Adrenergic Agonists (Sympathomimetics)

Characteristics of Adrenergic Agonists Most of adrenergic agonists are β-phenylethylamine derivatives. Substitution on either the benzene ring or on the ethylamine side chain give a great variety of compounds which can be divided into: Catecholamines non-catecholamines

Catecholamines Contain 3,4 dihydroxybenzene group Examples: Epinepheine, Norepinephrine, Isoproterenol & Dopamine Substitiution on the amine nitrogen They have common characters: Highest potency in activating α or β-receptors Rapid inactivation by MAO & COMT when given parenterally and inactive orally Poor penetration of CNS (anxiety, tremor & headache)

Noncatecholamines Characters: Example: Phenylepheine, Ephedrine & Amphetamine Characters: They are poor substrate for COMT & MAO i.e. longer duration of action Increased lipid solubility i.e. enter CNS

Pharmacokinetics Catecholamines Non-Catecholamines Metabolized by MAO & COMT Not metabolized by MAO & COMT Substrate for uptake 1 Rapid onset Shorter duration Longer duration & higher bioavailability Orally ineffective Only metabolites are Excreted in urine (VMA) Orally effective Excreted unchanged in urine ↑ by urine acidification Cross BBB

Mechanism of action of the Adrenergic agonists Direct-acting agonists: Epinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine & Phenylephrine -produce their effect by directly stimulating the receptor site. Indirect-acting agonists: Amphetamine & Tyramine - release endogenous norepinephrine which then stimulates the receptor. Mixed-action agonists: Ephedrine & Metaraminol either directly stimulate the receptor or release endogenous NA.

Direct-Acting Agonist: e.g. Phenylephrine (α1) Clonidine (α2) (sympathomimetic ?) Isoprenaline & Dobutamine (β1) Salbutamol & Terbutaline (β2)

Effects of Adrenergic Agonists Cardiovascular: Heart: ↑HR, contractility » ↑CO + O2 consumption ↑Conductivity (atria, AV node & ventricles) ↑Excitability » arrhythmia BV: VD or VC depending on the selective activity of drug and the anatomic site of vessels e.g. Skin, Splanchnic, Sk.M., renal BV BP: Depends on effect on heart, PR & venous return The effect of α-agonist is different from β-agonist

CVS Effect of α-agonist Vasoconstriction leading to rise in PR & BP ↑ Systolic & diastolic BP (abolished by α-blocker) Baroreceptor reflex causing ↑ vagal supply to the heart leading to bradycardia (blocked by atropine) CO is not decreased in proportion to the decrease in HR because the venous return increase the stroke volume

CVS Effect of β-agonist β1 : +ve chronotropic effect (↑ HR) +ve inotropic effect (↑ force of contraction) ↑ CO and so ↑ systolic BP β 2: Dilation of arterioles of Sk.M. (↓PR) and so ↓both of systolic & diastolic BP No vasoconstriction Slightly ↑ of systolic BP & ↓ diastolic BP

Summary Adrenalin (α & β): ↑ systolic BP & slight ↓diastolic BP NA: (α & β1) ↑ systolic & diastolic BP + Reflex bradycardia Isoproterenol (β-agonist): slight ↑ systolic BP & ↓diastolic BP Indirect acting sympathomimetics: ↑ BP (hypertensive crisis) Dopamine: ↑ D receptors (renal vasculature VD) + ↑ β1 (heart) + ↑ α1 at high doses (VC)

Effects of I.V. infusion of Norepinephrine and Isoprenaline in Humans Blood pressure Reflex bradycardia isoprenaline decrease DBP because they act on β2 Peripheral resistance Isoprenaline decrease resistance because it acts on β only without α

Effects of Adrenergic Agonists Smooth Muscles: Bronchi: bronchodilation (β2) & ↓ bronchial secretion (α1) GIT: relax wall & contract sphincter (constipation) Urinary Bladder: relax wall & contract sphincter (urinary retention) Eye: Ciliary muscle (β2) Vasoconstriction of conjunctival BV (decongestion) Active mydriasis (α1)

Effects of adrenergic agonists (cont.) METABOLISM Hyperglycemia: Increase liver glycogenolysis (β2) Increase glucagon release (β2) Decrease insulin release (α2) Lipolysis: Increase hydrolysis of TG into free fatty acids & glycerol (β3) cAMP

Central Nervous System (CNS) These drugs produce CNS excitation or alertness Higher doses produce anxiety, apprehension, restlessness, and tremors.

Dopamine Immediate precursor of NE Occurs in Activates: CNS (act as neurotransmitter) Adrenergic nerve ending Adrenal medulla Activates: α1(at high doses) β1 (at small doses) D1(occurs in renal vascular bed) D2 (occurs in presynaptic adrenergic neurons)

Pharmacological Effects of Dopamine CVS: +ve chronotropic & inotropic effects At high doses: VC of BV Renal & visceral: VD of renal and splanchnic arterioles Effective in treatment of shock (the drug of choice taken by continuous infusion)

Indirect-Acting Adrenergic Agonists They are structurally related to NA but lack one or two OH gp of catechol ring (Not metabolized by COMT) They are taken by uptake-1 and displace NA from vesicles without exocytosis, so their action do not require calcium ions They have CNS effect particularly amphetamine which depends on their ability to release, not only NA, but also 5-HT and dopamine from nerve terminals in the brain Tachyphylaxis

Indirect-Acting Adrenergic Agonists (cont.) Drug Interactions Reserpine: Abolishing their effect Depleting the stored vesicles MAOI: Potentiation They inhibit the metabolism of released NA & also tyramine TCA: Interfere with their effect Uptake-1 inhibitor

Inhibit storage

Ephedrine Plant origin, synthetic compound Mixed-action acting drug It is not a catechol and is a poor substrate for COMT and MAO Pharmacological effects: ↑ systolic & diastolic BP by VC and cardiac stimulation Bronchodilation (slowly and less than EP & isoproterenol), so used as prophylactic in chronic asthma (not acute) Mild CNS stimulation (↑ alertness, ↓ fatigue & prevent sleep) Improve athletic performance Nasal decongestant

Clinical Uses of Adrenergic Agonists Cardiovascular: Cardiogenic Shock, Cardiac arrest: β agonist: Adrenaline, dobutamine or dopamine Dopamine is clinically more useful in the treatment of shock, in which significant increase in sympathetic activity might compromise renal function and worsens the peripheral circulation Malignant hypertension: α2 agonist: Clonidine HYPOTENSION: α1 agonist phenylephrine Heart block : β agonist: isoprenaline It’s only used now to reverse the block which is produced by overdoses of β – blockers

N.B. cardiac arrest means : complete cessation of heart’s activity. While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles Anaphylactic reactions: Ad is the first line of treatment for bronchoconstriction & CV collapse Both β and α agonist required. We use EP with steroid and antihistamine to cause Bronchodilation, Increase BP

Clinical Uses of Adrenergic Agonists (cont.) ritordine Respiratory: Asthma and premature labor contractions: For treatment » Isoprenaline (β agonist), Salbutamol, Terbutalin & Salmeterol (selective β2 is preferred) For prophylaxis » Salmeterol & Formoterol Norepinephrine is NOT used in treatment of asthma Nasal Decongestion: Ephedrine Haemostatic in epistaxis: Adrenaline & Ephedrine Miscellaneous: Mydriatic: Ephedrine Glaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV. Depression: Amphetamine

With local anesthetics: Adrenaline & NA These drugs are used in dentistry because of their vasoconstrictive actions on blood vessels. They are added to local anesthetics because they prolong the action of the local anesthetic, reduce the risk for systemic toxicity, and help to create a dry field.

Central Nervous System Stimulation These medications are used for the treatment of attention deficit hyperactivity disorder, narcolepsy, and as diet aids.

Adverse Effects CNS disturbance: anxiety, fear, tension, headache & tremors Cerebral hemorrhage Tachycardia & Cardiac arrhythmias Tachyphylaxis occurs with indirectly acting drugs

Contraindications to use of adrenergics Cardiac dysrhythmias, angina pectoris Hypertension Hyperthyroidism Cerebrovascular disease Distal areas with a single blood supply such as fingers, toes, nose and ears Renal impairment use caution

Toxicity of adrenergics in critically ill patients Affects renal perfusion Can induce cardiac dysrhythmias Increases myocardial oxygen consumption May decrease perfusion of liver Tissue necrosis with extravasation

Phenylephrine Clinical uses: As a mydriatic agent to examine the fundus of the eye It acts on α1 – receptors in the radial dilator pupillary muscle As a decongestant Used as nasal drops to cause VC in the nasal blood vessels & relief congestion As a vasopressor agent in case of hypotension α1 stimulation causes VC leading to increase BP

Clinical use of Amphetamine-like drugs To suppress appetite In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite In narcolepsy Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine stimulates the CNS & makes the patient awake In ADHD “Attention Deficit Hyperactivity Disease”

Ephedrine Clinical uses: Pressor agent (used to increase BP) Decongestant It is no longer used to treated bronchial asthma. (because it’s less potent + slow onset of action)

Pseudoephedrine: Has similar pharmacological activities to ephedrine It is not controlled : OTC (over the counter) It is commonly used as a decongestant

Phenylpropranolamine: Again it is similar to pseudoephedrine, and was used as decongestant, but it was stopped because it may cause cerebral hemorrhage

Dobutamine: It is direct acting β 1 – selective agonist Given only parenterally (not orally) It causes increases in CO Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock.

Salbutamol: It is β2 – selective agonist Can be used orally, IV and by inhalation Formulations: (Tablets; Syrup; Injection; solution and Inhalation) Clinical Uses bronchial asthma by β2 stimulation, which leads to relaxation of bronchial smooth muscle and bronchodilation. Treatment of refractory hyperkalemia (I.V)

Salmetrol and Formoterol: These selective beta agonists, have longer duration of action as compared to Salbutamole. Uses: As inhalors for bronchial Asthma

Clonidine: It is a selective α2 – agonist Mechanism of action : (Acts centrally as a central sympatholytic drug.) Clonidine is Lipid – soluble, so, it freely passes BBB & reaches CNS to stimulate α2 – receptors in medulla and pons causing decreased sympathetic tone and finally decrease BP It act by it self not like Methyldopa Clinical use include: Treatment of mild to moderate hypertension Treatment of morphine withdrawal symptoms As analgesic during labour The dose = 1.25 ug/day It can be given I.M

Adverse affects of Clonidine Depression Dizziness, insomnia, & nightmares Impotence Alopecia تساقط الشعر Urticaria Weight gain Fluid retention Sudden withdrawal leads to rebound hypertension Metyldopa and the comparison between it and clonidine are in the lecture (adrenergic antagonists)

3. Apraclonidine Like clonidine it is selective α2 adrenoceptor agonist, however, main uses as adjuvant therapy for glaucoma via decrease of aqueous humour formation.