Andrade: Stimulants and Migraine Drugs

Question 1

Amphetamines

MOA:

Answer 1

MOA: cause the release of monoamines (NE, DA etc.) though a non-exocytotic mechanism

• Displaces NE/DA from vesicles and causes it to be released in large quantities from the neuron
• Act at plasmalemal transporter and vesicular monoamine transporter

Question 2

Amphetamines

Use in ADHD (Main Clinical Use of Stimulants):

Answer 2

Treat Core Symptoms: impulsivity, inattention and motor restlessness

Question 3

Amphetamines

Effective:

Answer 3

Effective: medication alone (slightly better) or in combination with behavioral treatment most effective form of treatment for ADHD

Question 4

Amphetamines

Effectiveness Important Point:

Answer 4

Important Point: although shown to be less effective, community care and behavioral treatment alone also result in noticeable improvements in ADHD symptoms (and effects may also be longer lived after the end of treatment)

Question 5

Amphetamines

How does it help with ADHD?

Answer 5

Reduces activity, inattention and impulsivity (in both normal adults/children and children with ADHD)

Increases NE and DA

Question 6

Amphetamines

Imaging Studies of Children with ADHD:

Answer 6

Show changes in the DA transporter levels in kids with ADHD

Some studies have suggested that DA transporter levels have normalized after treatment with methylphenidate (continues to be a contentious issue)

Question 7

Drugs Used for ADHD: (5)

Answer 7

Drugs Used for ADHD: note that ER/controlled release formulations now dominate (more convenient, provide stable effect of stimulant throughout the day)

• Amphetamine (Adderall)
• Methylphenidate (Ritalin)
• Dextroamphetamine (Dexedrine)
• Dexmethylphenidate (Focalin)
• Pemoline (Cyclert)- should not be a first line drug because of side effects of liver damage*

Question 8

Amphetamines
Side Effects
Mostly dose dependent: (4)

Answer 8

Decreased appetite
Insomnia
Increased anxiety/irritability
Mild stomach aches and headaches

Question 9

Amphetamines
Side Effects
Concerns in children: (2)

Answer 9

Potential toxicity

Growth suppression

Question 10

Other ADHD Medications (Non-Stimulant): (2)

Answer 10

Atomoxetine: NE reuptake inhibitor

Guanafacine/Clonidine: ER alpha2 adrenergic agonists

Question 11

Other Uses of Stimulants: (2)

Answer 11

Treatment of Excessive Daytime Sleepiness

Historical use as appetite suppressants

Question 12

Treatment of Excessive Daytime Sleepiness

Conditions:

Answer 12

Conditions: narcolepsy, idiopathic hypersomnia, obstructive sleep apnea, shift work sleep disorder etc.

Question 13

Treatment of Excessive Daytime Sleepiness

Agents Used:(2)

Answer 13

Agents Used:
Modafinil: mechanism unknown (possible DA uptake inhibitor)

Sodium oxybate (Xyrem): especially for treatment of narcolepsy
-	Sodium salt of GHB (date rape drug)

Question 14

Migraines

Headaches that are: (5)

Answer 14

o Unilateral
o Pulsatile or throbbing
o Associated with N/V (severe cases)
o Of sufficient intensity to interrupt daily activities
o Usually lasting 4-72 hours if left untreated

Question 15

Migraines

Prodrome/Aura:
Epidemiology:
Triggers:

Answer 15

Prodrome/Aura: distinguishes it from other types of headaches (occurs in most cases)

Epidemiology: 18% of women and 6% of men affected

Triggers: often dietary (~20% of cases)

Question 16

Migraines

Vascular Theory:

Answer 16

Vascular Theory: used to dominate

• Stated that it was purely a vascular disorder
• Vasodilation of blood vessels in the brain leading to pain

Question 17

Migraines

Neurogenic Inflammation:

Answer 17

Neurogenic Inflammation: now seems to provide a better explanation

• Some stimulus (probably spread of cortical depression) results in aura (when it crosses the visual cortex)
• As cortical depression spreads, mediators get released that cause vasodilation of vessels (ie. NO, K+, AA, H+), resulting in activating of the trigeminal nerves and the sensation of pain

Question 18

Migraines

Treatment of Non-Severe:

Answer 18

Non-Severe: no vomiting, use NSAIDs

Question 19

Migraines

Treatment of severe: (2)

Answer 19

Triptans

Dihydroergotamine

Question 20

Triptans

MOA:

Answer 20

MOA: 5HT 1B/1D receptor agonists

- Inhibit release of NTs that lead to vasodilation and extravasation

Question 21

Triptans

Drugs in this Class: (2)

Answer 21

Sumatriptan (Imitrex)

Frovatriptan (longer acting)

Question 22

Triptans

Efficacy:
Best when used in combination with:
Can also be combined with :
Early intervention:

Answer 22

Efficacy: very effective (mainstay of treatment for severe migraines)

Best when used in combination with an NSAID

Can also be combined with antiemetics (for N/V)

Early intervention is very important (ie. want to prevent release of mediators as early as possible to limit inflammatory process that causes pain)

Question 23

Triptans

Contraindications:
Other Issues:

Answer 23

Contraindications: people with coronary disease

Other Issues: high cost

Question 24

Dihydroergotamine:

Answer 24

Older drugs with more side effects and less efficacy than triptans

Question 25

Preventative Therapy

Beta Blockers:

Answer 25

Propanolol
Timolol
Metoprolol

Question 26

Preventative Therapy

Antiepiletic Drugs: (2)

Answer 26

Valproate

Topiramate

Question 27

Preventative Therapy

TCAs:

Answer 27

Amitriptiline

Question 28

Preventative Therapy

Non-Drug Therapy:

Answer 28

Behavioral therapies (relaxation training, EMG biofeedback, cognitive therapy)

Question 29

Pharmacotherapeutic Future
CGRP Receptor Antagonists:
CGRP:

Answer 29

CGRP Receptor Antagonists: currently in phase III clinical testing

CGRP: released by cells that innervate the cranial vasculature (very important part of vasodilation and extravasation)