Pharmacology Flashcards
1
Q
Youngest age to prescribe for ADHD without specialist consultation.
A
6 years
2
Q
Maximum age to treat ADHD
A
None.
3
Q
Effects of ADHD medication on pregnant / breastfeeding women.
A
Unknown. (CADDRA). Therefore proceed on case-by-case basis.
4
Q
Rate of emergence of psychosis/mania symptoms in children taking ADHD medication.
A
11 per 743 person-years (Mosholder et al 2009). Zero patients on placebo developed psychosis/mania. 2/3 of cases develop in days to weeks but in the remaining 1/3, developed after months or even years.
5
Q
Stimulant factors possibly associated with decreased anxiety in ADHD children.
A
MPH (RR=0.85 vs. RR=1.02 for AMP), short-acting (RR=0.83 vs. 0.99 for long-acting). Higher doses correlated with lower anxiety. (Coughlin et al 2015).
6
Q
Do psychostimulants increase anxiety in children?
A
Can be a side effect, but in patients on stimulants overall anxiety is significantly lower than patients on placebo (RR=0.86). (Coughlin et al 2015).
7
Q
Common themes in children who develop hallucinations on ADHD medications.
A
Visual and/or tactile - insects, snakes, worms. (Mosholder et al 2009)
8
Q
Percentage of children on ADHD medications who develop psychosis/mania who have no risk factors.
A
About 90% (Mosholder et al 2009)
9
Q
Why are long-acting stimulants preferred?
A
Less potential for abuse, misuse, and diversion; improve adherence; maintain privacy at school.
10
Q
Can stimulants be combined with atomoxetine or guanfacine?
A
Yes, off-label; no official indication or long-term studies on safety.
11
Q
Concerta %immediate/delayed release, duration
A
22/78, 10-12 hr
12
Q
Biphentin %immediate/delayed release, duration
A
40/60, 10-12 hr
13
Q
Vyvanse %immediate/delayed release, duration of action
A
prodrug; 13-14 hr
14
Q
Adderall XR %immediate/delayed release, duration
A
50/50, 12 hr
15
Q
Cost of Concerta in Canada - 30 day supply
A
$30-60 per CPS
16
Q
Cost of Biphentin in Canada - 30 day supply
A
$60-90 per CPS
17
Q
Cost of Vyvanse in Canada - 30 day supply
A
$120-150 per CPS
18
Q
Dexedrine %immediate/delayed release, duration
A
100/0, 4 hr
19
Q
Dexedrine spansules %immediate/delayed release, duration
A
50/50, 6-8 hr
20
Q
Adderall XR %immediate/delayed release, duration
A
50/50, 12 hr
21
Q
Methylphenidate IR %immediate/delayed release, duration
A
100/0, 3-4 hr
22
Q
Precautions with dexedrine IR and methylphenidate IR
A
Pill can be crushed easily - higher abuse potential.
23
Q
Alternate way of taking Vyvanse
A
Can be diluted in water, OJ, or yogurt
24
Q
Alternate way of taking Adderall XR
A
Sprinkable granules
25
Alternative way of taking Biphentin
Sprinkable granules
26
ADHD Pharmacologic treatment steps
Start with a long-acting stimulant; if failure / tolerance issue try another one. May augment with a non-stimulant or a short-acting stimulant. Then consider a switch to a non-stimulant.
27
Atomoxetine dosing (children)
0.5 mg / kg x 7-14 d, then 0.8 mg / kg x 7-14 d, then 1.2; max dose 1.4 mg/kg or 100 mg.
28
Atomoxetine dosing (adults)
40 mg x 7-14 days, then 60 mg, then 80 mg; max dose 100 mg.
29
ADHD medication that may be helpful if there is enuresis.
Atomoxetine
30
Advantages of atomoxetine
- Continuous coverage.
- Approved across the lifespan.
- Tics, anxiety
- Side effects of stimulants.
31
Efficacy of atomoxetine for comorbid anxiety in ADHD
Youth 8-17 years, ADHD with GAD/SAD/SP (n=176)
ES=0.8 for ADHD symptoms, 0.4 for anxiety (Geller et al., 2007)
Adults with ADHD+SP (n= 442)
ES=0.5 for ADHD symptoms, 0.3-0.4 for anxiety (Adler et al., 2009)
32
How high is too high for resting heart rate with psychostimulants?
The risk of mortality increases linearly with increasing heart rate compared to 45 BMP, but there was significantly increased risk of cardiovascular mortality observed at 90 beats/min in a meta-analysis of the general population. (Zhang, CMAJ 2015)
33
Which ADHD medication may be safe to use in schizophrenia?
Vyvanse was studied in an open-label trial in 2012, showing significant reductions in negative symptoms of schizophrenia and no evidence of overall positive symptom worsening. It may be safe to try psychostimulants for patients who are stable on antipsychotics and have minimal positive symptoms, but more research is needed.
34
Safety of amphetamine-based stimulants in pregnancy
No increased risk of malformations in a prospective study.
Another cohort study showed no increased risk.
Abuse of amphetamines in pregnancy has been associated with low birth weight, prematurity, and increased maternal and fetal morbidity, however (confounding factors are present, however).
(Humphreys et al Can Fam Physician. 2007 Jul; 53(7): 1153–1155.)
Amphetamine use in controlled doses during pregnancy is unlikely to pose a substantial teratogenic risk.
If medication [dextroamphetamine] was continued beyond the 28th week of pregnancy, there was a 100g to 400g reduction in weight of the infants, with no change in birth length or head circumference (Naeye 1983; Golub 2005).
35
Safety of methylphenidate in pregnancy
There are very few data on the teratogenicity of MPH in humans.
(Humphreys et al Can Fam Physician. 2007 Jul; 53(7): 1153–1155.) The literature includes 69 cases studies, with one cardiac defect reported. However, none of the studies were statistically powered to allow for definitive conclusions regarding the reproductive safety of Methylphenidate exposure.
36
Safety of atomoxetine in pregnancy.
There are no human studies to establish the safety of atomoxetine in pregnancy. Animal studies did find birth defects including decreased viability, blood vessel abnormalities, delayed ossification. Doses were higher than usual human exposure. Clinical significance for humans is unknown. (Humphreys et al Can Fam Physician. 2007 Jul; 53(7): 1153–1155.)
37
Effects of renal impairment on Vyvanse
With renal failure the drug clearance decreases. If GFR 15-30 mL/min/1.73 m2, then max dose 50 mg daily. For GFR \<15 mL/min/1.73 m2, then max dose = 30 mg daily. (Monograph).
38
Effects of renal impairment on methylphenidate.
No experience; theoretically no effect because MPH is extensively hepatically metabolized and the metabolite is not active, therefore renal impairment is not expected to affect clearance.
39
Mechanism of action of methylphenidate.
Inhibits reuptake of norepinephrine and dopamine.
40
Mechanism of action of amphetamine.
Increases release of norepinephrine and dopamine.
41
Growth suppression with stimulants.
2 cm over 3 years in children.
42
In students who misuse ADHD medication, which is the drug of choice?
The most commonly reported stimulant medication used was Adderall (77%) (2011 McNeil et al survey)
43
What percentage of college students prescribed ADHD medication, abuse their medications?
According to a survey of 334 ADHD-diagnosed college students taking prescription stimulants, 25% misused their own prescription medications to get “high” (Upadhyaya et al. 2005)
44
Rates of substance abuse in people receiving stimulant medication for ADHD?
People of any age receiving a stimulant for ADHD have no greater risk for illicit substance abuse compared with the general population (Wilens 2003).
45
Long-term cardiac risk of psychostimulants
The MTA study found that stimulant medication does not appear to increase the risk for abnormal elevations in blood pressure or heart rate over a 10-year period. There are no other long-term data available. Habel et al found no evidence of a link between ADHD medication and cardiovascular risk (myocardial infarction, sudden death, or stroke) - this was a large case-control study of 450,000 patients.
46
Safety of methylphenidate during breastfeeding.
Caution recommended. Infants receive 0.2% of the weight-adjusted maternal daily dose through breastmilk but limited data are available regarding adverse effects. (Fortinguerra, Clavenna, and Bonati, Pediatrics, 2009)
47
Safety of amphetamine during breastfeeding.
The infant dosage of amphetamine through breastmilk is about 2% of the maternal dosage. There are limited case studies to show that low amounts of amphetamine are secreted in breast milk but the effect on infant development is not well-studied. (Drugs.com, accessed 2016) There are reports of infant restlessness and poor sleeping behavior after breastfeeding from amphetamine-exposed mothers. The authors suggest that breastfeeding should be withheld 48 h after a dose of amphetamines. (Oei et al Journal of Perinatology 2012).
To minimise infant exposure to cocaine via breast milk, feeding should occur just prior to or as long as possible after the dose. (Australian Government, Models of intervention and care for psychostimulant users, 2nd edition - monograph series no. 51)
48
Safety of bupropion in pregnancy
Prospective study suggested that bupropion does not increase the rates of major malformation above baseline. The higher rates of spontaneous abortions are similar to other studies examining the safety of antidepressants during pregnancy. (Chun-Fai-Chan et al,Am J Obstet Gynecol, 2005)
49
Cytochrome P450 interactions of atomoxetine
Atomoxetine is a 2D6 substrate.
Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes.
(Clin Pharmacokinet. 2005;44(6):571-90.)
50
Pharmacogenetics of atomoxetine
In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours.
In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.
Clin Pharmacokinet. 2005;44(6):571-90.
51
Cytochrome P450 interactions of methylphenidate
One study suggests a lack of involvement of CYP2D6 in the metabolism of MPH. Drugs that are inhibitors of CYP2D6 when taken concurrently with MPH should not affect its plasma concentration.
(J Clin Psychopharmacol. 2000 Jun;20(3):347-9.)
May increase levels of fluoxetine and venlafaxine. "It also appears that methylphenidate is a substrate for 2D6 as well as a weak inhibitor of 2D6." However, reference for these claims are questionable.
(German J Psychiatry 2013; 16(1): 29-42
52
Cytochrome P450 interactions of amphetamine
Amphetamine is metabolized by 3A4 and 2D6. (Pharmacogenetics in Psychiatry)
Potential interaction with grapefruit juice.
Also 2D6 inhibitors - fluoxetine and paroxetine.
53
Long-term effects of psychostimulants
Two studies in 2012 suggest that chronic MPH or AMP started in peri-adolescence/adolescence at clinically relevant doses do not significantly alter DA system development nor do they affect physical growth in non-human primates. (Neuropsychopharmacology (2012) 37, 2551–2552)
There have been some longer-term foll
ow-up studies on clinical samples and there are data from adverse effects reporting. No major concerns identified. Questions about vulnerability to psychopathology, addictions, social adjustment, educational achievement are still not answered. Methodological issues include lack of randomization over time and selection effects that cannot be identified or controlled. (Benedetto Vitiello. Journal of Child and Adolescent Psychopharmacology. July 2004, 11(1): 25-34.)
54
How does guanfacine work in ADHD?
Activates post-synaptic Alpha 2 receptor -\> inhibits local cAMP -\> closing ion channels -\> strengthen glutamatergic synaptic inputs -\> increases PFC network firing. (Wang 2007)
55
What percentage of patients in the MTA study stopped medication between 14 months and 8 years?
61.5% stopped medication sometime after the 14-month trial and the 8-year follow-up. (Molina et al 2011)
56
Long-term outcomes in the MTA study
At 8-year follow-up, it appears that when treatment intensity is relaxed, the differential effects of the interventions attenuate. Thus there is a "sustained absence of long-term effects of an initial period of randomly assigned treatment". Children improve over their baseline but the type of teratment does not predict outcomes in late adolescence. Children still taking medication at 8 years fared no better than their non-medicated counterparts. (Brooke et al 2011)
57
Risk of treatment-emergent mania with methylphenidate in bipolar disorder.
Increased rate of manic episodes with methylphenidate monotherapy (hazard ratio 6.7); with mood stabilizer, hazard ratio = 0.7.
58
Mechanism of action of methylphenidate
Inhibits reuptake of norepinephrine (NET) and dopamine (DAT), increasing availability of NE and DA at the synapse.
59
Aspect of mechanism that amphetamine has that MPH does not.
Both prevent reuptake of NE and DA, and increase NE release. Methylphenidate releases dopamine via reserpine-sensitive granular vesicles; amphetamine causes release through reserpine-insensitive cytoplasmic pool (reverse transport through the transporters).
60
Can Ritalin SR tablets be cut in half?
There is a statistically significant faster dissolution of halved Ritalin SR tablets compared to whole tabs (74% vs 57%) at 2 hours. At 7 hours, there was no difference in cumulative dissolution. Therefore, medication may be released more quickly but the absolute difference is not great so it may be an acceptable means of achieving a small increment / decrement in dose without changing to IR (Erramouspe and Jarvi 1997).
61
Difference between l- and d-amphetamine
D-amphetamine is 4 times more potent.
62
Effect of food on methylphenidate absorption
Increases absorption (area under the curve, and max concentration) of MPH.
63
Effect of food on Concerta
Tmax is delayed by 1 hour and Cmax is increased by 10-30% after high-fat meal. (Clinically Significant Interactions with Stimulants and Other Non-stimulants for ADHD, Kattura and Crismon 2016)
64
Effect of food on amphetamine
Increased renal excretion with acidic foods, decreased renal excretion with urinary alkalizers.
65
Effect of food on Adderal
Decreased area under the curve over the first 8 hours post exposure to high-fat meal (Clinically Significant Interactions with Stimulants and Other Non-stimulants for ADHD 2016; 2002 CAFE study)
66
Possible effects of buspirone on methylphenidate and amphetamine.
Pre-synaptic D2 receptor antagonism from buspirone; tolerance to stimulants may result from stimulating presynpatic D2 autoreceptors and decreasing dopamine synthesis and packaging in vesicles (Ford 2014). Buspirone might counteract this. Open study indicated beneficial effects of buspirone on hyperactivity and attention (Niederhofer 2003).
