What are the basic steps of cholinergic synaptic transmission?

Synthesis of ACh → Storage/Release of ACh → Receptor binding (Muscarinic & Nicotinic) → Degradation of ACh.

What physiological functions do cholinergic synapses control?

They mediate EPSPs or IPSPs and are involved in autonomic and somatic motor functions.

What happens if ACh synthesis or AChE is inhibited?

Inhibition of ACh synthesis reduces ACh levels; inhibition of AChE increases ACh activity at synapses.

Difference between nicotinic and muscarinic receptor agonists?

Nicotinic agonists: stimulate skeletal muscle and autonomic ganglia

Muscarinic agonists: affect parasympathetic organs.

Depolarizing vs non-depolarizing blockade?

Depolarizing (e.g., succinylcholine): Persistent activation of receptor → paralysis.

Non-depolarizing (e.g., pancuronium): Competitive antagonist that blocks the receptor without activating it.

What are parasympathomimetic drugs?

Drugs that mimic parasympathetic activity by stimulating muscarinic receptors or inhibiting acetylcholinesterase (AChE).

What are the subtypes of muscarinic receptors and their general functions?

• M1 – Increases brain activity and stomach acid.
• M2 – Slows heart rate.
• M3 – Contracts smooth muscle, increases gland secretions, constricts pupils, dilates blood vessels (via NO).
• M4 – Regulates nerve signals in the brain.
• M5 – Helps release dopamine, may widen brain blood vessels.

"Mind’s Memory Makes Muscles Move More."

• M1 – Mind’s → Brain & stomach acid
• M2 – Memory → Slows the heart (remembering to rest)
• M3 – Makes → Smooth muscles contract, glands secrete
• M4 – Muscles → Brain motor control
• M5 – Move More → Dopamine release & brain blood flow

Basic steps in adrenergic synaptic transmission?

Synthesis of Norepinephrine/ Epinephrine→ Storage/Release → Receptor binding (α and β) → Reuptake/metabolism (e.g., MAO, COMT).

What is a sympathomimetic vs sympatholytic drug?

Sympathomimetic: Mimics sympathetic nervous system activity.

Sympatholytic: Blocks or reduces sympathetic nervous system activity.

What are the types and mechanisms of adrenergic receptors?

Alpha-1: Vasoconstriction (↑ BP), mydriasis (Dilated pupils) and bladder sphincter contraction via Gq

Alpha-2: Inhibits Norepinephrine (NE) release (negative feedback), insulin secretion, and lipolysis via Gi

Beta-1: Increases heart rate, contractility and Renin release via Gs

Beta-2: Bronchodilation, vasodilation and smooth muscle (uterine) relaxation via Gs

How are adrenergic receptors regulated?

Through desensitization and downregulation via GRKs and β-arrestins (homologous and heterologous regulation).

Examples of indirect-acting sympathomimetic drugs?

Amphetamines and ephedrines — they increase NE release or block its reuptake.

What is the effect of inhibiting norepinephrine reuptake (NET inhibition)?

Mechanism: Inhibits reuptake of NE from the synaptic cleft → prolonged stimulation

Example: Cocaine.

Organ Effects:

• Heart – ↑ heart rate and contractility
• Blood vessels – vasoconstriction → ↑ blood pressure
• CNS – stimulation (euphoria, alertness)

What is the effect of inhibiting catecholamine metabolism (MAO inhibitors)?

Mechanism: Blocks breakdown of NE, E, and dopamine by MAO → ↑ catecholamines.

Organ Effects:

• Heart – ↑ HR and BP
• CNS – excitation, mood elevation
• Risk of hypertensive crisis with tyramine (e.g., aged cheese)

What are sympathomimetic drugs and their general effects?

Mechanism: Mimic sympathetic nervous system activity by stimulating α or β adrenergic receptors.

Organ Effects:

• Heart – ↑ HR, ↑ contractility (β1)
• Lungs – bronchodilation (β2)
• Blood vessels – vasoconstriction (α1)
• Eyes – mydriasis/dilation (α1)
• GI/GU – ↓ motility, urinary retention (α1, β2)

Compare specific, mixed-action, and indirect-acting sympathomimetics.

Specific: Direct receptor binding (e.g., phenylephrine → α1)

Mixed: Receptor stimulation + ↑ NE release (e.g., ephedrine)

Indirect: Only ↑ NE release or inhibit reuptake (e.g., amphetamine, tyramine)

Organ Effects: Similar to general adrenergic stimulation depending on receptor target

What are the 3 main types of sympathomimetic drugs based on mechanism?

1. Direct-Acting: Bind directly to adrenergic receptors (e.g., phenylephrine, albuterol).

2. Indirect-Acting: Increase NE availability by enhancing release or inhibiting reuptake (e.g., amphetamines, cocaine).

3. Mixed-Acting: Both bind receptors and increase NE release (e.g., ephedrine).

What is a Direct-Acting Sympathomimetic drug?

Mechanism: Directly activates α or β adrenergic receptors.

Examples:

• Phenylephrine (α1 agonist)
• Albuterol (β2 agonist) Effect: Mimics NE/E on target organs.

What is an Indirect-Acting Sympathomimetic drug?

Mechanism: Increases levels of NE/E by:

• Stimulating NE release
• Inhibiting NE reuptake
• Inhibiting NE metabolism

Examples:

• Amphetamine – increases NE release
• Cocaine – blocks NE reuptake
• Tyramine – displaces NE from vesicles

Key Sign: No receptor binding; effect depends on endogenous NE.

What is a Mixed-Acting Sympathomimetic drug?

Mechanism: Directly stimulates receptors and increases NE release.

Example:

Ephedrine Effects:

• α and β receptor stimulation
• Enhanced NE release from nerve terminals
• Used for: Nasal decongestion, hypotension.

How can you identify a drug’s class based on its mechanism?

Direct-Acting: Known receptor affinity; effect persists without NE stores.

Indirect-Acting: Ineffective if NE stores are depleted (e.g., after reserpine).

Mixed-Acting: Retains partial effect even if NE is depleted.

What class is amphetamine and how does it work?

Class: Indirect-acting sympathomimetic

Mechanism: Increases NE release from nerve terminals.

Effect: ↑ HR, BP, CNS stimulation

What class is ephedrine and how does it work?

Class: Mixed-acting sympathomimetic

Mechanism: Direct α/β receptor stimulation + increases NE release.

Effect: ↑ BP, bronchodilation, decongestion

How would you classify a drug that increases NE release but has no direct receptor activity?

Indirect-acting sympathomimetic (e.g., amphetamine, tyramine)

How would you classify a drug that stimulates β2 receptors and causes bronchodilation?

Direct-acting sympathomimetic (e.g., albuterol)

How would you classify a drug that causes vasoconstriction and also increases NE release?

Mixed-acting sympathomimetic (e.g., ephedrine)

Alpha receptor agonists – MOA and organ effects

α1 agonists (e.g., phenylephrine):

Vasoconstriction → ↑ BP, Mydriasis (pupil dilation), and Urinary retention (bladder sphincter contraction)

α2 agonists (e.g., clonidine):

↓ NE release → ↓ BP and HR (centrally acting)

Beta receptor agonists – MOA and organ effects

β1 agonists (e.g., dobutamine):

↑ Heart rate and contractility → used in heart failure

β2 agonists (e.g., albuterol):

Bronchodilation → used in asthma, Uterine relaxation → prevents premature labor, and Vasodilation → mild ↓ BP

Alpha receptor antagonists – MOA and organ effects

Mechanism: Block α receptors → vasodilation

Examples: Prazosin (α1), Phentolamine (non-selective)

Organ Effects:

• Blood vessels – ↓ peripheral resistance → ↓ BP
• Bladder/prostate – relax sphincter/smooth muscle → used for BPH

Beta receptor antagonists (Beta blockers) – MOA and organ effects

Mechanism: Block β1 and/or β2 receptors

Examples: Propranolol (non-selective), Atenolol (β1-selective), Labetalol (mixed α/β)

Organ Effects:

• Heart – ↓ HR, ↓ contractility → ↓ BP
• Kidney – ↓ renin release
• Lungs – may cause bronchoconstriction (β2 blockade in non-selective agents)

Receptor desensitization and downregulation – what is it and what organs are affected?

Mechanism:

• Prolonged exposure to agonists leads to decreased receptor responsiveness (desensitization)
• ↓ Receptor number over time (downregulation)• Mediated by GRKs and β-arrestins

Organ Impact: All adrenergic target tissues (heart, vessels, lungs) may show reduced response to chronic drug use