Epinephrine Synthesis, Adrenergic Receptors & Pharmacology

Epinephrine and Norepinephrine Synthesis

The synthesis pathway for catecholamines like norepinephrine and epinephrine is as follows:

1. Phenylalanine is converted to Tyrosine.
2. Tyrosine is taken into the neuron via a transporter.
3. Tyrosine is converted to L-DOPA by the enzyme Tyrosine Hydroxylase. (This is the rate-limiting step in the pathway).
4. L-DOPA is converted to Dopamine by the enzyme Dopa Decarboxylase.
5. Dopamine is transported into a vesicle via the Vesicular Monoamine Transporter (VMAT).
6. Inside the vesicle, Dopamine is converted to Norepinephrine by the enzyme Dopamine Beta-Hydroxylase.
7. Synthesis may stop at Norepinephrine, depending on the cell type.
8. In the adrenal medulla, Norepinephrine can be further converted to Epinephrine by the enzyme Phenylethanolamine N-Methyltransferase (PNMT).

Effects of Catecholamines on Blood Pressure

Catecholamines generally increase blood pressure (BP). The specific effects depend on the relative stimulation of alpha and beta receptors:

• Stimulation leading to increased Cardiac Output (CO) and BP (e.g., Beta-1 effects).
• Stimulation leading to increased Peripheral Resistance (PR) and BP (e.g., Alpha-1 effects).

Adrenergic Receptors and Effects

Alpha Receptors

Alpha-1 Receptors

• Effects: Vasoconstriction, increased Peripheral Vascular Resistance (PVR), increased Blood Pressure (BP), bladder contraction, pupil dilation (mydriasis).
• Mechanism: Gq protein coupled, leading to activation of Phospholipase C, increasing IP3 and DAG, which causes an increase in intracellular Calcium (Ca++). This leads to smooth muscle contraction.

Alpha-2 Receptors

• Effects: Primarily located presynaptically, inhibiting norepinephrine release. Postsynaptic effects include vasodilation (centrally mediated), decreased BP, decreased insulin secretion, decreased aqueous humor production, decreased saliva production, and platelet aggregation.
• Mechanism: Gi protein coupled, leading to inhibition of Adenylyl Cyclase, decreasing cAMP levels.
• Note: Effects like decreased saliva contribute to 'anti-SLUDGE' like symptoms (though this mnemonic is more classic for anticholinergics).

Beta Receptors

Beta-1 Receptors

• Location: Primarily the heart, kidney.
• Effects: Increased Heart Rate (HR), increased contractility, increased renin release.
• Mechanism: Gs protein coupled, increasing cAMP.

Beta-2 Receptors

• Location: Lungs (bronchial smooth muscle), vascular smooth muscle, liver, uterus.
• Effects: Bronchodilation, vasodilation (leading to decreased BP), glycogenolysis.
• Mechanism: Gs protein coupled, increasing cAMP.

Related Pharmacology

Adrenergic Drugs

Beta Blockers

• Uses: Often given after Myocardial Infarction (MI), hypertension, angina, arrhythmias, glaucoma, anxiety. They lower HR and BP.
• Side Effects (SE): Fatigue, bradycardia (slowed heart rate), hypotension. Nonselective beta blockers can cause bronchoconstriction (contraindicated in asthma/COPD).

Beta Agonists

• Side Effects: Can cause tremors.

Structure-Activity Relationship (SAR)

• Definition: SAR is the relationship between the chemical structure of a molecule and its biological activity.
• Amine Group Modification: For catecholamines, larger R groups attached to the amine nitrogen generally increase selectivity for Beta receptors over Alpha receptors. Adding more or larger R groups tends to favor Beta-2 selectivity.

Key Terms and Concepts

• Hypotension: Low blood pressure.
• Miosis: Constriction of the pupils.
• Mydriasis: Dilation of the pupils.
• Tyrosine Hydroxylase: Enzyme that converts tyrosine to L-DOPA; the rate-limiting step in catecholamine synthesis.
• Dopa Decarboxylase: Enzyme that converts L-DOPA to dopamine.
• Tachyphylaxis: A rapid decrease in response to a drug after repeated administration; also known as "acute tolerance".
• Catecholamines: Neurotransmitters (like dopamine, norepinephrine, epinephrine) derived from tyrosine, having marked effects on the central nervous and cardiovascular systems.
• Monoamine Oxidase (MAO): Enzymes that catalyze the metabolism of monoamines, including norepinephrine, dopamine, and serotonin. MAO inhibitors are used to treat depression.
• DAT (Dopamine Transporter): Responsible for the reuptake of dopamine from the synaptic cleft.
• NET (Norepinephrine Transporter): Responsible for the reuptake of norepinephrine from the synaptic cleft.
• SERT (Serotonin Transporter): Responsible for the reuptake of serotonin from the synaptic cleft.
• Adrenergic: Relating to or denoting nerve cells in which epinephrine (adrenaline), norepinephrine (noradrenaline), or a similar substance acts as a neurotransmitter. Activated by epinephrine; relates to the sympathetic nervous system.
• Pheochromocytoma: A tumor of adrenal gland tissue (specifically the medulla) that results in the excessive release of epinephrine and norepinephrine, causing symptoms like hypertension.

Other Notes

• Norepinephrine acts as a potent vasoconstrictor and neurotransmitter (stimulant).
• Drug Effects on Cardiovascular Parameters:
  • Beta blockers decrease renin release (via Beta-1).
  • Alpha-1 blockers decrease peripheral resistance (PR).
  • Alpha-2 agonists decrease cardiac output (CO) and PR (centrally).
• Cardiovascular Parameters List: PVR (Peripheral Vascular Resistance), HR (Heart Rate), CF (Contractile Force), VT (Vascular Tone - inferred), CO (Cardiac Output), SV (Stroke Volume), VR (Venous Return), BV (Blood Volume).