UNIT II

DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM

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ADRENERGIC NEUROTRANSMITTERS

P R E PA R E D B Y:

MRS.KETAKI DHANE

D E PA R T M E NT O F P H A R M AC E UT I CA L C H E M I ST RY

ADRENERGIC NEUROTRANSMITTERS

BIOSYNTHESIS &CATABOLISM OF CATECHOLAMINES

Synthesis

• The endogenous catecholamines- dopamine, noradrenaline and adrenaline are all synthesized from tyrosine.
• The tyrosine enters the adrenergic nerve via aromatic L amino acid transporter. (Na+-tyrosine symporter).
• Tyrosine hydroxylase oxidizes tyrosine to dihydroxyphenylalanine (L-DOPA).
• Aromatic L-amino acid decarboxylase converts L-DOPA into dopamine.
• Dopamine enters the synaptic vesicles via vesicular monoamine transporter (VMAT) in exchange with H+ ions. Within synaptic vesicles dopamine gets converted to noradrenaline by the enzyme dopamine-β- hydroxylase. Dopamine is the neurotransmitter in the dopaminergic neurons.
• Noradrenaline is the main NT in the adrenergic neurons. But in the adrenal medulla noradrenaline is converted into adrenaline by the enzyme phenylethanolamine N-methyl transferase (PNMT). Hence adrenaline is the main NT in the adrenal medulla.

Release

• On arrival of an impulse at the adrenergic nerve ending, the voltage gated calcium channels get opened.
• This leads to influx of calcium ions.
• The triggered calcium causes rupture of synaptic vesicles by a process called exocytosis.
• This releases the noradrenaline into the synaptic cleft (NEJ-neuro effector junction). The noradrenaline binds to the alpha receptors or beta receptors present on the presynaptic or post synaptic membrane.
• This initiates the pharmacological response.

METABOLISM

• Noradrenaline is metabolized by two main enzymes- Catechol-o-methyl transferase (COMT) and monoamine oxidase (MAO).
• COMT is present in the circulating blood and this enzyme degrades the circulating catecholamines.
• Whereas MAO is located in the adrenergic neurons and this degrade the noradrenaline located in the adrenergic nerves (outside the vesicles).
• COMT, MAO and aldehyde dehydragenase degrade the catecholamines into multiple intermediates and finally into vanillyl mandelic acid (VMA), which is excreted through urine.

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Adrenergic Agonists

Direct -acting

Selective

Phenylepinep hrine

Clonidine Dobutamine

terbutaline

Non-selective

Epinephrine Norepinephrine Oxymetazoline Isoprenaline

Mixed acting

ephedrine

Indirect Acting

Releasing agent

Ampheta mine

Tyramine

Uptake inhibtor

cocaine

MAO inhibitors &

COMT

Inhibitors

Selegiline

Entacapone

Adrenergic receptors- (adrenoceptors) are selective for nor adrenaline and adrenaline. There are two types- α-adrenoceptors and β-adrenoceptors.

1). α-adrenoceptors- They are divided into α1 and α2 subclasses.

• α1 adrenoceptor is a G protein coupled receptor (GPCR) associated with Gq type of G protein.
• When adrenaline binds to this receptor, GDP converted to GTP.
• The -GTP complex binds to the membrane bound phospho lipase-C (PLC).
• The activated PLC converts membrane phospholipids phosphatidylinositol-4,5bisphosphate (PIP2) into inositol-1,4,5- triphosphate (IP3) and diacylglycerol (DAG).
• The DAG remains in the membrane and activates protein kinase C (PKC).
• The activated PKC phosphorylates several cellular proteins.
• IP3 stimulates the release of calcium from ER into the cytosol.
• The released calcium ions are responsible for the action.
• The calcium ions bound to the calmodulin protein (CaM). Ca2+- CaM complex activates the MLCK (Myosin light chain kinase).
• The activated MLCK causes the phosphorylation of myosin-LC.
• The myosin-LC-P causes smooth muscle contraction

Important locations of α1 adrenoceptors- Vascular smooth muscles, genitourinary smooth muscle, radial muscle, intestinal smooth muscle, heart and liver (Except intestine all actions are excitatory).

1. Vascular smooth muscles- Vasoconstriction (MOA as above).
2. Genitourinary smooth muscles- Contractions (MOA as above).
3. Radial muscle- Contraction –mydriasis (MOA as above).
4. Heart- Increases the rate and force of heart contraction. MOA- The calcium ions bind to the troponin, this leads to the interaction of actin-myosin causing heart muscle contraction.
5. Liver- Increases glycogenolysis and gluconeogenesis. MOA- DAG causes activation of PKC. The activated PKC causes the

phosphorylation of enzymes needed for glycogenolysis and gluconeogenesis.

6. Intestinal muscles- Relaxation. The activated protein kinase causes phosphorylation of cellular proteins. For eg K+ channel activation leads to efflux of K+ ions leading hyperpolarization (IPSP). The IPSP is also due to inactivation of calcium channels.

α2 adrenoceptor- is a G protein coupled receptor (GPCR) associated with Gi type of G protein.

• When adrenaline binds to this receptor, GDP converted to GTP, αβγ subunits of G protein gets detached.
• The α-GTP complex binds to the membrane bound adenylyl cyclase (AC).
• The inhibited AC decreases the formation of cAMP. The α-GTP complex also activates the K+ channel.
• This increases the removal of K+ ions from the cell to outside.
• This decreases the potential inside the cell (hyperpolarization).
• The α-GTP complex also inactivates the Ca2+ channels.
• This decreases the influx of Ca2+ ions into the cell.
• This also decreases the potential within the cell causing hyperpolarization. Hence the action is inhibition.

Important locations of α2 adrenoceptors-

Pancreatic β cells, platelets, nerve, vascular smooth muscles. (all actions are inhibitory except vascular smooth muscle).

a) Pancreatic β cells- Decreases insulin secretion. b)Platelets- Aggregation.

3. Nerve- Function as auto-receptors, neuronal inhibition.
4. Vascular smooth muscle- Vasoconstriction (both α1 and α2 causes vasoconstriction)

β-adrenoceptors

These are divided into three types- β1, β2 and β3.

All three belongs to stimulatory (Gs) type of G protein coupled receptors. β-adrenoceptor is a G protein coupled receptor (GPCR) associated with Gs type of G protein. When adrenaline binds to this receptor, GDP converted to GTP, αβγ subunits of G protein gets detached. The α-GTP complex binds to the membrane bound adenylyl cyclase (AC). The stimulated AC increases the formation of cAMP. Increased cAMP activates protein kinases (especially protein kinase A), which phosphorylates cellular proteins, including ion channels.

• β1 receptors located on heart (SAN and myocardium), renal juxta glomerular cells. Increases the heart rate (chronotropy) and force of heart contraction (inotropy) and increases the rennin secretion.
• β2 receptors are located in smooth muscles, liver, and skeletal muscles. Stimulation of β2 receptors in bronchial smooth muscles causes bronchodilatation. This effect is due to Gs independent activation of K+ channels resulting in hyperpolarization. This relaxes the bronchial smooth muscles. In liver stimulation of β2 receptors results in increased blood sugar level. In skeletal

muscle β2 receptors results in increased glycogenolysis.

• β3 receptors are located in adipose tissue. In adipose tissue stimulation of β3 receptors results in increased lipolysis.

Structure activity relationship (SAR)

• Phenylethylamine is the parent compound from which sympathomimetic drugs are derived.
• it consists of a benzene ring with an ethylamine side chain.

The of modification of phenylethylamine change the affinity of the drugs for receptors, the intrinsic ability and pharmacokinetics.

PK and SAR

• Subst. by OH- gp at C 3 & 4 yields catecholamines
• Chem str – determines activity at various receptors and also PK properties

Catecholamines –

• High potency ,
• Rapid inactivation,
• not absorbed orally ,
• Poor CNS penetration

Relative selectivity of adrenoceptor agonists

• Alpha agonists
• Phenylephrine, methoxamine: selective α1
• Clonidine, : α2
• Beta agonists
• Dobutamine :β1 Isoprenaline : β1 = β2
• Salbutamol, terbutaline, ritodrine : β2
• Mixed alpha & beta agonists
• Norepinehrine : α1 = α2 , β1 > > β2
• Epinephrine : α1 = α2 , β1 = β2
• Dopamine agonists
• Dopamine :D1=D2 > > β > > α

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