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Clinical Pharmacology Exam 3 > CNS Pharmacology > Flashcards

CNS Pharmacology Flashcards

1
Q

Idiopathic epilepsy clinical picture

A
  • Breed predilection: Golden Retrievers, Beagles, Labradors, GSD, etc.
  • 1-5 years of age with onset of first seizure
  • No interictal neurologic defects
  • Diagnosis made by ruling out structural and metabolic causes
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2
Q

Treatment for idiopathic epilepsy

A
  • best treatment is to address the underlying cause

- SYmptomatic treatment with anticonvulsants

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3
Q

When to treat with anticonvulsants?

A
  • More than 1 seizure per month
  • Cluster seizures
  • Status epilepticus
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4
Q

Therapeutic goals for idiopathic epilepsy

A
  • Acute: end seizure activity as rapidly and effectively as possible without causing serious side effects
  • Maintenance: to DECREASE the frequency and severity of seizures (rarely abolish)
  • MUST MANAGE OWNER EXPECTATIONS
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5
Q

Important properties for drugs treating acute seizure management

A
  • Highly lipid soluble to rapidly reach CNS concentrations
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6
Q

Look at the A & B scenario in her slides for which drug has the greatest efficacy

A
  • Just do it
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7
Q

What is pharmacological effect proportional to?

A
  • Concentration of the drug at the site of action
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8
Q

What is the concentration of the drug at the site of action proportional to?

A
  • Concentration of drug in the blood
  • Therapeutic plasma concentrations for anticonvulsants are known (measure concentration of the drug in the plasma or blood)
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9
Q

When does a drug reach steady-state?

A
  • After five half-lives
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10
Q

When do you want to measure if a patient has therapeutic concentrations of a drug?

A
  • After five half-lives, when it has reached steady state
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11
Q

If you start phenobarbital and the half-life is 48 hours, when do you want to measure to see if you have therapeutic drug concentrations?

A
  • 10 days
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12
Q

Elimination half-life and therapeutic drug monitoring

A
  • If frequency > half-life, you have more fluctuation and less accumulation
  • This dog would be prone to having seizures
  • If you have an animal with breakthrough seizures, important to do TWO plasma concentrations: one at the peak (4 hours after dosing) and one at the trough (immediately before dosing again)
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13
Q

When does the peak for drug dose tend to be?

A
  • About 4 hours after dosing
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14
Q

When is the trough for drug dosing typically measured?

A
  • Immediately before dosing again
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15
Q

When do you want to take just a peak sample?

A
  • If you think the dog is experiencing toxicity

- If we are worried that the concentration is too high, we will take a peak sample

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16
Q

When do you have a trough sample?

A
  • If you are worried that your therapy isn’t working

- E.g. for anti-convulsant medications, if you have breakthrough seizures

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17
Q

Loading dose

A
  • Used to get plasma drug concentrations into the therapeutic range as quickly as possible
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18
Q

Who can do therapeutic drug monitoring?

A

ANYONE

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19
Q

WIthdrawal of anticonvulsants

A
  • Abrupt withdrawal can precipitate status epilepticus
  • Client education
  • MUST WEAN PATIENT OFF MEDICATION GRADUALLY, even if they haven’t seizured for a year
  • Phenobarbital is not a drug that you can run out of over the weekend
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20
Q

Maintenance anticonvulsants

A
  • Phenobarbital
  • Bromide
  • Leviteracetam
  • Others
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21
Q

Phenobarbital drug class

A
  • Barbiturate
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22
Q

Phenobarbital MOA

A
  • Primarily stimulates GABA-gated chloride channel (inhibitory NT)
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23
Q

Metabolism of phenobarbital

A
  • Cytochrome P450

- If a patient has severe liver problems, you don’t want to use this

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24
Q

Phenobarbital elimination half-life

A
  • Average of 48 hours but varies

- 10 days to steady state

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25
Q

Adverse drug reactions of phenobarbital

A
  • CNS mediated
  • PU/PD/PP
  • Sedation and ataxia (often seen shortly after initiating therapy, but decreases after a few weeks)
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26
Q

Phenobarbital sedation

A
  • Can happen for the first 2 months, and owners don’t like it
  • 90% of the time it will go away
  • If you tell them up front, it may bother them less
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27
Q

Hepatic toxicity of phenobarbital

A
  • Dose related (plasma concentrations >30 µg/mL carry higher risk)
  • Induce ALP activity
  • Mild to moderate increases in ALT
  • ALP (5-10x baseline )
  • Monitor liver enzymes and liver function
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28
Q

What can you do further to investigate if ALP is elevated on phenobarbital?

A
  • Measure bile acids
  • Hypoalbuminemia
  • Look at cholesterol
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29
Q

What is the therapeutic level of phenobarbital that you should never exceed?

A
  • 40 µg/mL

- Really greater than 30 carries a higher risk

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30
Q

Bile acid elevation and phenobarbital

A
  • If bile acids are elevated, do not use phenobarbital
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31
Q

Phenobarbital CYP450

A
  • Induces CYP enzymes therefore is perpetrator of drug interactions
  • Metabolizes CYP 450 enzymes therefore is “victim” of drug interactions
  • Induction has a ceiling
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32
Q

Phenobarbital monitoring

A
  • Two weeks after starting PB or after any dose change: get a PB level
  • Every 6 months: CBC, serum chemistry, UA, bile acids (pre- and post), PB level
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33
Q

What is most important out of 6 month monitoring of phenobarbital levels?

A
  • Phenobarbital level and biochemistry panel
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34
Q

Bromides

A
  • Potassium bromide

- Sodium bromide

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35
Q

MOA of bromides

A
  • Traveses chloride channels resulting in hyperpolarization (inhibition) of neurons
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36
Q

Metabolization of bromide

A
  • 100% excreted by kidney
  • NOT METABOLIZED
  • Good choice for a patient that has liver disease
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37
Q

Elimination half-life of KBr in dogs

A
  • 25 days in dogs
  • Takes 4 months to steady state!
  • Loading doses often used to reach therapeutic concentrations faster
  • TDM sample collection timing - doesn’t matter
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38
Q

Elimination half life of KBr in cats

A
  • 10 days

- Takes 7 weeks to reach steady state in cats

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39
Q

Therapeutic level of KBr

A
  • 1-3 mg/mL
  • Can exceed therapeutic level as long as the patient is not showing signs of bromide toxicity (severe sedation and ataxia)
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40
Q

KBr toxicity

A
  • severe sedation and ataxia
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41
Q

KBr formulation

A
  • COMPOUNDING IS OKAY! (FDA says it’s fine)
  • She promotes compounding this
  • Solution might be best
  • Tablets and capsules available but they are hypertonic and can cause direct GI irritation and vomiting
  • GIVE WITH FOOD***
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42
Q

Adverse drug reactions of Bromides

A
  • CNS depression (ataxia, sedation)
  • These occur at higher doses, during initial dosing, and DEFINITELY after loading
  • PU/PD
  • Polyphagia
  • GI signs, pancreatitis
  • NOT LIVER adverse effects
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43
Q

Bromides in cats

A
  • Fatal respiratory distress in 30-50% of cats (AVOID)

- If that’s all you could do, you could try it

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44
Q

Drug/diet interactions with bromide

A
  • Basically acts like chloride, so a lot of potential food an drug reactions
  • Furosemide enhances excretion of bromide
  • Saline (fluid therapy) enhances excretion of bromide
  • Increase in dietary salt content increases excretion of bromide
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45
Q

Clin path changes with bromide

A
  • Measured as chloride
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46
Q

Leviteracetam mechanism

A
  • interferes with presynaptic neurotransmitter release (glutamate side)
47
Q

Metabolism of leviteracetam

A
  • No hepatic metabolism
48
Q

Elimination of leviteracetam

A
  • Primary renal elimination
49
Q

Half-life of leviteracetam

A
  • ~4 hours in dogs
  • 5-6 hours in cats
  • Ends up being three times a day dosing in dogs and cats; 2x in horses
  • Also expensive
50
Q

Which antiepileptic should be first choice?

A
  • Doesn’t really matter
  • Some neurologists use different ones, which is reasonable
  • Often phenobarbital or KBr but leviteracetam, zonisamide also reasonable
51
Q

Potential side effects of leviteracetam

A
  • Tolerance in some dogs
  • Minimal side effects - sedation, vomiting, ataxia (rarely)
  • Safe for liver
52
Q

Clinical result of leviteracetam in cats

A
  • Tolerable side effects
  • Cost less of an issue
  • Probably one of the better 2nd line drugs (given that there isn’t likely another one)
53
Q

Other maintenance convulsants

A
  • There’s a lot

- Zonisamide is probably next most commonly used

54
Q

What to do with anticonvulsants if seizures continue at unacceptable frequency and/or severity: phenobarbital?

A
  • Increase dose of phenobarbital until either:
  1. ) you reach mid 30’s µg/mL
  2. ) Side effects are unacceptable
55
Q

What to do with anticonvulsants if seizures continue at unacceptable frequency and/or severity: KBr?

A
  • Increase dose of KBr until side effects are unacceptable
56
Q

What can you do if you max out on the first drug?

A
  • Add a second drug

- Don’t typically take them off of the first drug unless they have severe liver toxicity

57
Q

What route of administration is preferred for acute seizure management?

A
  • IV preferred
  • Most rapid
  • Diazepam (valium)
58
Q

What route should be avoided for acute seizure management?

A
  • Oral route
  • Delayed absorption
  • Risk of injury
  • Possible aspiration
59
Q

What other routes work for acute seizure management with diazepam

A
  • IV preferred
  • IM doesn’t work great (slow, erratic absorption; painful)
  • RECTAL (reaches peak concentrations in systemic circulation in minutes)
  • Intranasal (in babies)
60
Q

MOA of Diazepam

A
  • Enhance GABA activity (Inhibitory NT
61
Q

Diazepam pharmacokinetics

A
  1. HIGH lipid solubility
  2. SHORT half-life
  3. Metabolized by liver
62
Q

High lipid solubility of diazepam

A
  • Fast distribution to CNS

- Makes diazpeam tx of choice for acute seizures

63
Q

Half-life of diazepam

A
  • Frequent administration so not a good maintenance
  • Short half life
  • May require CRI
64
Q

Metabolism of diazepam

A
  • Liver
65
Q

Adverse drug reaction of diazepam that is universal to all species

A
  • Sedation
66
Q

Adverse drug reaction of diazepam unique to cats

A
  • Idiosyncratic hepatic necrosis
  • Rare but fatal
  • Develops early in the course of treatment
  • Small fraction of cats will develop it
67
Q

Drug interactions with diazepam

A
  • Not a problem clinically
68
Q

Diazepam practical considerations

A
  • Binding to plastic, light sensitive, precipitates

- The more flexible the plastic, the more it sticks

69
Q

Status epilepticus with leviteracetam with diazepam

A
  • May help in combination

- More helpful than placebo

70
Q

What might be your next best bet if pharmacist won’t let you give a dog with hx of seizures emergency diazepam?

A
  • Leviteracetam

- Can be given rectally

71
Q

What is 3rd choice anti-convulsant drug for refractory cases?

A
  • Propofol
  • May cause seizures in cats
  • Isoflurane
72
Q

Which neurotransmitters do most behavior modifying drugs target?

A
  • Serotonin
  • Dopamine
  • Norepinephrine
  • GABA
73
Q

FDA Approval of Behavior Modifying drugs

A
  • Only 3 are FDA approved FOR DOGS
  • Clomipramine
  • Fluoxetine
  • L-deprenyl; selegiline
74
Q

Buspirone drug class

A
  • Anxiolytic
75
Q

Buspirone mechanism of actinon

A
  • Inhibits serotonin (5-HT) synthesis by binding at presynaptic 5HT1a receptors
  • may enhance dopamine activity
76
Q

Adverse drug reactions with buspirone

A
  • No sedative effects

- Cats may experience increased aggression toward other cats

77
Q

Clinical use of buspirone (we skipped)

A
  • canine aggression
  • feline spraying
  • Thunderstorm phobias
  • Self mutilation
78
Q

Clomipramine and other antidepressant general use

A
  • Treat behaviors that we (humans) find unacceptable
79
Q

MOA of Clomipramine and other antidepressants

A
  • Enhance activity of neurotransmitters (Serotonin 5HT and Norepinephrine NE)
  • Block physiologic inactivation by reuptake pumps at the synapse
80
Q

Clomipramine class

A
  • Tricyclic antidepressant

- Blocking the serotonin and noreinpehrine reuptake inhibitors

81
Q

Therapeutic index of clomipramine

A
  • VERY NARROW
82
Q

Clomipramine side effects (less serious)

A
  • Behavior changes, lethargy, GI
83
Q

Clomipramine side effects (fatal)

A
  • Cardiac arrhythmias
  • Hypotension
  • CNS depression (coma, death)
84
Q

What type of containers should be used for any drug but especially for tricyclic antidepressants?

A
  • CHILDPROOF CONTAINERS
85
Q

What enzyme metabolizes tricyclic antidepressants like clomipramine?

A
  • CYP450 enzymes
86
Q

Drug interactions with TCAs

A
  • Any p450 inhibitor or inducer
  • Inhibitors (toxic effect): Ketoconazole, rifampin, cimetidine, fluoroquinolones
  • inducers (subtherapeutic effect): phenobarbital, griseofulvin
87
Q

Other drug interactions that may potentiate NE or 5HT

A
  • MAO inhibitors
88
Q

Clinical use of tricyclic antidepressants (label)

A
  • Labeled for separation anxiety in dogs
89
Q

Clinical use of tricyclic antidepressants (extra-label)

A
  • Dog, cat, and horse behaviors associated with fear, aggression, OCD, self-mutilation
90
Q

How long does it take to see effects with TCAs (e.g. clomipramine)?

A

– Several weeks

  • Don’t give up until you’ve reached 2+ months
91
Q

SSRIs potential benefit over TCA

A
  • Less likely to cause sedation, which is an advantage in human patients
  • Less likely to cause sedation
92
Q

SSRI example

A
  • Fluoxetine
93
Q

SSRI mechanism

A
  • Similar to TCAs but just specific for the serotonin reuptake pump
  • Does not impact norepinephrine
94
Q

Adverse drug reactions of SSRI (e.g. fluoxetine)

A
  • Fewer than TCAs
95
Q

Drug interactions with SSRI (e.g. fluoxetine)

A
  • Can inhibit CYP 450 (not super strong)

- Can cause serotonin syndrome

96
Q

FDA approved use of SSRIs (e.g. fluoxetine)

A
  • Separation anxiety
97
Q

Off-label use of SSRIs (e.g. fluoxetine)

A
  • lick granulomas
  • Tail mutilation
  • Aggression
  • Psychogenic alopecia
  • Other behavior disorders
98
Q

What drug is used for canine cognitive dysfunction?

A
  • Selegiline or l-deprenyl (anipryl)

- Pfizer has a website to help owners diagnose it

99
Q

MOA of selegiline

A
  • MAO inhibitor

- Essentially inhibits metabolism of norepinephrine, dopamine, and serotonin to their inactive metabolites

100
Q

What is an interesting metabolite of selegiline?

A
  • Methamphetamine
  • They appear more active sometimes
  • Cannot use in horses
101
Q

Adverse effects of selegiline

A
  • Anorexia
  • Restlessness
  • Repetitive movements
  • Potential for human abuse
102
Q

Drug interactions with selegiline

A
  • Serotonin syndrome
103
Q

Clinical use of selegiline

A
  • Canine cognitive dysfunction

- In humans, potential benefits in people with Alzheimer’s

104
Q

Selegiline and use in performance horses

A
  • Considered as a drug with high abuse potential in performance horses
  • Methamphetamine and amphetamine detectable in urine of horses after treatment with selegiline
105
Q

Serotonin syndrome

A
  • Excess serotonin in CNS
106
Q

Risk factors for serotonin syndrome

A
  • Any drug that potentiates serotonin in the brain
  • Increases catecholamines and serotonin in the CNS
  • Potentially fatal drug reaction
107
Q

Signs associated with serotonin syndrome

A
  • Hypertension
  • Seizures
  • Tremors
  • Hyperesthesia
  • Ataxia
  • Blindness
  • Vomiting/diarrhea
  • Abdominal pain
  • Hypersalivation
  • Hyperthermia
  • Death
108
Q

Drugs that can lead to serotonin syndrome

A
  • MAO inhibitors
  • Mitoban (mange treatment)
  • Amitraz
  • St. John’s Wort
  • Ginseng
  • Clomipramine or any TCA
    Fluoxetine or any SSRI
  • Dextromethorphan
  • Selegiline
109
Q

Treating behavioral disorders in general

A
  • Often trial and error

- Few retrospective studies

110
Q

What level of improvement will you generally see with behavioral medications?

A
  • Often improvement but not 100% improvement
111
Q

Are newer drugs generally better?

A
  • NOPE

- She likes to wait

112
Q

Are more drugs better medicine?

A
  • Nope
113
Q

Is any drug truly safe?

A
  • NOPE

- It’s about the dose

Clinical Pharmacology Exam 3 (5 decks)

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