Class 5- bipolar Flashcards
1
Q
Drugs and drugs that can precipitate a
manic episode
A
• Stimulants or hallucinogens
• Antidepressants
• Hormones
(synthroid, corticosteroids)
2
Q
MOOD STABILIZERS definition
A
Efficacy either in treating manic or depressive symptoms, without causing any switch of polarity (e.g. lamotrigine)
3
Q
Li is a
A
Monovalent cation
4
Q
Li
CLINICAL USE
A
o Bipolar disorder
o Schizo-affective disorder
o Major depressive disorder (adjunctive medication)
o Neutropenia secondary to clozapine (to increase
leukocytes)
5
Q
Li Contraindications
A
- Breastfeeding
- Brain damage
- Heart failure and other heart disease
- Kidney failure
6
Q
Absorption Li
A
Good absorption through the gastrointestinal tract
7
Q
Distribution Li
A
Distributed in body water
8
Q
Metabolism Li
A
Not metabolized by the liver so no interaction with cytochrome
9
Q
Elimination Li
A
o Almost totally through the kidneys
o Large proportion is reabsorbed by the proximal tubule
o Elimination related to glomerular filtration rate
• Age
• Creatinine clearance
10
Q
Half-life time Li
A
o 8 to 35 hours (24h)
o Steady state reached in 5 days
11
Q
DOSING Li
A
o Gradual increase
o Often administered BID to TID at the beginning of the treatment
• In order to reduce the “peaks” of plasma concentration
• Less GI side effects
o Adjust dose according to serum concentration
o Once the target dose is reached, lithium can be administered once daily (HS)
12
Q
Therapeutic interval Li
A
0,6 – 1,2 mmol/L
13
Q
Therapeutic interval Li acute
A
0,8 – 1,2 mmol/L
14
Q
Therapeutic interval Li maintenance
A
0,6 – 1 mmol/L
15
Q
Therapeutic interval Li elderly
A
0,6 – 0,8 mmol/L
16
Q
Li, At steady state, when the dose is changed, the serum concentration should change ???
A
proportionally
17
Q
LITHIUM CONCENTRATION IN BLOOD CELLS why use
A
Could potentially better predict the toxic effects of lithium
18
Q
sign of intoxication Lithium in blood cells
A
> 0,6 mmol/L
19
Q
STARTING LITHIUM
A
- Lithium 300 mg BID days 1 to 3
- Lithium 450 mg BID days 4 to 5
- Serum dose of lithium on the day 10 or 11
• Steady state about 5 days after last dose increase
• If < 0.6 mmol/L, increase the dose
• If between 0.6 and 1.2 mmol/L, contrôle serum dosage within a week (if hospitalized) or in two weeks (if outpatient)
20
Q
MECHANISM OF ADVERSE EFFECTS Li
A
It replaces sodium (Na) in transmembrary
exchanges
21
Q
SIDE EFFECTS Li
A
v ACNE - Up to 33% of patients - Development or worsening of acne v PSORIASIS v ARRYTHMIAS v CHANGES TO THE ECG, QTC PROLONGATION - Especially in case of intoxication v NAUSEA - Especially at the beginning of treatment v DRY MOUTH, THIRST - Up to 75% of patients v POLYURIA - About 30% of patients - Reduce serum lithium concentration - Use once a day - Investigating nephrogenic insipid diabetes v KIDNEY DAMAGE - Especially in case of intoxication - In rarer cases: epithelial tubular damage, acute tubular necrosis, nephrotic syndrome v CHRONIC KIDNEY FAILURE? - Gradually appears over the years - Very rare end-stage kidney failure (0.2 to 1% of patients receiving lithium for > 15 years) v HYPOTHYROIDISM - 8 - 19% of patients, may be irreversible - Not a contraindication to start lithium v HYPERPARATHYROIDISM - Recommended basic calcium level, then tracked - If hypercalcemia à PTH v WEIGHT GAIN - Especially at the beginning of treatment - 4 -6 kg v LEUKOCYTOSIS - Often benign v FINE TREMORS - Related to blood concentration; reduce the dose - Add propranolol 10 - 30 mg BID - TID v OTHER CONCENTRATION-DEPENDANT EFFECTS - Delirium, confusion, convulsions, coma
22
Q
RISK FACTORS FOR DEVELOPING CHRONIC KIDNEY FAILURE on Li :
A
- High lithium levels
- Multiple lithium poisonings
- Several takes a day (taking once a day, trough post 12 h isn’t at true lowest)
- Concurrent medication (e.g. AINS, IECA/ARA, diuretics): all the ampril and sartan
- Comorbidities (e.g. high blood pressure, diabetes)
- Age
23
Q
Toxicity Li 1,5 – 2 mmol/L
A
Diarrhea, vomiting, drowsiness, muscle weakness,
decreased coordination
24
Q
Toxicity Li 2 – 2,5 mmol/L
A
Ataxia, blurred vision, ringing in the ears, change to the
ECG
25
Toxicity Li> 3 mmol/L
Changes neurology, coma
26
Acute intoxication on chronic intoxication Li
= potentially fatal
| Possible permanent neurotoxicity: memory impairment, ataxia, dysarthria and tremors
27
TOXICITY
| TREATMENT Li
o Stop lithium
o Gastric washing if lithium intake is recent
o Maintain volemia and electrolytes.
o Activated charcoal does not adsorb lithium, but can be administered if polyintoxication is suspected.
o Dialysis is effective and may be necessary for cases with target organ damage.
28
↑ LITHIUM CONCENTRATION interaction
* NSAID
* Diuretics
* Angiotensin Conversion Enzyme Inhibitors (IECA)
* Angiotensin II receptor antagonists (ARA)
* Alcohol (dehydrates)
29
↓ LITHIUM CONCENTRATION interaction
* Table salt
| * Theophylline
30
PATIENT EDUCATION Li
```
HE NEEDS TO KNOW THE INTERACTIONS
Products that stimulate urine production
Risk of dehydration
Drugs for pain (NSAID)
Acétaminophène (TylenolTM) is safe
Beware of medications used to treat cold
Some antihypertensives
Alcohol
Always consult a health care professional before purchasing a new drug (prescription or over-thecounter)
Proper hydration
Diarrhea or vomiting=Rehydration STAT
Sweating (Heatwave, physical exercise)
```
31
Before treatment protocol Li
o Recent physical examination
o FSC, urea, creatinine, electrolytes, calcium, TSH, urine analysis, b-hcg and fasting blood sugar, weight
o ECG if > 40 years old
32
During treatment protocol Li
o TSH q3 month x 2 years then q6 months
o Every year: FSC, urea, creatinine, electrolytes, total calcium, urine analysis, fasting blood sugar,
weight
o Vital signs at each serum dosage
33
FREQUENCY OF SERUM DOSAGE Li
-Initiation of treatment
• 1 to 2 times a week depending on the titration ad stabilization
• 1 to 2 times a month for a month
-Maintenance treatment
• q3 month x 2 years, q6 months thereafter
-In the following cases :
• prescription modification, addition of concurrent treatment, doubts about adherence, signs and
symptoms of toxicity, drug interactions or clinical situation warrants it
34
Valproic acid / Divalproex class
anticonvulsants
35
CLINICAL USE (MENTAL HEALTH) val
o Bipolar disorder
o Schizo-affective disorder
o Irritability, aggression, behavioural problems
o Intellectual disability
36
Contraindications val
* Pregnancy
* Liver failure
* Disorders of the urea cycle
37
Absorption val
o Valproic acid is absorbed quickly
o Divalproex must dissolve, dissociate into valproic acid +
sodium valproate, which are absorbed
38
Distribution val
o Very strong bond to plasma proteins
39
Metabolism val
o Hepatic
40
Half-time life val
o 9 to 19 hours
| o Steady state reached in 5 days
41
Loading dose val
o To achieve a therapeutic serum concentration faster
| o 20 mg/kg
42
Gradual titration val
oStarting dose : 500 – 750 mg / day
43
Therapeutic interval : val
Ø 350 – 700 umol/L
Ø Therapeutic index wider than lithium
Ø Exact concentration not known for BD
** When you ask for a serum concentration of valproate, you immediately receive the TOTAL concentration (protein-bound + free fraction)
44
PLASMA PROTEIN BINDING val
90 – 95 %: Concentration-dependent and saturable
| FREE FRACTION: Active ingredient available to be active, be metabolized or eliminated
45
TARGETED THERAPEUTIC INTERVAL OF FREE FRACTION val
35 – 70 umol/L
46
Relevant laboratory in specific situations : val
- Hypoalbuminemia, especially if < 30 g/L (e.g. malnourished patient)
- Shifting binding sites
Medical condition (e.g. liver or kidney disease)
Drugs (e.g. phenytoin, high-dose aspirin)
47
SIDE EFFECTS Val
v SKIN REACTIONS
- Rash
- Stevens-Johnson syndrome / toxic epidermal
necrosis (rare)
v ALOPECIA
- 6 – 24 %
- Concentration-dependent
- Zinc supplement or selenium could be beneficial?
v NAUSEA, VOMITING, DIARRHEA, CONSTIPATION
- Especially at the beginning of treatment, fade
over time
v HEPATOTOXICITY AND ↑ TRANSAMINASES
- Slight rise of transaminases
- Monitor liver transaminases and intervene if > 3 times normal
v PANCREATITIS
- 5 % of patients
- Stop valproate if necessary
v WEIGHT GAIN
- 50 % of patients
- 6 – 8 kg
v HYPERAMMONEMIA
- Altered state of consciousness, change in
behaviour, vomiting
- Especially if toxicity, high serum concentration
or drug interaction
- Light: reduce dose or suspend valproate
- Moderate - severe: L-carnitine or lactulose
v THROMBOCYTOPENIA
- 1 – 30 %
- Slight to moderate: valproate can be continued,
but closely monitored
-platelets less than 50 = stop epival
v ATAXIA
v DIPLOPIA
v DIZZINESS
v SEDATION
v TREMORS
- High-dose
48
Toxicity val > 525 umol/L
Ataxia, fatigue, sedation, lethargy
| * Possible tolerance (slow titration)
49
Toxicity val> 700 umol/L
Tremors
50
Toxicity val> 1200 umol/L
Stupor or coma
51
PHARMACOKINETIC INTERACTIONS vAL
LAMOTRIGINE
• Divalproex increases lamotrigine serum concentration
• Risk of serious skin rash (e.g. Stevens- Johnson syndrome)
• Caution!!
HIGH-DOSE ASPIRIN
• Increases free fraction of divalproex by shifting the binding to plasma proteins
• High doses of ASA are rarely used in clinical practice
52
Before treatment VAL
```
o Recent physical examination
o FSC, liver function tests (AST, ALT, total bilirubin, alkaline phosphatase), fasting blood glucose, lipid profile, weight, waist circumference
oPregnancy test (if clinical indication)
```
53
During treatment VAL
o FSC, liver function, weight and waist circumference q3 months x 1 year then each year
o Blood pressure, fasting blood glucose and lipid profile q6 months x 1 year then each year
54
Carbamazépine class
anticonvulsants
55
CLINICAL USE (MENTAL HEALTH) carb
o Type 1 and Type 2 BD
| o Irritability, aggression, behavioural problems
56
carb Contraindications
Bone marrow supression
57
Metabolism carb
o Hepatic, via several cytochromes
o Enzymatic inductor
Ø Inductor of his own metabolism: ↑ dose = Induction it's own metabolism= ↑ clearance = Steady state serum
concentration (2 – 3 weeks) = ↑ dose
Ø Many interactions with other drugs
o Toxic metabolite can accumulate and cause side effects
58
Half-life time carb
25 – 65 hours
59
Therapeutic interval :carb
17 – 54 umol/L
| More frequent monitoring at the beginning of treatment (self-induction of the drug)
60
SIDE EFFECTS carb
- Rash
- Stevens-Johnson syndrome / toxic epidermal
necrosis (rare) especially in asians
v NAUSEA
v VOMITING
v CONSTIPATION
v DRY MOUTH
v HYPONATREMIA
- Ad 40 %
- Possibly related to a SIADH
v AGRANULOCYTOSIS / MEDULLARY APLASIA
- Risk 5 to 8 x higher than the general population
- Do not administer with clozapine
v ATAXIA, DIZZINESS, DROWSINESS, TREMORS
- Concentration-dependent
v CONVULSIONS
- Rare
61
TOXICITY carb > 63 umol/L
Ataxia, nystagmus
62
TOXICITY carb > 106 umol/L
Possibility of a pro-convulsive effect, coma
63
Lamotrigine class
anticonvulsants
64
Lamotrigine Clinical use (mental health)
o Treatment of depressive episodes
o Prevention depressive episodes
o Not effective in the treatment of mania
65
POSOLOGY Lamotrigine
SLOW TITRATION
o To reduce the risk of Stevens-Johnson syndrome or toxic epidermal necrosis
o Reduce the speed of titration by 50% in the presence of valproate
66
SIDE EFFECTS Lamotrigine
```
v RASH
- About 7 %
v STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROSIS
- Rare
- Increased risk if fast titration
- Quickly stop lamotrigine
v NAUSEA
v VOMITING
v DIARRHEA
v ATAXIA
v DIZZINESS
v SEDATION
v DIPLOPIA
```
67
PHARMACOKINETIC INTERACTIONS Lamotrigine
DIVALPROEX
• Divalproex increases serum lamotrigine
concentrations
• Risk of serious skin side effects (e.g. Stevens-Johnson syndrome)
• Caution!!
CONTRACEPTIVES
• Reduced serum lamotrigine concentration by 50%
68
Several atypical antipsychotics are effective in BD for:
o Treatment of mania
o Treatment of depression
o Maintenance treatment
In BD with or without psychotic symptoms
69
ATYPICAL ANTIPSYCHOTICS
| Recommended as a first-line (CANMAT)
o Quétiapine in monotherapy or combination
o Asenapine in monotherapy or combination
o Aripiprazole in monotherapy or combination
o Palipéridone in monotherapy
o Risperidone in monotherapy or combination
70
BEFORE INTRODUCING TREATMENT
ELIMINATE PRECIPITATING FACTORS
Substance-induced mania :
v Stop the substance or drug involved
v E.g. antidepressants, stimulants, drugs
v Limit caffeine/alcohol consumption
Mania induced by a medical condition (e.g. neurological condition)
71
MONOTHERAPY OR COMBINATION?
| Decision based on :
o The desired response time (e.g. combinations tend to work quickly)
o Patient history (e.g., partial prior response to monotherapy)
o Severity of the mania episode
o Concerns about the tolerability of a combination
72
MONOTHERAPY
o Approximately 50% of patients will
respond to monotherapy in 3 to 4 weeks
o Comparable efficacy between different drugs
73
COMBINATION
o Often the standard in the treatment of
bipolar affective disease (two poles to be
treated)
o About 20% more patients would respond to a combination
74
EFFICACY
Therapeutic response expected in 1 to 2 weeks
75
In the event of non-response or partial response to
| treatment:
o Optimizing the dose
o Assess adherence to the drug
o Assess substance abuse
76
In general, one of these drugs is used as a first-line treatment of mania:
q Lithium
q Valproate
q Atypical antipsychotic (e.g. quetiapine, aripiprazole, risperidone)
Monotherapy or combination
77
If manic episode with psychotic features :
Prefer an antipsychotic
Often used: Li/DVP + antipsychotic
Benzodiazepines: Often used as adjuvants for restlessness, anxiety or insomnia. Caution in patients at risk of abuse
78
ANTIDEPRESSANTS IN BD
1. Avoid if antecedent of "switch" in mania on antidepressant
2. Avoid during a mixed episode or during rapid cycling
3. Use in monotherapy is not recommended for type 1 BD
v Less clear evidence in type II BD
v Less risk of 'switch', monotherapy possible for some antidepressants
less risk for bupropion, zoloft
79
In general, one of these drugs is used as a first-line treatment for bipolar depression:
q Quetiapine
q Lurasidone (alone or in combination)
q Lamotrigine (alone or in combination)
q Lithium
80
the risk of relapse is higher within
2 to 4 months of the response to treatment,
81
MAINTENANCE TREATMENT
Minimize the number of drugs
Use the smallest effective dose
Generally the same drug is targeted as acute treatment
82
J.L. is a 74-year-old woman treated for bipolar disorder, hypertension, type II
diabetes and osteoarthritis. She is non-smoking and does not use alcohol or drugs. She is
currently receiving the following medications:
- lithium (Carbolith) 900 mg HS
- risperidone (Risperdal) 2 mg HS
- amlodipine (Norvasc) 5 mg DIE
- metformin (Glucophage) 500 mg BID
- glyburide (Diabeta) 5 mg DIE
She shows up for her monthly appointment at your clinic. On examination, you notice that she
has tremors and that she seems slightly confused. Her husband tells you that she presented
diarrhea in the last 2 days.
a) What do you think is the most likely cause of her symptoms?
Li toxicity
83
J.L. is a 74-year-old woman treated for bipolar disorder, hypertension, type II
diabetes and osteoarthritis. She is non-smoking and does not use alcohol or drugs. She is
currently receiving the following medications:
- lithium (Carbolith) 900 mg HS
- risperidone (Risperdal) 2 mg HS
- amlodipine (Norvasc) 5 mg DIE
- metformin (Glucophage) 500 mg BID
- glyburide (Diabeta) 5 mg DIE
She shows up for her monthly appointment at your clinic. On examination, you notice that she
has tremors and that she seems slightly confused. Her husband tells you that she presented
diarrhea in the last 2 days.
In your questionnaire, you ask her if she has been taking her medication as prescribed in the
last few weeks and she answers you positively. She added that she went to the pharmacy to get
over-the-counter medications to treat her osteoarthritis. She can't remember the name but
knows it’s an anti-inflammatory. She only took one tablet. How can this affect the patient's drug
therapy?
Increase in Li concentration
84
Topiramate pros and cons
1
85
ECT which meds to stop
1
86
Mr. SV has been taking risperidone 6 mg HS for the past year. His psychiatrist added
carbamazepine despite himself (not popular in psychiatry ...) for relapse in manic episodes
requiring hospitalization. Treatment begins at 200 mg BID. The anxious psychiatrist prescribes
therapeutic monitoring of carbamazepine within a week. Result: 24 mmol/L (15-80 nmol/L).
Everyone is happy, the patient is discharged. Are you?
no steady state is only reached after 2-3 w
87
Mr. PR was taking Divalproex 1000 mg HS, which has been increased to 1250 mg
HS recently. He's been shaking for a few days. The serum dosage of Divalproex at steady state is
500 umol/L. What laboratory would it be appropriate to ask?
as for unbound
