They're Subdivided Into Three Subtypes: Beta1, Beta2 and Beta3

1 :Beta Adrenoceptors

.They're subdivided into three subtypes: Beta1, Beta2 and Beta3

:Beta1 receptors (1

Action Location Increased Automaticity of SA node with increased heart * Heart (1 rate( +ve chronotropic effect),increased Conductivity of AV node(+ve dromotropic effect), increased Excitability of AV node and muscles predispose to arrhythmias.increased Contractility of the myocardium(+ve inotropic effect) result in increased stroke volume and Cardiac output and work and increased .Oxygen consumption .Decreased Refractory Period

Stimulation of Beta1 receptors on juxtaglomerular cells will Kidney (2 increase Renin release (Renin converts Angiotensinogen into ( Angiotensin I

.Presynaptic adrenergic and cholinergic terminals Nerves (3

:the action of Beta1 receptors in the heart is the followings :*

increased Automaticity of SA node with increased heart rate (i.e. positive  .(chronotropic effect

Increased conductivity (velocity) in conducting tissues including AV node (i.e.  .(positive dromotropic effect

.Increased excitability of AV node and muscles 

.predisposing to arythmias 

Increased contractility of myocardium (i.e. positive inotropic effect)  resulting in increasing stroke volume  increased cardiac output and work 

.increased O2 consumption and decreased refractory period of all tissues

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:Beta2 Receptors (2

Action Location Vasodilation of skeletal muscles, renal and visceral Blood Vessels (1 .vessels .(Decreased total peripheral resistance (TPR

Bronchodilation Lung (2

Smooth muscles in the intestinal wall are relaxed GIT (3

.Relaxation of Bladder wall Genitourinary (4 Pregnant uterus relaxation  delay of premature labour system

+ Activation of Beta2 receptors  Tremor and increased K Skeletal muscles (5 by skeletal muscles  Hypokalemia

.Decreased Histamine release Mast Cells (6

Increased Gluconeogenesis and Glycogenolysis Liver (7 .This will lead to Hyperglycemia

Increase release of Glucagon lead to Hyperglycemia Pancreas (8

.Heart has beta2 but much lesser than other organs Heart (9

:Notes

Cardiac Stimulation is largely determined by Beta1 receptors and to lesser 

.extent by Beta2 receptors

Ciliary muscles of eye have Beta Receptors( the subtype undetermined), their  (action isprobably relaxation.(not important

:Beta3 receptors (3

.Were found recently in fat cells, their action is to enhance lipolysis

3 Page :Mechanism of Activation of Beta Receptors

Activation of all subtypes of Beta receptors lead to activation of adenyl - cyclase and this will lead to increased conversion of ATP to cAMP, both are .(mediated by protein Gs (stimulatory

.cAMP is the major 2nd messenger of beta receptor activation -

In the heart, the activation of beta receptors  increased influx of calcium - across cell membrane and its sequestration from sarcoplasmic reticulum .inside the cell

Relaxation of smooth muscle may involve the Phosphorylation (inactivation) - .of myosin light chain kinase

4 Page Beta activation  increase cAMP  Phosphorylation of myosin light chain kinase  inactive form  vasodilation and relaxation

Nitrate  increase cGMP  dephosphorylation of myosin light chain kinase  .inactive form  relaxation

:Dopamine Receptors

:They're of 5 subtypes arranged in two families

Family (1)  D1 and D5

Family (2)  D2, D3 and D4

Stimulation of D1 family  stimulation of adenyl cyclase  smooth muscle relaxation  renal vessels dilation

Stimulation of D2 family  inhibit adenylyl cyclaes and open potassium channels  modulate transmitter release

:Desensitization of Receptors

Happens due to prolonged exposure to catecholamines  reduces responsivity. It is also known as tachyphylaxis or tolerance. Three mechanisms explain this :phenomenon and they function over hours or days

Sequestration of the receptor (1

Down-Regulation (2

Inability to couple to G-protein because the receptor has been (3 phosphorylated on the cytoplasmic side by eitherof protein kinase A or beta .(adrenergic receptor kinase (BARK

:Supersensitivity:occure when there is

Depletion of Noradrenaline in synaptic cleft by receptors (1

(Cut off adrenergic nerve supply (de-innervation (2

5 Page Up-regulation.:this happens when someone used to take a drug for a while this (3 will increase the no of receptors to that drug then when suddenly he stops using that drug the effect will be much greater than before even before he began to .use the drug

To avoid such cases we're "Tapering" the drug. I.e. gradually decrease the doses till .stopping the drug

:Adrenergic Agonists

.According to chemical structure .I

.According to receptor sensitivity .II

.According to their mode of action .III

:According to chemical structure

Catecholamine (1

They're sympathomimitic amine that contains 3,4-dihydroxybenzene group like .adrenaline, Noradrenaline, dopamine, Dobutamine and Isoprenaline

.Both Dobutamine and Isoprenaline are synthetic 

:Characteristics 

.Show the highest potency (1

(Shortest half-life in pharmacology (2 min (2

.Do not readily penetrate into CNS (3

Metabolized by COMT (postsynaptically and in the gut wall), MAO (4 .((intraneuronally in the mitochondria of liver cells and gut wall cells

.They're ineffective if given orally except Isoprenaline (5

6 Page :Non-Catecholamine (2

,They're phenylisopropylamines compounds lack the catechol hydroxyl groups

.They include: phenylphrine, ephedrine and amphetamine group

:Characteristics 

Not metabolized by COMT and they're poor substrates for MAO so they are (1 .given ORALLY

.Have prolonged duration of action (2

.Have increased lipid solubility (3

Have greater access to CNS due to lipid solubility and they may act indirectly (4 .producing unwanted side effects

:According to receptor sensitivity

.Alpha-agonist (1

.Beta-agonist (2

:According to their mode of action

.(Direct acting agonists. Ex: (catecholamine and phenylephrine (1

.These drugs act directly on alpha and beta receptors

.(Indirectly acting agonists. Ex: (Amphetamine, Tyramine (2

Tyramine found in cheese, chocolate and beer, it's one of the sympathomimitics that act indirectly. It interacts with MAO inhibitors .causing hypertensive crisis

7 Page These drugs are taken up into Presynaptic neurons and cause the release of .NA from cytoplasmic pool or vesicles of adrenergic neuron

Mixed action  some agonist have both modes of action, they can directly (3 stimulate Adrenoceptors and release NA from adrenergic neurons (indirect .(action

(Ex: Ephedrine (mainly direct

(Metaraminol (mainly indirect

:Effect of Adrenergic Agonists: depends on

.Selectivity of drug or Affinity of the receptor (1

.Dose of the drug (2

:Homeostatic reflexes (3

The most important one is the baroreceptors reflex which is mediated by the .stretch receptors located in the carotid sinus, aortic arch and atrium

Drop of Blood Pressure  Reduce Stretch of baroreceptors  reduced afferent impulses to the medulla oblongata  production of efferent reflex via ANS  inhibition of parasympathetic and activation of sympathetic nervous system  increase TPR and increase cardiac output  Increase Blood Pressures

:Catecholamine

:Noradrenaline

.Mainly affects alpha receptors

Has weak effect on Beta1 receptors

8 Page .Has no effect on Beta2 receptors

So action on alpha1 = alpha2 and beta1 >> beta2

:Adrenaline

Interacts with both alpha and beta receptors

:At low doses

.Beta effect (vasodilation) on the vascular system predominates

:At Higher doses

.Alpha effect (vasoconstriction) is strongest

So action on alpha1 = alpha2 and beta1 = beta2

:Isoprenaline

Predominantly stimulated beta adrenergic receptors, it's action on alpha .receptors is insignificant

So; beta1 = beta2 >>>>>>>> alpha

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