Drugs used to modify behaviour - Anticonvulsive, Antiepileptics

Question 1

Drugs used to modify behaviour:

Answer 1

• Sedatives (neuroleptics, benzodiazepines)
• antidepressants
• B-adrenoceptor blocking drugs (propranolol)
• Antiepileptics (Carbamazepine, Phenobarbital)
• Opioid antagonists (naloxone, naltrexone)
• CNS-stimulants (Dexamphetamine)
• Antihistamines (Megestrol, Cabergoine, Demadinon)
• Cerebral Vasodilators (Nicergoline, Propentofylline)
• Artificial pherormones (Feliway, Felitriend, DAP)
• Feed supplements (alpha casozeipine, tryptophan)

Question 2

Name some Antidepressants:

Answer 2

1. Tricuclic antidepressants (TCAs):
   - Amitryptiline, Clomipramine, Doxepin, Imipramine
2. Serotonin reoptake inhibitors (SRIs):
   - Fluoxetine, Flavoxamine, Sertraline
3. Monoamine Oxidase inhibitors (MAOIs):
   - Selegiline
4. Lithium:
   - narrow margin of safety, not used in Vet.med

Question 3

Tricyclic Antidepressants (TCAs):

• Mechanism of action, Pharmacokinetics

Question 4

Mechanism of action:

• Inhibition of serotonin and NA reuptake (+ anto-cholinergic, anti-adrenergic, anti-histamine)

Pharmacokinetics:

• Oral absorption is good, high availability, bounded to albumin (90-95%), Cpss 2-3 weeks, metabolism in liver, elimination via urine.

Question 5

Tricyclic Antidepressants (TCAs)

• Side-effects, indications:

Answer 5

Side-effects:

• moderate sedation, occasional vomitting, changes in appetite or lethargy, antimuscarinic effects, urniary retention

Indications:

• separation relaxed anxiety, feline urine spraying, stereotypes, acral lick dermatitis

Question 6

Serotinin reuptake inhibitors (SRIs)

• Mechanism of action, Pharmacokinetics:

Answer 6

Mechanism of action:

• selective inhibition of serotonin reuptake

Pharmacokinetics:

• oral absorption is good, high availability (F=0.7)
• bounded to albumin.
• metabolism in liver flyoxetine –> norflyoxetin
• elimination half-life of the metabolites 7-9 days.

Question 7

Serotinin reuptake inhibitors (SRIs)

• side effects, indications, dose:

Answer 7

Side-effects:

• infrequent, occasional comiting, diarrhea, increased CYP450 activity
• warnings: severe hepatic and/or renal imparment, diabetes mellitus, epilepsy

Indications:

• stereotypes, aggression, depression, generalised and recurrent fears, (separation related anxiety, feline urine spraying)

Dose:

• dogs 1-4 mg/kg (1x), caps 4 times less

Question 8

Monoamine Oxidase Inhibitors (MAOIs)

• mechanism of action, pharmacokinetics:

Answer 8

Mechanism of action:

• decreased intracellular metabolism of adrenaline, noradrenaline, prolonged NT action in synapses

Pharmacokinetics:

• Oral absorption is bad, low oral bioavailabiity (dog F= 0.1), Cpss after 3-4 weeks.

Question 9

Monoamine Oxidase Inhibitors (MAOIs)

• Side-effects, indications, dose:

Answer 9

Side-effects:

• gastrointestinal signs (salivation, vomitting, diarrhea), behavioural changes, excitements.
• interactions (eg. opioids)
• active metabolites (amfertamines) -> missuse

Indications:

• stereotypes, aggression, older dogs: changes in cognitive functions, older cats: vocalisation

Dose:

• 0.5-1 mg/kg (1x)

Question 10

What are Benzodiazepines?

Answer 10

sedative- anxiolytic- hypnotic effects- relatively safe drugs

Eg:

• Alprazolam: faster onset, shorter action
• diazepam: short ativity in dogs, in cats longer
• Lorazepam

Question 11

Difference between Grand mal seizures and Petit mal seizures:

Answer 11

• Tonic-clonic seizures, formerly known as Grand mal seizures, are the seizures type most commonly associated with epilepsy and are a type of generalized seixure affecting the entire brain.
• Absence seizures may occur in several forms of epilepsy = pepti mal seizures.

Question 12

Classification of Antiepileptics:

Answer 12

Question 13

Mechanism of action of Anticonvulsant drugs

• Main categories:

Answer 13

• Inhibitory synaptic processes
• excitatory neurotransimmsion
• stabilisation of membranes
• modulation of the release of neurotransmitters

Question 14

Mechanism of action of Anticonvulsant drugs.

• Inhibitory syneptic process

Answer 14

• BZD, PB, Imepitoin: GABA-ergic receptor agonsit (allosteric)
• Progabide: pro-drug of GABA
• Vigabatrin: inhibitor for GABA-transaminase
• GABApentin: synthesis of GABA increase

Question 15

Mechanism of action of Anticonvulsant drugs

• Excitatory neurotransmission:

Answer 15

• BZD: inhibition of release of excitatory neurotransmitters
• PB, penytoin, valproate: presynaptic effect
• Felbamate: antagonist of glutamate-receptors
• Lamotrigiene: release of glutamate decrease

Question 16

Mechanism of action of Anticonvulsant drugs

• stabilisation of membrane

Answer 16

• reduction of electrical excitability of cell membranes, possibly thorugh use-dependent block of sodium channels
• Carbamazepine, phenytoin, valproate

Modulation of the release neutrotransmitters:

• inhibition of the presynaptic Ca-channels
• Lecetiracetam

Question 17

Phenobarbital:

• Function, effective therapeutic level, kinetics

Answer 17

Function:

• pronounced depression of the CNS
• Ach, NE, glutamate release decreases, GABA-mimetic (allosteric)

Effective therapeutic level:

• in dog: 15.45 ug/ml, in cat: 23-30 ug/ml

Kinetics:

• PO bioavailability; 90% tmax 4-8 hr, long T_1/2 (37-73 hr)
• Cpss after 30-45 days, plasma binding 40-45%
• Metabolism: liver strong micros. enzyme induction
• Dose –> steroids, deoxycycline, quinidine, phenylbutazone

Question 18

Phenobarbital:

• side effects, dosage

Answer 18

Side effects:

• sedation, drowsiness, ataxia, polyphagia, polyuria, rarely: facial pruritus, thrombocytopenia, neutropenia, idiosyncrasy (hepatotoxic, pancreatitis, necrolytic dermatits)

Dosage:

• 1-5 (40) mg/kg PO
• Status epilepticus: 2-4 mg/kg IV bolus

Pentobarbital status epilepticus: 2-15 mg/kg IV

Question 19

Diazepam:

Answer 19

Benzodiazepines

Dogs: dugs of choice for controlling status epilepticus

• not suitable for oram maintenance therapy (absorbed poorly, eliminated rapidly, and a tolerance to anticonvulsant effects develop rapidly
• dose: IV bolus 5-10 mg/kg, followed by infusion 2-5 mg/hour. Per rectum: 0.5-0.2 mg/kg, up to 3 times in 24 hr.

Cats: maintennce therapy 0.25-0.5 mg/kg, PO BID-TID

• slower elimination rate than dogs but also do not develop a tolerance.
• tatus epilepticus: 0.5-2 mg/kg IV

Horses:

• long elimination half-life (7-22 hr), therefore the anticonvulsant of choise (5-20 mg/dose IV)
• for seizures: 25-50 mg/dose IV

Question 20

Clonazepam:

Answer 20

Benzodiazepines

• in dogs tolerance develops less rapidly and it is more properly absorbed orally, can be used for oral maintenance therapy in dogs.
• in maintenance therapy it is best used as an adjunct to phenobarital at sodages of 0.1-0.5 mg/kg/day, or alone at 0.5mg/kg TID
• diarrhea sometimes develops, but can be avoided by increasing the dose frequency from 1 to 3 times/day

Question 21

Chlorazeopate:

Answer 21

• adjunct to phenobarbital treatment in dogs. 2-6 mg/kg BID

Question 22

Carbamazepine

Answer 22

• similar to that of phenytoin, but with fewer unwanted side-effects
• not recommended

Question 23

Phenytoin:

Answer 23

• A membrane stabilising agent (use-dependent block of sodium channels and GABA enhancing activity)

–> cardiac anti-dysrhytmic activity and anticonvulsant activity

• absorption and metabolism are variable
• short elimination half-life in dog, extremely long in cat (toxicity!)
• it is difficult to avhieve therapeutic plasma-drug concentrations in dogs because of rapid elinination half-life
• not recommended

Question 24

Primidone:

Answer 24

• is the 2-deoxy analouge of phenobarbitone, the antipeltic activity is due to its metabolites
• do not use together with barbiturates

Question 25

Sodium (potassium) Bromide:

Answer 25

• in monotherapy effective blood level: 2,5 mg/ml with PB: 1-1,5 mg/ml
• long half life: 21-24 days in dogs
• side effects: sedation, ataxia, stupor, pruritic skin lesions, polydipsia, pancreatitis, muscle degeneration, anaphropdisia

Question 26

Drugs contraindicated in epileptic patients:

Answer 26