Adrenoceptor Agonists

Adrenoceptor Agonists

definition • Drugs that mimic the actions of epinephrine or norepinephrine • Sympathomimetic drugs

Classification • Depend on the affinity for different groups of receptor • α-adrenoceptor agonists • β-adrenoceptor agonists • α, β-adrenoceptor agonists

Chemistry • Parent compound: phenylethylamine • Change the affinity for α or β receptors • Change pharmacokinetics properties

Chemistry and pharmacokinetics • Substitutions • On the terminal amino group: increase β receptors activity • On the benzene ring: increase bioavailability and prolongs the duration of action; increase the distribution of molecule to CNS • On the alpha or beta carbons: block oxidation by MAO

α-adrenoceptor agonists • Norepinephrine • Metaraminol • α 1 -adrenoceptor agonists: phenylephrine and methoxamine

Norepinephrine • Potent effect of α receptor • Relative little effect on β1 receptor • Little effect on β2 receptor

Pharmacological Effects • Blood vessels: constrict (skin vessels, renal vessels); coronary artery dilate • Heart: pacemaker activity, conduction velocity, and intrinsic contractility increase. HR decrease by a reflex response.

Pharmacological Effects • Blood pressure: systolic pressure increase at low concentration; at high concentration both systolic and diastolic pressure increase

pharmacokinetics • i.v. drip. • Be uptake and metabolized quickly

Therapeutic Uses • neurogenic shock, cardiogenic shock • Hypotension • hemorrhage of upper digestive tract

Adverse reaction • Avascular necrosis • Acute renal failure • Contraindication: hypertension, atherosclerosis, cardiopathy

Metaraminol • excite α-R • replace the NA in vesicles，increase NA release from vesicles directly • More stable to MAO, prolong the action • Acute tolerance

Pharmacological Effects • similar to NA in its action, but less potent • increase systolic and diastolic blood pressure • its major therapeutic use is in the treatment of hypotensive state

Phenylephrine, Methoxamine • α1-R agonists • similar to those of NA, but less potent and has a longer duration of action • vasoconstriction, increase arterial pressure, and reflex bradycardia

Clinical Uses • hypotension state; • supraventricular paraxosmal • pupil mydriasis

α、β-R agonist • Adrenaline • Dopamine • ephedrine

Adrenaline • At low concentration ,β effects predominate; at high concentration , α effects predominate. • β2-R are more sensitive to Adr than the α-R.

pharmacokinetics • Adr- absorption is poor with oral administration • can be given iv or im

Pharmacological Effects • Heart • a direct effect on β1-R ; increase in heart rate , and increase cardiac output; • a propensity toward arrhythmias • coronary artery dilate

Pharmacological Effects • Blood vessel • Constrict (skin vessels, renal vessels) • Dilate: vessels in skeletal muscle , hepatic vessels • coronary blood flow

Pharmacological Effects • blood pressure • At low concentration: systolic pressure increase • At high concentration: both systolic and diastolic pressure increase

Pharmacological Effects • Smooth muscle: • Bronchiolar smooth muscle relaxes • blood vessel constrict • Block the release of histamine

Pharmacological Effects • Metabolic effects • increase in glucoses and lactate production via glycogenolysis • inhibition of insulin secretion (α-R) • increase in free fatty acid and oxygen consumption .

Therapeutic Uses • cardiac arrest • acute or severe hypersensitivity reaction , it is primary treatment for anaphylactic shock , asthma • prolong the duration of local anesthesia

Adverse Effects • Palpitation, BP • Hypertension, diabetes mellitus, hyperthyroidism

Dopamine • activate α、β1 and dopa-receptor • Be metabolized by MAO and COMT quickly • No effect on CNS

Dopamine • heart: positive inotropic effect on the myocardium, increase cardiac output • blood vessels • At low or intermediate concentration: act on D1 receptor, dilate • At high concentration : act on α-receptor, constrict

Pharmacological Effects • Kidney • At low or intermediate concentration: reduce arterial resistance in the mesentery and kidney • At high concentration: cause vasoconstriction with consequent reduction in renal function

Clinical uses • Shock • Acute renal failure • Adverse reaction: arrhythmia, reduction in renal function

Ephedrine • absorbed when taken orally • resistant to COMT and MAO, so that its action is prolonged • CNS effects may occur: such as insomnia, nervousness, nausea and agitation • Acute tolerance

pharmacological Effects • increase cardiac output, increase blood pressure • Relax smooth muscle • CNS: excitement

Clinical Uses • bronchial asthma • nasal decongestant • hypotension without crisis • Adverse reactions: CNS

β-R agonist • β1 and β2-R agonist • Isoprenaline: lower selectivity to both β1 and β2-R, little effect on α-R

pharmacological Effects • heart: positive inotropic effect ,increase the heart rate and conduction, cardiac output increase • blood vessels : reduction of peripheral vascular resistance in skeletal muscle, renal and mesenteric vascular beds;

pharmacological Effects • blood pressure: diastolic blood pressure falls , systolic blood pressure may increase • Relax both bronchial and gastrointestinal smooth muscle • Metabolic effects

pharmacokinetics • Resistance to MAO • less be uptaken • aerosol

Clinical uses • bronchial asthma • Atrioventricular block • cardiac arrest • Infectious shock

Adverse Effects • palpitation; dizziness • overdosage by inhalation can produce fatal ventricular arrhythmia • Contraindication: myocarditis ,coronary heart disease; hyperthyroidism

β1-R agonist • β1 reaction is more potent thanβ2 reaction • Dobutamine

Dobutamine • direct β1-R agonist • greater inotropic effect than chronotropic effect • little effects on peripheral vascular resistance. • Clinical uses: improve myocardial function in congestive heart failure .

Adverse reactions • BP , palpitation • Contraindication: IHSS, atrial fibrillation

β2-R agonist • bronchial asthma

Adrenoceptor Agonists