Tiêu đề 10. ADRENERGIC AND ANTI-ADRENERGIC DRUGS.pdf ✅

PHARMD GURU Page 1  Adrenergic drugs are also called “Sympathomimetics”.  Anti-Adrenergic drugs are also called “Sympatholytics”.  Adrenaline is also called “Epinephrine (E)”.  Nor-Adrenaline is also called “Nor-Epinephrine (NE)”. ADRENERGIC DRUGS ENDOGENOUS:  Nor-adrenaline (NA) is the major neurotransmitter of SNS.  Adrenaline is the primary hormone secreted by adrenal medulla.  Nor-adrenaline is precursor of adrenaline. Dopamine (DA) is the precursor of nor- adrenaline.  All these three (adrenaline, nor-adrenaline and dopamine) together are called as catecholamines. ADRENERGIC NEUROTRANSMITTERS: Dopamine, nor-adrenaline and adrenaline are the adrenergic neurotransmitters. BIOSYNTHESIS:  The steps in biosynthesis of dopamine, nor-adrenaline and adrenaline are indicated in below flow chart.  Biosynthesis of catecholamines starts with the dietary amino acid L-phenyl alanine which is absorbed from GIT.  In liver phenyl alanine gets oxidised by the enzyme phenyl alanine hydroxylase (hepatic hydroxylase) to form L-tyrosine. ADRENERGIC AND ANTI-ADRENERGIC DRUGS

PHARMD GURU Page 3 hydroxylase, located in synaptic vesicles. Nor-adrenaline is stored in synaptic vesicles and works as a neurotransmitter in SNS.  The adrenal medulla has two distinct types of catecholamine containing cells: one for Nor-adrenaline and another for adrenaline. An enzyme called phenyl ethanolamine-N methyl transferase converts Nor-adrenaline to adrenaline. After its synthesis, adrenaline re-enters the chromaffin granules where it is stored till its release.  In adults, 80% of catecholamines are present as adrenaline in adrenal medulla, while remaining 20% is Nor-adrenaline. STORAGE: The endogenous NE, located in the nerve terminal is stored in the synaptic vesicles as a complex with ATP (4 molecules of ATP complex with 1 molecule of NE) along with a soluble binding protein called as chromogranin-A. Inside the storage vesicles, there is acidic pH which provides a positive charge on amino group of NE. This prevents outside diffusion through the vesicle membrane. RELEASE: The release occurs either due to action potential or due to a spontaneous effect. 1) Action potential induced release: An action potential after reaching to the synaptic vesicles causes changes in membrane permeability. As a result sodium, calcium and chloride ions enter the synaptic vesicle while potassium ions come out. Influx of calcium ions disrupts the storage vesicle to release NE, ATP, chromogenin along with small amounts of dopamine β-hydroxylase enzyme in to synaptic cleft by the process of exocytosis. 2) Spontaneous release: The random migration of storage vesicles towards the end of neuron can result in spontaneous discharge of NE. This release is very small and the process is of less importance. ACTION ON DIFFERENT RECEPTORS: The liberated NE, then stimulates different post-synaptic adrenoceptors as mentioned below. Epinephrine (E) activates all five sub-types, while NE primarily activates all sub-types except β2. Out of five sub-types, α2 and β2 receptors are
PHARMD GURU Page 4 located on pre-synaptic terminals. Other sub-types are located on post-synaptic sites. See Fig. 3.12. (i) α1-Receptors: These receptors are present post-synaptically and when activated produce excitatory effects in organs like vascular smooth muscles, salivary glands, bronchi, uterus, radial muscle of iris and liver cells. In the intestine, they produce inhibitory effects leading to relaxation. (ii) α2-Receptors: These receptors are located on pre-synaptic terminals of sympathetic post-ganglionic neurons. Stimulation of these receptors by NE decreases further release of NE. when these receptors are activated by NE, release of ACh is also decreased. In the brain stimulation of these receptors decrease sympathetic out flow. (iii) β1-Receptors: These are located post-synaptically. They are found primarily in heart where they produce positive ionotropic and positive chronotropic effect, after activation by NE or E. the receptors are also present in kidneys where they promote release of rennin. E exhibits moderate and NE exhibits strong actions on these receptors. (iv) β2-Receptors: These are present post-synaptically, primarily on bronchi, blood vessels supplying to skeletal muscle, coronary arteries, uterus, GIT and cardiac smooth muscle. Except in myocardium, their activation causes an inhibitory effect leading to relaxation of smooth muscles. E exhibits stronger affinity to these receptors. Comparatively, NE has very less affinity for them. The receptors have also been identified pre-synaptically on adrenergic nerve terminals. Activation of pre-synaptic β2 receptors by NE/E, facilitates release of the neurotransmitter. (v) β3-Receptors: These receptors are present on adipocytes. Their activation promotes lipolysis (rise in blood free fatty acids) and thermogenesis (rise in temperature). NE has stronger action as compared to E on these receptors.