Pharmacological Actions of Adrenergic Drugs

ACTIONS

The peripheral actions of Adr in most tissues have been clearly differentiated into those mediated by α or β receptors depending on the predominant receptor type present in a given tissue. These are tabulated in Table 9.5. The

receptor subtype, wherever defined, has been mentioned in parenthesis. The actions of a particular sympathomimetic amine depend on its relative activity at different types of adrenergic receptors.

Adr :       α₁ + α₂ + β₁ + β₂ and weak β₃ action

NA: α₁ + α₂ + β₁ + β₃ but no β₂ action

Iso:  β₁ + β₂ + β₃ but no α action

The overall actions are —

Heart

Adr increases heart rate by increasing the slope of slow diastolic depolarization of cells in the SA node. It also activates latent pacemakers in AV node and Purkinje fibres; arrhythmias can occur with high doses that raise BP markedly. Raised BP reflexly depresses the SA node and unmasks the latent pacemakers. Certain anaesthetics (chloroform, halothane) sensitize the heart to arrhythmic action of Adr. Idioventricular rate is increased in patients with complete heart block.

Force of cardiac contraction is increased. Development of tension as well as relaxation are accelerated. Thus, systole is shortened more than diastole. Cardiac output and oxygen consumption of the heart are markedly enhanced.

Conduction velocity through AV node, bundle of His, atrial and ventricular fibres is increased; partial AV block may be overcome. Refractory period (RP) of all types of cardiac cells is reduced. All cardiac actions are predominantly β₁ receptor mediated.

When BP rises markedly, reflex bradycardia occurs due to stimulation of vagus— this is the usual response seen when NA is injected i.v.

Blood Vessels

Both vasoconstriction (α) and vasodilatation (β₂) can occur depending on the drug, its dose and vascular bed. Constriction predominates in cutaneous, mucous membrane and renal beds. Vasoconstriction occurs through both α₁ and α₂ receptors. However, location of α₂ (extrajunctional) receptors is such that they are activated only by circulating CAs, whereas α₁ (junctional) receptors primarily mediate responses to neuronally released NA. Dilatation predominates in skeletal muscles, liver and coronaries. The direct effect on cerebral vessels is not prominent— blood flow through this bed parallels change in BP.

Action is most marked on arterioles; larger arteries and veins are affected at higher doses.

BP

The effect depends on the amine, its dose and rate of administration.

• NA causes rise in systolic, diastolic and mean BP; it does not cause vasodilatation (no β₂ action), peripheral resistance increases consistently due to α action.

• Isoprenaline causes rise in systolic but marked fall in diastolic BP (β₁—cardiac stimulation, β₂— vasodilatation). The mean BP generally falls.

•  Adr given by slow i.v. infusion or s.c. injection causes rise in systolic but fall in diastolic BP; peripheral resistance decreases because vascular β₂ receptors are more sensitive than α receptors. Mean BP generally rises. Pulse pressure is increased.

Rapid i.v. injection of Adr (in animals) produces a marked increase in both systolic as well as diastolic BP (at high concentration response predominates and vasoconstriction occurs even in skeletal muscles). The BP returns to normal within a few minutes and a secondary fall in mean BP follows. The mechanism is—rapid uptake and dissipation → concentration of Adr is reduced → low concentrations are not able to act on α receptors but continue to act on β₂ receptors.

When an α blocker has been given, only fall in BP is seen—vasomotor reversal of Dale.

Respiration

Adr and isoprenaline, but not NA are potent bronchodilators (β₂). This action is more marked when the bronchi are constricted. Adr given by aerosol additionally decongests bronchial mucosa by α action. Adr can directly stimulate respiratory centre (RC) but this action is seldom manifest at clinically used doses. Rapid i.v. injection (in animals) causes transient apnoea due to reflex inhibition of RC. Toxic doses of Adr cause pulmonary edema by shifting blood from systemic to pulmonary circuit.

Eye

Mydriasis occurs due to contraction of radial muscles of iris (α₁), but this is minimal after topical application, because Adr penetrates cornea poorly. The intraocular tension tends to fall, especially in wide angle glaucoma.

Adr has complex effects on aqueous humor dynamics.

Overall, aqueous formation is reduced and outflow is facilitated.

GIT

In isolated preparations of gut, relaxation occurs through activation of both α and β receptors. In intact animals and man peristalsis is reduced and sphincters are constricted, but the effects are brief and of no clinical import.

Bladder

Detrusor is relaxed (β) and trigone is constricted (α): both actions tend to hinder micturition.

Uterus

Adr can both contract and relax uterine muscle, respectively through α and β receptors. The overall effect varies with species, hormonal and gestational status.

Splenic Capsule

Contracts (α) and more RBCs are poured in circulation. This action is not evident in man.

Skeletal Muscle

Neuromuscular transmission is facilitated. In contrast to action on autonomic nerve endings, α receptor activation on motor nerve endings augments ACh release, probably because it is of the α₁ subtype. The direct effect on muscle fibres is exerted through β₂ receptors and differs according to the type of fibre. The active state is abbreviated and less tension is developed in the slow contracting red fibres— incomplete fusion of individual responses. This along with enhanced firing of muscle spindles is responsible for the tremors produced by β₂ agonists. The action on rapidly contracting white fibres is to prolong the active state and increase the tension developed.

CNS

Adr, in clinically used doses, does not produce any marked CNS effects because of poor penetration in brain, but restlessness, apprehension and tremor may occur. Activation of α₂ receptors in the brainstem results in decreased sympathetic outflow → fall in BP and bradycardia.

Metabolic

Adr produces glycogenolysis → hyperglycaemia, hyperlactacidaemia (β₂); lipolysis →rise in plasma free fatty acid (FFA), calorigenesis (β₂ + β₃) and transient hyperkalaemia followed by hypokalaemia due to direct action on liver, muscle and adipose tissue cells. In addition metabolic effects result from reduction of insulin (α₂) and augmentation of glucagon (β₂) secretion.