
- liver
How regularly are plasma levels needed with Imepitoin?
N/A
Reasons for epilepsy tx failure?
- incorrect dx (MRI?)
- incorrect choice of AED
- incorrect dosage/low AED levels
- newly developed dz (liver/kidney/pancreatic dz)
- change in patent weight
- patient tolerance to drug (PB/benzos)
- monotherapy is insufficent
- refractory seizures
- pooor compliance
How can tx failure be overcome?
- monitor and adjust drug dose
- monitor drug levels
- add anticonvulsant
- consider new drug
How is refracory epilepsy defined?
- seizre frequency reduction of less than 50%
How many dogs will be refractory to both PB and KBr combination?
20-330%
Give egs of add on drugs fo refractory seizures
- gabapentin
- pregabalin
- levetiriracetam
- zonisamide
- felbamate
First choice of AED in CATS? Dose, t1/2, time to steady state, therapeutic range and side effects?
- 2-3mg/kgOP SID/BID
- 3-43hrs
- 10-14d
- 10-30.2ug/ml
- polyphagia, bone marrow suppression, cutaneous hypersensitivities
- does NOT induce liver enzymes as much as dogs
2nd choice AED for cats? t1/2, dose and side effects?
> Diazepam
- 15-20hrs (6x longer than in dogs!!)
- 5-10mg PO BID/ID
- acute fulminant hepatotoxicosis
What should be monitored with diazepam in cats?
- evaluation liver enzymes 5-7d after initiation
Which other AED may be used in cats?
- levatiracetam (dose 10-20mg/kg PO TID, t1/2 5.3hrs)
- gabapentin (dose 5-10mg/kg TID)
What are the consequences of status epilepticus?
> Seizure up to 30mins - high symp tone - arterial hypertension - ^ cerebral blood flow - hypoxaemia - hypercarbaemia - hyperglycaemia - lactic acidosis > seizure >30mins - continuous muscle contraction - hyperthermia - acidosis - myolysis (myoglobinuria, hyperkalaemia: renal failure) - hypoglycaemia (energy depletion) - hypotension - cardiac arrythmias
What effects may treatment following seizure have?
- v HR
- v R
- v BP
combined with seizure -> hypoxia and hypotension
How can hypoxia and hypotension, hyperthermia be treated?
- oxygen
- fluids
- cool down
How can pathologic effects of seizures be classified?
1* and 2* effects (complications)
What can the ultimate result of status epilepticus be?
energy depletion, circulatory collapse and organ hypoperfusion -> multiple organ failure
3 goals of tx of status epilepticus
- stop the seizures
- protect the brain
- think about the future
Which drugs are indicated for use in status epilepticus lasting 120mins??
5-30mins: Diazepam, Midazolam
30-60mins: Phenobarbitol, KBr
60-120mins: Levetiracotam, propofol anaesthesia
120min+: Ketamine anaesthesia, iso- or sevoflurane anaesthesia, Pentobarbital, Phenobarbital and KBr
How can 2* complications of status epilepticus be minimised
> monitor - HR - BP - O2 - electrolyte/fluid ballance - body temp > minimise brain injury - tx hypotension (volume expansion, fluid balance) - tx hypoxaemia (O2 upplementation) - minimise hyperthermia - minimise renal impairment
What must be addressed when looking at status epilepticus?
Dx and Tx udnerlying disease
- hypoglycaemia/electrolyte imbalance (correct)
- possible toxicity (diuresis and decontamination)
- intracranial cause (imaging, CSF analysis)
- referral
