Lecture 27 ADHD Medicinal chemistry

Why is it difficult to diagnose

there are no biological markers only standardised rating scales 

What are some neurotransmitter theories 

Functional differences in some neurotransmitter systems

e.g. dopamine and norepinephrine

some differences in volume in some brain regions and connectivity

Treatment guidelines

Adults:

1. Offer Methylphenidate or lisdexamfetamine (environmental modifications no effect + sig impairment

2. dexamphetamine if patient cannot tolerate longer profile

3. Atomoxetine if no response or cannot tolerate

Trial in 6 weeks and review efficacy 

Trial and error basis

What are stimulant medications

•Methylphenidate: dopamine and norepinephrine reuptake inhibitor

•Amphetamine: dopamine and norepinephrine reuptake inhibitor and releaser

What are some non-stimulant medication

•Atomoxetine – norepinephrine reuptake inhibitor (useful when stimulant medications are contraindicated) (NRI)

•Guanfacine and clonidine – norepinephrine receptor agonists (a₂-adrenoceptor agonists) (NRA)

What is the effect of cocaine and amphetamine on neurotransmitters

Increase dopamine release or inhibit re-uptake

Psychostimulants

Release more DA into synaptic cleft

What are some adverse effects

Decreased appetite, deficits in height/weight gain

Increased blood pressure or heart rate

Sleep disturbance

Tics

Seizures

Psychotic symptoms

Some patients may try to self medicate to reduce symptoms

Why are medications discontinued

• side effects not tolerated

• perceived lack of effectiveness

• dislike of taking medications

• stigma

What is lisdexamfetamine

An Amphetamine prodrug

Describe the immediate release profile of lisdexamfetamine

short Tmax

rapid symptom control

effects not long lasting

Describe the extended release profile

formulations of amphetamine and methylphenidate

•Methylphenidate (extended release): 12h

•Methylphenidate (delayed and extended release): 11h after 10-12h delay

Describe the structure of lisdexamfetamine

Amide bond

Which enzyme is used in hydrolysis

cytosolic amino peptidase

Describe hydrolysis pathway

Describe the stability of amide bonds

not very reactive as they are stable

Therefore require a lewis acid

What lewis acid is used

Zn2+ or H+

What mechanisms cross BBB

1. Passive, transcellular diffusion: more lipophilic drugs

2. Active transport: needs glucose or amino acid to cross

3. Receptor-mediated transport: needs a receptor to be released by endocytosis

Describe how lisdexamfetamine is absorbed 

• High aqueous solubility and low lipophilicity

• Rapid absorption through PEPT1 high affinity receptor in the small intestine

• Converted into dextoamphetamine and L-lysine

• Poorly diffused from GI tract 

What is the active form of lisdexamfentamine

D-Amphetamine

D-amphetamine vs LDX

D-amphetamine is the active form so it well and rapidly absorbed

resulting in a high mean plasma concentration from 2 hours

This increases with higher doses

VS

LDX poor absorbed

mean plasma concentration declines quite raiply

take 1 hour longer to reach peak levels

Long lasting Lisdexamfetamine

Typically only extended release has a prolonged effect but Lisdexamfetamine is the only exception

But this may be due to slow onset of the drug rather than extended half life

Chemical structures of CNS drugs

beware sometimes the lipinski rules don’t always apply

1 hydrogen bonds

lipophilic (positive log P)

Issues with tolerance

One explanation is that the slower onset and lower Cmax of LDX causes less acute tolerance than immediate release preparations, leading to an extended duration of action

so even though the given dose via immediate or oral release has the same AUC and t1/2

there may be underlying effects that induce tolerance quicker