2.1 Principles of Neuropharmacology Flashcards
What are the two ways fluid can enter the brain?
blood CSF barrier: vessels from the brain invaginate the ventricles in a structure called the choroid plexus; hydrostatic pressure forces plasma out of the blood through the vessel wall and then through the ventrical wall, which is covered by a special epithelium called the ependymal epithelium (modifies this into appropriate CSF)
blood brain barrier: endothelial cells form a tight junction between the blood and the brain (many mitochondria present in these cells, as there is a lot of active transport from the blood for certain substances); a continuous basement membrane surrounds the entire blood vessel (exterior), and pericytes (smooth muscle-like cells) are embedded in the BM
What factors are required for drug penetration of the CNS?
- high lipid solubility
- small molecular size
- low plasma protein binding
- drug ionization (only neutral drugs readily penetrate CNS)
What methods help antibacterials ender the CNS?
high antimicrobial concentrations are necessary:
- as brain has limited natural antibodies / phagocytic properties
- most common choices are penicillin, cephalosporins, and aminoglycosides (hydrophilic and polar), therefore high doses are required to produce a high concentration gradient at the BBB
Why are CNS tumors difficult to treat with chemotherapy?
chemotherapy agents are typically water-soluble with limited BBB penetration
- difficult to achieve adequate and sustained concentrations at tumor: contributes to failure
What is MDR-1, and how can it differ in some patients?
ABCB1, p-glycoprotein
ATP-dependent efflux pump found on the luminal surface of brain capillary endothelial cells
- excludes important drugs from the CNS (dexamethasone, abx, ivermectin, etc)
- this p-glycoprotein can be defective (drug accumulation), unregulated (refractory to some drugs), or highly expressed (via malignant glioma)
What are the mechanisms of action for antiepileptic drugs (AEDs)?
drugs that act on the GABA receptor do not stop a seizure from starting, but do limit its spread
- enhances GABA inhibitory signalling
- reduces excitatory signalling
- modulation of membrane cation conductance
What is GABA?
the main inhibitory neurotransmitter in the CNS; binds two different receptor subtypes:
- GABA(a): ligand-gated chloride ion channel
- GABA(b): metabotropic (G-protein linked)
Explain how GABA(a) binding takes its effects.
- GABA binding opens chloride ion channel and increases influx of Cl- into the neuron
- this hyperpolarizes the neuronal membrane, reducing the likelihood of another action potential
note: barbituates and benzodiazipines bind this receptor and enhance GABA inhibitory signalling
Explain how GABA(b) binding takes its effects.
increases potassium ion conductance: K+ moves out of the cells leading to a hyperpolarized membrane
What is status epilecticus?
a seizure that lasts >5 minutes, or 2 or more episodes between which there is incomplete recovery of consciousness
- considered an emergency: increased autonomic discharge leads to hypertension, tachycardia, and arrhythmia
- can further lead to hyperthermia, rhabdomyolysis, lactic acidosis, and hyperkalemia
- if untreated, evergy deman will exceed supply and trigger multiple organ failure
- ~60% of dogs with idiopathic epilepsy have 1 or more episode of status epilepticus in their lifetime
When do you begin treatment for seizures?
studies do not show any effect in starting treatment after the first seizure; treatment is indicated after the second seizure, depending on the time between them
start treatment when:
- cluster seizure (2 or more in 24hrs)
- status epilepticus
- severe post-ictal signs
- worsening frequency or severity of seizures
- 2+ seizures in 6 months
- underlying structural lesion
What are the goals of seizure treatment?
eliminating seizures is rare (15-30% of idiopathic epilectic dogs achieve freedom from seizures): a successful treatment is the reduction of 50% of seizure activity
also aim to:
- reduce severity
- reduce seizure related mortality / morbidity
- avoid medication adverse effects
What are the two type of adverse effects?
Type I: dose-dependent, predictable, caused by a known property of drug
Type II: often irrespective of dosage, reaction cannot be explained by the drug’s known mechanism of action, often immune-mediated hypersensitivity
Generally, which AEDs are recommended on the basis of efficacy and safety? What is current first line and second line treatment in a healthy dog?
efficacy:
(1) phenobarbital/imepitoin >
(2) potassium bromide >
(3) levetiracetam >
(4) zonisamide and others
safety:
(1) leveteracetam >
(2) imepitoin >
(3) phenobarbital >
(4) potassium bromide
first line therapy:
phenobarbital OR imepitoin (limited supply - not lisenced for clusture seizures)
second-line therapy:
potassium bromide
(use when phenobarb. is at max concentration and seizure control isnt sufficient, or if pheno. is contraindicated, e.g., hepatic disease)
What is phenobarbital?
- GABA receptor agonist: hyperpolarized post-synaptic membrane
- time to reach steady state: 10-14 days
- contraindicated in dogs with hepatic disfunction (~70% hepatic metabolization)
