U01.05.018 Autonomic drugs

Understanding the modulation of neurotransmitter release and the mechanisms of autonomic drugs is essential for USMLE Step 1. Below is an organized summary focusing on norepinephrine (NE) release and amphetamines, along with cholinergic and adrenergic neurotransmission.

1. Modulation of Norepinephrine Release

Presynaptic α2-Autoreceptors
- Function: Norepinephrine (NE) acts on presynaptic α2-autoreceptors as part of a negative feedback mechanism, which reduces further release of NE from the sympathetic nerve endings.

2. Amphetamine Mechanism of Action

Mechanism:
- Entry into Presynaptic Terminal: Amphetamines use the norepinephrine transporter (NET) to enter the presynaptic terminal.
- Displacement of NE: Once inside, amphetamines utilize the vesicular monoamine transporter (VMAT) to enter neurosecretory vesicles, displacing NE.
- Action of NET Reversal: As the concentration of NE increases within the presynaptic terminal, NET’s action is reversed, and NE is expelled into the synaptic cleft, increasing the synaptic concentration of NE and producing the characteristic effects of amphetamines.

3. Key Cholinergic and Adrenergic Pathways

Neurotransmitter	Process	Receptors	Drugs
Acetylcholine (ACh)	Synthesis: Choline + Acetyl-CoA	Nicotinic, Muscarinic	AChE Inhibitors (e.g., Donepezil)
Norepinephrine (NE)	Synthesis: Tyrosine → DOPA → Dopamine → NE	α1, α2, β1, β2, β3	Cocaine, TCAs, Amphetamines

4. Cholinergic and Adrenergic Transporters

Cholinergic Pathway:
- Choline Transporter (CHT): Transports Choline into the presynaptic neuron for Acetylcholine synthesis.
- Acetylcholinesterase (AChE): Breaks down Acetylcholine into Choline and acetate at the synaptic cleft.
Adrenergic Pathway:
- Norepinephrine Transporter (NET): Responsible for reuptake of NE from the synaptic cleft back into the presynaptic neuron.
- Vesicular Monoamine Transporter (VMAT): Transports NE into storage vesicles.

5. Points to Remember

Negative Feedback in NE Release: NE exerts autoreceptors-mediated negative feedback on its release at presynaptic terminals via α2 receptors.
Amphetamines increase NE levels in the synaptic cleft by reversing the NET transport mechanism.
Drugs like Cocaine and TCAs inhibit NET function, resulting in increased NE availability in the synaptic cleft.
Cholinergic Drugs often target AChE inhibitors to enhance ACh activity at synaptic clefts.
Adrenergic Drugs can influence NE reuptake via NET inhibitors and VMAT modulators.

Learning Objectives

Understand the role of presynaptic α2-autoreceptors in regulating NE release.
Identify how amphetamines increase synaptic NE levels and their mechanism of action.
Be able to distinguish between cholinergic and adrenergic pathways, their transporters, and the effect of drugs like cocaine, TCAs, and amphetamines.

USMLE Step 1 Review Series

Curriculum