Drug Treatment of ADHD. by Dr Christine Sutherland

Transcription

1 Drug Treatment of ADHD by Dr Christine Sutherland

2 Psychostimulant Actions Who put the Benzedrine, in Mrs. Murphy's Ovaltine? Where did she get that stuff Now she just can't get enough She stays up nights making all the rounds They say she lost about 69 pounds Now Mr. Murphy claims she's getting awful thin Who put the Benzedrine, in Mrs. Murphy's Ovaltine? Now she wants to swing the Highland Fling She says that Benzedrine's the thing that makes her spring. Harry Gibson, Who put the Benzedrine in Mrs. Murphy's Ovaltine? From album Boogie Woogie in Blue, 1944

3 Pharmacokinetics and Pharmacodynamics of ADHD drugs

4 Pharmacokinetics: What the body does to the drug Pharmacodynamics: What the drug does to the body

5 Medication Types Stimulants: Non stimulants: Amphetamines Methylphenidate Atomoxetine Bupropion Modafinil TCA Venlafaxine Clonidine/guafacine

6 Stimulants

7 Formulations available in the UK Stimulants : Dexamfetamine instant release Methylphenidate instant release Methylphenidate slow release: Extended release Osmotic release

8 Formulations available abroad Dexamfetamine slow release Mixed amfetamine salts instant and slow release Methamfetamine Methylphenidate patches.

9 Amphetamine : Dynamic Interactions Noradrenergic actions Dopaminergic actions Adrenaline blocking agents may diminish effect: propanolol Antipsychotics may diminish effect Caution in concomitant use with substances that increase dop/nor-a. At high doses amphetamine has a serotoninergic effect.

10 Amphetamines: Pharmacodynamics Competitive inhibitor of: Dopamine transporter Noradrenaline transporter Vesicular monoamine transporter (VMAT)

11 Amphetamine: pharmacokinetics Easily absorbed in small intestine Rapidly distributed to tissues Peak effect 2-3 h Metabolized in liver : CYP450 2D6* Renal excretion: 30% unchanged. Acidification of urine increases excretion Caution in kidney insufficiency

12 Amphetamine in the Liver Metabolized by CYP 2D6 pathway, significant enzyme inhibitors may increase plasma levels of Amphetamines : Fluoxetine Paroxetine Tricyclics Cocaine Significant inducers will decrease plasma concentrations: Carbamazepine

13 Clinical Key points: Pk/Pd of amphetamine 30% eliminated as active metabolite by kidney. Caution in kidney insufficiency*, acidificate urine in overdose. 2D6 inhibitors eg. Fluoxetine, Paroxetine, Tricyclics, Cocaine may increase levels of amphetamine in plasma. Caution in liver diseases Acts on dopamine and noradrenaline: Adrenaline blocking agents may diminish effect: propanolol Antipsychotics may diminish effect Caution in concomitant use with substances that increase dop/nor-a.

14 Methylphenidate Pharmacokinetics Easily absorbed, faster with food 30% bioavailable Metabolism by de sterification in gut No interactions with P450 enzymes Carbamazepine reduces levels of Methylphenidate* Methylphenidate increases levels of warfarin and tricyclics* Renal excretion as an inactive metabolite (PPA) No major problems in renal insuficiency

15 Pharmacodynamics of Methylphenidate Blocks reuptake of Dopamine and Noradrenaline D D D D D D/Na transporter D ME D D ME D D D

16 Clinical Key points: Pk/Pd of Methylphenidate Fairly clean drug. Carbamazepine diminishes levels of Methylphenidate Methylphenidate may increase levels of tricyclics and warfarin Blocks reuptake of dopamine and noradrenaline: Caution with dopaminergic drugs. Caution with central alpha adrenergic agonists

17 Non Stimulants

18 Non stimulant treatments Meszaros et al, 2009

19 Atomoxetine Key Facts It is a non-stimulant...but can still cause BP Can take up to 3 months to have full effect (more similar to antidepressant than stimulant) Exerts effect over full 24 hours Useful if patient has a Hx of substance misuse Tends to cause unpleasant but not life threatening side effects

20 Atomoxetine - Indications Atomoxetine is a 2 nd line treatment for Adult ADHD after Methylphenidate Consider Atomoxetine when: A stimulant is not tolerated or produces side effects (tics, anxiety) There are concerns about stimulant misuse Patient has been successfully treated with Atomoxetine in the past ( graduates )

21 Atomoxetine Side effects Some of the more common side effects (which cause people to stop taking it) include: Anorexia Nausea and vomiting (and general GI disturbance) Dry mouth Dizziness and palpitations Hot flushes and sweating It can cause both postural hypotension and hypertension monitor BP 3/12

22 Atomoxetine Side effects (CSM) Importantly, it has been associated with agitation, irritability, suicidal thinking and self harm in children, young people and adults Make patients aware of these potential problems Follow-up closely over the first few months of treatment and after a dose change Liver damage is a rare (idiosyncratic) side effect Warn patients about it and typical symptoms (abdo pain, nausea, malaise, dark urine, jaundice)

23 Atomoxetine - Contraindications angle- The only contraindication is closure glaucoma Caution advised in: Cardiovascular disease (including hypertension, tachycardia and postural hypotension) Hepatic impairment Pregnancy Breast feeding

24 Pharmacokinetics of atomoxetine Easily absorbed Metabolism in liver: P450 Cyp 2D6 7%* are poor metabolizers (PM). In PMs half life increases from 4h to 22h. PMs may have more side effects, but have also greater improvement in ADHD symptoms. Caution in liver problems

25 Pharmacodynamics of atomoxetine Selective noradrenaline reuptake inhibitor, initiation of effect may take weeks N N Nor-a transporter N N ATO N N N N N N ATO

26 Interactions atomoxetine Caution with nor adrenergic drugs Caution with beta blockers Caution with CYP2D6 inhibitors, as they will increase plasma levels of atomoxetine No interactions with warfarin No interactions with Methylphenidate

27 Clinical key points : Pk/Pd of Atomoxetine Caution in liver impairment Caution with CYP2D6 inhibitors, as they will increase plasma levels of atomoxetine Poor metabolizers will have more side effects Side effects may not be severe but lead to abandon treatment Slow initiation of action Less effective than stimulants

28 Other non stimulant drugs Bupropion: Dopamine and noradrenaline reuptake inhibitor Decreases seizure threshold and reduces efficacy of antiepileptics. Mania. Modafinil: Release of histamine and orexin, weak DAT blocker. Rash, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, cardiovascular effects:transient ECG changes, hyperthophy.hypomania, suicidality. Clonidine and Guanfazine: Non selective alpha2 adrenergic agonists.

29 Stimulants and risk of abuse

30 Abuse and addiction? Much loved by the media Dealing reported in college, o.d./ addiction to stimulants rarely reported. Stimulant treatment of children does not increase adult drug dependence No evidence of priming to other drug use in adults with possible exception of increased smoking

31 Abuse and addiction? Most ADHD drug treatments are not easily abusable or much liked. Slow release formulations are especially hard to abuse as extracting drug very difficult if not impossible

32 Does stimulant therapy of ADHD lead to later substance use disorders? Author ADHD (N) ADHD (N) Controls (N) Age F/U Time F/U Drug abuse Alcohol Abuse Treatment + Treatment - OR 95% CI OR 95% CI Lambert > 18 > Biederman Huss Loney Molma Barkley (2003) Pooled estimate: OR = 1.9, 95% CI , p=.03 Suggests around 2-fold decrease in risk of SUD Age effect: OR = 5.8 for adolescent F/U; OR = 1.4 in adult F/U (Wilens et al., 2005)

33 Reasons why treatment may reduce substance use better personal achievements and social integration and reduced pleasure from drug use c.f. bupropion for smoking cessation

34 Pharmacokinetics of Amphetamine

35 Methylphenidate: potential abuse Route: Volkow and Swanson, 2003

36 Methylphenidate much slower Concentration in Blood and Brain brain entry Blood Brain um Weikop, Time (min)

37 Methylphenidate: potential abuse Frequency of administration: Same dose, regular intervals Tonic dopamine release Irregular dose, increasingly frequent intervals Phasic dopamine release

38 Methylphenidate: potential abuse N.B. There is marked individual difference : Not weight/ mass dependent Small subjects may need large doses and vice versa. Not absortion dependent Subjects that require high doses have high concentrations in blood, and subjects who require low doses have low doses in blood Dopamine cell activity Lazy dopamine cells vs. hyperactive dopamine cells Sensitivity of dopamine receptors Subjects with low numbers of D2 receptors liked Methylphenidate Subjects with high numbers of D2 receptors disliked Methylphenidate