Basic Pharmacology

CATECHOLAMINE SYNTHESIS:

• Tyrosine ------> DOPA (Tyrosine Hydroxylase)
  • This is the rate-limiting step in synthesis.
  • alpha-Methyltyrosine is a false substrate for this step and inhibits the enzyme.
• DOPA ------> Dopamine (DOPA Decarboxylase)
• Dopamine ------> Norepinephrine (Dopamine beta-Hydroxylase)
• Norepinephrine ------> Epinephrine (Phenylethanolamine N-Methyltransferase, PNMT)
  • The methyl group is obtained from S-Adenosyl-Methionine (SAM)
    
     

SYNTHESIS OF ACETYLCHOLINE: Choline + Acetyl-CoA ------> Acetylcholine (Choline Acetyltransferase)

 

ACETYLCHOLINE RELEASE: Other neurotransmitters are released along with ACh.

• ATP
• VIP
• Prostaglandins
  
   
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CATECHOLAMINE RELEASE: Other neurotransmitters are released along with NE.

• Neuropeptide-Y (NPY)
• Dopamine
• Metenkephalin
• CGRP
  
   

CATECHOLAMINE BREAKDOWN: The primary way to get rid of NE is reuptake back into the pre-synaptic neuron.

• UPTAKE I: Reuptake of NE back into the presynaptic neuron.
  • Monoamine Oxidase (MAO): Breaks down Norepinephrine in the pre-synaptic neuron. Before it can work, NE must be reuptaken into the presynaptic neuron.
• UPTAKE II: Reuptake of NE back into non-neuronal cells -- glial and smooth muscle cells.
  • Catechol-O-Methyltransferase (COMT): Breaks down NE in glial cells and other non-neuronal cells.
  • The methylated products of COMT then diffuse out of the glial cells and make their way back to neurons, where they are further broken down MAO. So, MAO is required in either case.
• Catecholamine Metabolites: Two metabolites are found in urine and can be measured to estimate Catecholamine turnover.
  • NE ------> Vanillyl Mandelic Acid (VMA)
  • Epi ------> Vanillyl Mandelic Acid (VMA)
  • Dopamine ------> Homovanillic Acid (HVA)
    
     

AUTONOMIC RECEPTORS: Brief summary

Receptor	Location	Effect
Nicotinic Ganglionic (NG)	ANS Ganglions	Activation of parasympathetic and sympathetic post-synaptic neurons.
Nicotinic Neuromuscular Junction (NMJ)	Neuromuscular Junction	Activation of skeletal muscle
Muscarinic (M1) IP3 / DAG	Sympathetic post-ganglionics	Inhibit sympathetic NE release. This is the way in which ACh causes relaxation of vascular smooth muscle: ACh ------> inhibit NE ------> vasodilation.
Muscarinic (M2) Inhibitory: cAMP, K+ influx	Heart	Lower rate (on SA node) and force (on myocardium)
	Eye	Pupillary constriction (contract iris muscle); accommodation
	GI / UG	Contraction of GI smooth muscle and relaxation of sphincters.
	Respiratory	Bronchoconstriction and increased secretions
	Penis	Erection (via NO), vasodilation
Muscarinic (M3) IP3 / DAG	Vascular	Vasodilation: Strong indirect vasodilatory effect due to inhibition of sympathetics. At low doses, this leads to a reflex tachycardia. Some direct vasodilatory effect (especially when exogenous ACh is given)
	Exocrine glands	Increased sweating in non-adrenergic sweating areas (regular eccrine sweat glands). Under sympathetic control, but they are M3 muscarinic receptors.
Adrenergic (alpha1) IP3 / DAG ------> Ca+2	Vascular smooth muscle	Vasoconstriction (via IP3 / DAG, increased Ca+2)
	GI / UG	Smooth muscle relaxation and contraction of sphincters
	Eye	Pupillary dilation (contract radial muscle)
Adrenergic (alpha2) Gi ------> cAMP	Post-ganglionics	Inhibitory on sympathetic and parasympathetic post-ganglionic neurons. For sympathetics, this is auto-regulatory feedback. Gi ------> inhibit cAMP
	Pancreatic beta-Cells	NE Inhibits the release of insulin ------> hyperglycemia
Adrenergic (beta1) Adenyl Cyclase / cAMP	Heart	Increase rate (SA node) and inotropic state (myocardium)
	Lipocytes	Increase lipolysis
	Brain	NE stimulatory CNS effects.
	Kidney	Increased Renin release ------> higher b.p. ultimately
Adrenergic (beta2) Adenyl Cyclase / cAMP	Vascular	Relaxation of vascular smooth muscle in skeletal muscle and brain.
	Pancreatic beta-Cells	Stimulate release of insulin in Pancreatic beta-Cells. Thus beta-Blockers can lead to hyperglycemia as side-effect.
Dopamine (D1) G-Protein, cAMP	Vasculature	Vasodilation, especially in Kidney ------> higher Renal Blood Flow.
Dopamine (D2) G-Protein, cAMP	Anterior Pituitary	Inhibit Prolactin Release
	CNS	Various stimulatory effects.



  

VASCULATURE: There are little or no parasympathetics innervating the vasculature.

• alpha₁-Receptors: Vasoconstrictive. They predominate in the splanchnic beds and kidneys, which do not need a lot of blood flow during sympathetic stimulation.
  • The vasculature is primarily under sympathetic control, via alpha₁ receptors.
• Muscarinic Receptors: There are, however, muscarinic receptors on vascular smooth muscle, and they do cause vasodilation. Thus, if there is ever a muscarinic agonist (such as ACh) in the blood, then you will see a pharmacologic effect of direct vasodilation on vascular smooth muscle.
  • Coronary Arteries: An exception to the rule. Dilation of coronary arteries occurs by parasympathetic stimulation ------> vasodilation.
• beta₂-Receptors: Vasodilatory. They predominate in skeletal muscle and brain, which get all the blood flow during sympathetic stimulation.
  
   

SWEAT GLANDS:

• Cholinergic Sweat Glands: Thermoregulatory sweat glands throughout the body are under sympathetic control, but they release ACh and synapse with muscarinic receptors.
• Adrenergic Sweat Glands: Nervous sweating on palms, soles, and armpits is also under sympathetic control, but it releases NorE and synapses with adrenergic receptors.