Lecture 7 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 isoprenaline decrease DBP because they act on β2 Reflex bradycardia Isoprenaline decrease resistance because it acts on β only without α Blood pressure Peripheral resistance

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.

Effects of Dopamine Immediate precursor of NE Occurs in –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: Epinephrine, 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

Clinical Uses of Adrenergic Agonists  Heart block : β agonist: Isoproternol (isoprenaline).  Isoproternol is only used now to reverse the block produced by overdoses of β– blockers -Cardiac arrest means complete cessation of heart’s activity. -Heart block means partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles.

Clinical Uses of Adrenergic Agonists Anaphylactic reactions: Epinephrine is the first line of the treatment for bronchoconstriction & CV collapse Both β and α agonist required. EP is used to cause Bronchodilation, Increase BP and stablizes mast cells.

Clinical Uses of Adrenergic Agonists (cont.) 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: Psudoephedrine  Haemostatic in epistaxis: Adrenaline Miscellaneous:  Glaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV. ritordine

Clinical Uses of Adrenergic Agonists (cont.) With local anesthetics: Epinephrine, Norepinephrine and Phenylephrine These drugs are used in dentistry because of their vasoconstrictive action 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.

Adverse Effects of Adrenergic Agonists –CNS disturbance: anxiety, fear, tension, headache & tremors –Cerebral hemorrhage –Tachycardia & Cardiac arrhythmias

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

α- agonists 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

β- agonist Isoproterenol Predominantly stimulates both β1, β2 and β3 adrenergic receptors. Its non selectivity is one of its drawbacks and the reason why it is rarely used. Cardiovascular effects -Produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output. -It is useful in the treatment of atrioventricular block or cardiac arrest.

Isoproterenol (Continued) -Isoproterenol dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. -It may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressure.

Isoproterenol (Continued) Bronchodilatation - Isoproterenol produces bronchodilatation through stimulation of β2 receptors in Trachea and Bronchi.

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

Isoproterenol (Continued) Therapeutic uses: Isoproterenol is now rarely used as a broncho-dilator in asthma. It can be employed to stimulate the heart in emergency situations. Pharmacokinetics: Isoproterenol can be absorbed systemically by the sublingual mucosa but is more reliably absorbed when given parenterally or as an inhaled aerosol. Adverse effects: The adverse effects of isoproterenol are similar to those of epinephrine.

Dobutamine synthetic, direct-acting catecholamine which acts mainly on β1-receptors of the heart. It increases the force of contraction with mild effect on HR, BP and vasodilatation. It does not cause release of endogenous NE. Dobutamine is used to increase cardiac output in congestive heart failure, in septic and cardiogenic shock. Given only parenterally (not orally)

Salbutamol: It is β 2 – selective agonist Can be used orally, IV and by inhalation Formulations: (Tablets; Syrup; Injection; solution and Inhalation) Clinical Uses –bronchial asthma by β 2 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.) –Cloni dine 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

Clonidine (continued) Adverse affects of Clonidine –Depression –Dizziness, insomnia, & nightmares –Impotence –Alopecia تساقط الشعر –Urticaria –Weight gain –Fluid retention –Sudden withdrawal leads to rebound hypertension

Ephedrine Clinical uses: Pressor agent (used to increase BP) Nasal Decongestant It is no longer used to treated bronchial asthma. (because it’s less potent + slow onset of action) The clinical uses of ephedrine is rare due to its abuse. Pseudoephedrine substituted ephedrine in treatment of nasal congestion.

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

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

Summary –Epinephrine (α, β1 and β2): ↑ systolic BP & slight ↓diastolic BP –NE: (α & β1): ↑ systolic & diastolic BP + Reflex bradycardia –Isoproterenol (β-agonist): slight ↑ systolic BP & ↓diastolic BP –Indirect acting sympathomimetics: ↑ BP (hypertensive crisis) –Dopamine: Activates D receptors (renal vasculature VD) + Activates β1 (heart) + Activates α1 at high doses (VC)