Lecture 9 - Sympaathomimetic Amines

Non-Enzymatic pathway This involves the uptake of noradrenaline and related amines into neuronal and extraneuronal tissues. Two uptake processes • Uptake1 (neuronal uptake) • Uptake2 (extraneuronal uptake)

Uptake1: This is uptake followed by storage. It b) Is an active transport process c) is sodium dependent d) is proportional to the density of adrenergic innervation f) is saturable g) conserves transmitter

This process is inhibited by cocaine, tricyclic antidepressants and adrenergic neuron blockers. Other substrates for the process include dopamine and tyramine.

Mechanisms of Action of Cocaine and reserpine

Uptake2: This is uptake followed by destruction. It • occurs at high substrate concentrations • becomes important when uptake1 is blocked or saturated c) is inhibited by steroids

Sympathomimetic Amines

Sympathomimetic Amines These are compounds that mimic the effects of sympathetic nerve stimulation. These compounds are usually grouped into 2 classes: 5) Indirectly acting sympathomimetic amines such as tyramine, ephedrine and amphetamine. 2) Directly acting noradrenaline, adrenaline, phenylephrine and isoprenaline.

Indirectly acting sympathomimetic amines act by releasing noradrenaline from adrenergic nerve terminals.

Characteristics: • They are substrates for the uptake1 process, so are transported into the nerve terminal where they displace noradrenaline from the storage vesicles. b) Their actions are abolished when neuronal stores of catecholamines are depleted c) They exhibit tachyphylaxis

Characteristics (cont’d): d) Their actions are inhibited by inhibitors of neuronal uptake e) Their actions are lost when adrenergic nerves are destroyed. Examples: tyramine

amphetamine,

ephedrine,

Directly acting sympathomimetic amines Compounds in this category stimulate adrenergic receptors directly. They are usually divided into 2 groups based on their chemical structure. 1) Phenylethylamine derivatives such as noradrenaline and phenylephrine 2) Imidazoline derivatives such as oxymetazoline and clonidine

Adrenergic Receptors Adrenergic receptors were originally classified into two, α- and β subtypes, based on tissue sensitivity to a number of adrenergic agonists.

α Adrenaline ≥ Noradrenaline >>Isoprenaline. α-mediated effects are selectively antagonized by phentolamine. β Isoprenaline > Adrenaline > Noradrenaline. β-mediated effects are selectively antagonized by propranolol.

α-Adrenoceptors are subclassified into two: α 1- located postjunctionally. These receptors mediate the effects of neuronally released noradrenaline and exogenous sympathomimetic amines.

α 2- located prejunctionally on the nerve terminals. When activated, these receptors exert a negative feedback effect preventing further release of the neurotransmitter. α 2-Adrenoceptors are also found postjunctionally where they mediate the effects of circulating adrenaline from the adrenal gland.

Some selected agonists and antagonists at α 1- and α 2-adrenoceptor sites. α 1-Adrenoceptors α2-Adrenoceptors Agonists

*Noradrenaline

*NoradrenalineClonidine

Phenylephrine

*Oxymetazoline

Methoxamine

Brimonidine (UK 14304)

*Oxymetazoline Antagonists *Phentolamine

*Phentolamine

Prazosin

Yohimbine

Alfuzosin

Rauwolscine

Phenoxybenzamine

Mechanism of action  Promote

influx of extracellular

calcium

 Release

stores

calcium from intracellular

 Sensitize

contractile myofilaments to

calcium  α2-adrenoceptor agonists can also be

Signal Transduction by α 1 - Adrenergic Receptors

Gq q

q

Signal Transduction by α 2 - and β - Adrenergic Receptors

Pharmacological Actions mediated by α-adrenoceptors. a) Contraction of smooth muscles in arteries and veins. e) Increase in airway resistance especially in asthmatics c) Reduction of blood pressure h) Relaxation of non-pregnant uterus and contraction immediately after parturition

a) Contraction of radial muscle of the iris leading to dilation of the pupils – mydriasis f) Induction of platelet aggregation g) Relaxation of gastrointestinal smooth muscle h) Reduction of insulin secretions i) Inhibition of lipolysis j) Increased myocardial force of contraction

Pharmacological Actions mediated by α-adrenoceptors. a) Contraction of smooth muscles in arteries and veins (α 1- and α 2-) b) Increase in airway resistance especially in asthmatics (α 1-) c) Reduction of blood pressure – through activation of α 2-adrenoceptors in the brain d) Relaxation of non-pregnant uterus and contraction immediately after parturition (α 1-)

a) Contraction of radial muscle of the iris leading to dilation of the pupils mydriasis (α 1-) f) Induction of platelet aggregation (α 2-) g) Relaxation of gastrointestinal smooth muscle (α 1- and α 2-) h) Reduction of insulin secretions (α 2-) i) Inhibition of lipolysis (α 2-) j) Increased myocardial force of contraction (α 1-)

Uses of α-Adrenoceptor Agonists. b) Vasoconstrictors in hypotensive states eg anaphylactic shock b) Local vasoconstrictors to reduce local blood flow e.g with local anaesthetics to prevent diffusion away from the site of administration c) Nasal decongestants h) Treatment of hypertension (centrally acting α 2-adrenoceptor agonists) e) Opthalmic uses - to induce mydriasis and in the treatment of glaucoma.

Adrenoceptor Antagonists  These are substances that bind to adrenergic receptors thus preventing the access of the agonists to the receptor site.  Usually, antagonists have high affinity for the receptors but lack intrinsic activity.

α-Adrenoceptor antagonists There are 2 types: ----- competitive (reversible) ----- non-competitive (irreversible).

Non-competitive antagonists Example: phenoxybenzamine  These are haloalkylamine derivatives.  They alkylate the receptors and therefore reduce the density of functional receptors.  They produce a long lasting action depending on the time taken for new receptors to be synthesized.

 Phenoxybenzamine blocks both α 1- and α 2-adrenoceptors but is more selective for α 1-adrenoceptors.  It also blocks other receptor types such as cholinergic, histaminergic and serotonergic receptors but has no action on β-adrenoceptors.

Other pharmacological actions include: a) Inhibition of neuronal and extraneuronal uptake b) Increase transmitter release due to blockade of prejunctional α 2-adrenoceptors.

Competitive antagonists Examples include – phentolamine, prazosin, alfuzosin, doxazosin. They compete with the agonists for binding to the receptors. They do not change the structure of the receptors.

Phentolamine Phentolamine is a non-selective α 1- and α 2-adrenoceptor antagonist. It also has a direct vasodilator effect in addition to blocking α-adrenoceptors.

Selective α 1-adrenoceptor antagonists Prazosin, doxazosin and alfuzosin Selective α 2-adrenoceptor antagonists Rauwolscine and yohimbine

Uses of α 1-adrenoceptor antagonists b) preoperative management of patients with phaechromocytoma b) hypertension (tolerance develops to the use of these compounds in this condition) c) peripheral vascular disease such as Raynaud’s disease d) urinary obstruction (patients with benign prostate hyperplasia) e) male sexual dysfunction (erectile dysfunction)

Side effects • postural hypotension • diarrhea • failure of ejaculation

β-Adrenoceptors β-Adrenoceptors are non-selectively stimulated by isoprenaline and antagonized by propranolol. There are 3 subclasses of β-adrenoceptors. These are: β 1- Isoprenaline > Adrenaline = Noradrenaline β 2- Isoprenaline > Adrenaline > Nordarenaline β 3- Isoprenaline > Noradrenaline > Adrenaline

 Both β 1- and β 3-adrenoceptors are located postjunctionally while β 2-adrenoceptors are located both pre- and postjunctionally.  Prejunctionally located β 2-adrenoceptors facilitate the release of neurotransmitters.

Some selected agonists and antagonists at β 1-, β 2and β 3-adrenoceptor sites β1Agonists

β2-

*Isoprenaline *Isoprenaline Dobutamine Terbutaline Noradrenaline Salmeterol

Antagonists AtenololMeto prolol*Propra nolol*Cyanop indolol

β3*Isoprenaline BRL 37344

ICI 118551 Cyanopindolol Butoxamine *Propranolol *Cyanopindolol

Signal Transduction by α 2 - and β - Adrenergic Receptors

Pharmacological Actions: They c) increase rate and force of myocardial contractions (β 1-adrenoceptors) b) relax vascular smooth muscles (β 2-adrenoceptors) c) relax bronchial and urinogenital smooth muscles (β 2-adrenoceptors) d) increase glycogenolysis in the liver – hyperglycemia (β 2-adrenoceptors)

e) relax gastrointestinal smooth muscles (β 2- and β 3-adrenoceptors) f) inhibit platelet aggregation (β 2- adrenoceptors) g) increase lipolysis (β 3-adrenoceptors) h) inhibit immune function (β 2-adrenoceptors ) i) increase insulin secretion (β 3-adrenoceptors)

Uses of β-adrenoceptor Agonists. 1.They are used in the treatment of cardiogenic shock- to increase stroke volume, heart rate and improve perfusion of vital organs 2.They are used as bronchodilators in bronchial asthma 3.They are used as uterine sedatives 4.They can be used in the treatment of obesity and diabetes 5.They can also be used to increase skeletal muscle mass

β-Adrenoceptor Antagonists Examples: β 1-selective  atenolol, metoprolol β 2-selective  butoxamine, ICI 118551 Propranolol is non-selective

Other antagonists include labetalol (which also blocks α-adrenoceptors) and carvedilol (a newer antagonist with proven effectiveness in hypertension and congestive heart failure).

Pharmacological actions b) reduce the rate and force of myocardial contraction (β 1-antagonists) b) reduce peripheral vascular resistance (thus lowering blood pressure) when administered chronically but not acutely (β 1-selective antagonists)

Pharmacological actions c) increase in airways resistance (especially in asthmatics, β 2-selective) d) decrease intraocular pressure by decreasing the formation of aqueous humour e) Inhibit lypolysis and glycogenolysis

Pharmacokinetics a) most are well absorbed after oral administration b) they are subject to first pass effect even though to a variable extent c) are well distributed in the body d) lipid soluble members penetrate rapidly into the CNS

Uses • hypertension • angina pectoris • cardiac arrhythmias • heart failure • glaucoma • hyperthyroidism • migrane

Side effects • heart block • sedation, sleep disturbances and depression • worsening of existing bronchoconstriction in asthmatics d) adrenoceptor supersensitivity and increased risk of cardiovascular disease if withdrawn abruptly e) risk of impotence