Adrenergic Receptors and Drugs

By: Naghman Zuberi

Adrenergic receptor

The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. The sympathetic nervous system is responsible for the fight-or-flight response, which includes widening the pupils of the eye, mobilizing energy, and diverting blood flow from nonessential organs to skeletal muscle.

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Categories

There are two main groups of adrenergic receptors, and , with several subtypes. receptors have the subtypes 1 (a Gq coupled receptor) and 2 (a Gi coupled receptor). Phenylephrine is a selective agonist of the receptor. receptors have the subtypes 1, 2 and 3. All three are linked to Gs proteins (although 2 also couples to Gi),which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a non-selective agonist.

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Molecular Basis of Adrenergic Receptors

Also glycogenolysis in liver

Inhibition of Insulin release and Platelet aggregation Gluconeogene sis

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Adrenergic receptors - alpha

Type 1

Acts by phospholipase C activation, which forms IP3 and DAG In blood vessels these cause vasoconstriction Blood vessels with alpha-1 receptors are present in the skin and the genitourinary system, and during the fight-or-flight response there is decreased blood flow to these organs Acts by inactivation of adenylate cyclase, cyclic AMP levels within the cell decrease These are found on pre-synaptic nerve terminals

Type 2

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Differences between 1 and 2

Alpha-1 Alpha-2

Location Function

Post junctional Stimulatory GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Phenylephrine, Methoxamine

Prejunctional
Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Clonidine

Agonist

Antagonist Prazosin

Yohimbine

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Eye -- Mydriasis Arterioles Constriction Uterus -- Contraction Skin -- Sweat Platelet - Aggregation Male ejaculation Hyperkalaemia Bladder Sphincter Contraction 2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release
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1 adenoceptor Clinical effects

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Beta receptors

All receptors activate adenylate cyclase, raising the intracellular cAMP concentration Type 1:

Type 2:

These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells

Type 3:

These are in the vessels of skeletal muscle, and cause vasodilatation, which allows more blood to flow to the muscles, and reduce total peripheral resistance Stimulated by adrenaline, but not noradrenaline Beta-2 receptors are also present in bronchial smooth muscle, and cause bronchodilatation when activated Bronchodilator salbutamol work by binding to and stimulating the 2 receptors
Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism

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Differences between 1, 2 and 3

Beta-1
Location Heart and JG cells

Beta-2
Bronchi, uterus, Blood vessels, urinary tract, eye Salbutamol Alpha-methyl propranolol Weak

Beta-3
Adipose tissue

Agonist

Dobutamine

Antagonist Metoprolol, Atenolol Action on NA

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Moderate

Strong
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2 Adrenoceptor Clinical Effects

Bronchi -- Relaxation Arterioles -- Dilatation Uterus Relaxation Skeletal Muscle - Tremor Hypokalaemia Hepatic Glycogenolysis

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Dopamine receptors

D1-receptors are post synaptic receptors located in blood vessels and CNS
D2-receptors are presynaptic present in CNS, ganglia, renal cortex

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Noradrenergic transmission

Nor-adrenaline is the major neurotransmitter of the Sympathetic system Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia They have long axons which end in varicosities where NA is synthesized and stored
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Adrenergic transmission
Catecholamines: Natural: Adrenaline, Noradrenaline, Dopamine Synthetic: Isoprenaline, Dobutamine Non-Catecholamines:

Ephedrine, Amphetamines, Phenylepherine, Methoxamine, Mephentermine

Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group
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Biosynthesis of Catecholamines
Phenylalanine
PH

Alpha-methyl-ptyrosine

Rate limiting Enzyme

5-HT, alpha Methyldopa

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Storage of Noradrenaline

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Release of NA Feedback Control

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Regulators of NA release

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Uptake of Catecholamines

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Reuptake

Sympathetic nerves take up amines and release them as neurotransmitters Uptake I is a high efficiency system more specific for NA

Uptake 2 is less specific for NA

Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines

Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

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Metabolism of CAs

Mono Amine Oxidase (MAO)

Intracellular bound to mitochondrial membrane Present in NA terminals and liver/ intestine MAO inhibitors are used as antidepressants

Catechol-o-methyl-transferase (COMT)

Neuronal and non-neuronal tissue Acts on catecholamines and byproducts VMA Naghman Zuberi levels are diagnostic for tumours

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Metabolism of CAs

(Homovanillic acid)

(Vanillylmandelic acid)

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Dopamine receptors

D1-receptors are post synaptic receptors located in blood vessels and CNS
D2-receptors are presynaptic present in CNS, ganglia, renal cortex

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Adrenaline as prototype

Potent stimulant of alpha and beta receptors Complex actions on target organs

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Blood Pressure

Most potent vasopressor known Both systolic and Diastolic BP rise Has a characteristic effect on BP Rapid rise to a peak:

+ve ionotropic

Direct myocardial stimulation Increased heart rate

+ve chronotropic Vasoconstriction which leads to increased peripheral resistance Reflex Bradycardia

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Blood Vessels

Seen mainly in the smaller vessels - arterioles Decreased blood flow to skin and mucus membranes alpha effect Increased blood flow to skeletal muscles- (Beta2 effect) counterbalanced by a vasoconstrictor effect of alpha receptors If alpha receptors are blocked there is no opposing effect and this leads to fall of BP
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Heart

Powerful Cardiac stimulant Acts on beta-1 receptors in myocardium, pacemaker cells and conducting tissue

Heart rate increases Rhythm is altered Cardiac systole is shorter and more powerful Cardiac output is enhanced Oxygen consumption is increased Cardiac efficiency is markedly decreased
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Actions of Adrenaline
Respiratory: Powerful bronchodilator Relaxes bronchial smooth muscle Beta-2 mediated effect Physiological antagonist to mediators of bronchoconstriction e.g. Histamine Smooth Muscles: Effects on vascular smooth muscle are important GIT and Urinary tract smooth muscle are relaxed but are clinically unimportant In the pregnant uterus there is inhibition of tone and contractions Naghman Zuberi

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Metabolic effects

Increases concentration of glucose and lactic acid Calorigenesis (-2 and -3) Inhibits insulin secretion (-2) Decreases uptake of glucose by peripheral tissue Simulates glycogenolysis - Beta effect Increases free fatty acid concentration in blood

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ADME

Ineffective orally Absorbed slowly from subcutaneous tissue Faster from IM site Inhalation is locally effective Not usually given IV Rapidly inactivated in Liver by MAO and COMT
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Adrenaline Clinical uses

Injectable preparations are available in dilutions 1:1000, 1:10000 and 1:100000 Usual dose is 0.3-0.5 mg sc of 1: 10000 solution Used in:

Anaphylactic shock Prolong action of local anaesthetics Cardiac arrest Topically, to stop bleeding

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Adverse Drug Reactions

Restlessness, Throbbing headache, Tremor, Palpitations Cerebral hemorrhage, cardiac arrhythmias

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Noradrenaline

Neurotransmitter released from postganglionic adrenergic nerve endings (80%) Orally ineffective and poor SC absorption IV administered Metabolized by MAO, COMT Short duration of action
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Actions and uses

Agonist at 1, 2 and 1 Adrenergic receptors Equipotent on 1, but No effect on 2 Increases systolic, diastolic B.P, mean pressure, pulse pressure and stroke volume Total peripheral resistance (TPR) increases due to vasoconstriction Decreases blood flow to kidney, liver and skeletal muscles Increases coronary blood flow Uses: Injection Noradrenal bitartrate slow IV infusion at the rate of 2-4mg/ minute used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B.P

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Noradrenaline Adverse Drug Reactions

Anxiety, palpitation, respiratory difficulty Rise of B.P, headache Extravasations causes necrosis, gangrene Contracts gravid uterus Severe hypertension, violent headache, photophobia, anginal pain, pallor and sweating in hyperthyroid and hypertensive patients
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Dopamine

Immediate metabolic precursor of Noradrenalin High concentration in basal ganglia, limbic system and hypothalamus Central neurotransmitter, regulates body movements ineffective orally, IV use only, Short T 1/2 (3-5minutes)
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Dopamine

Agonists at dopaminergic D1, D2 receptors Agonist at adrenergic 1 and 1

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Dopamine

In small doses 2-5g/kg/minute, it stimulates D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation

Renal vsoconstriction occurs in CVS shock due to sympathetic overctivity

Increases renal blood flow, GFR an causes natriuresis

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Dopamine

Moderate dose (5-10 g/kg/minute), stimulates 1-receptors in heart producing positive inotropic and chronotropic actions actions Releases Noradrenaline from nerves by 1stimulation Does not change TPR and HR Great Clinical benefit in CVS shock and CCF High dose (10-30 g/kg/minute), stimulates vascular adrenergic 1-receptors vasoconstriction and decreased renal blood flow
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Alpha adrenergic agonists

Selective Alpha-1 Agonists:

Selective Alpha-2 Agonists:

Phenylepherine Methoxamine Metaraminol Mephentermine

Nasal Decongestants:

Clonidine -methyldopa Guanfacine, Guanabenz

Ephederine, Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline an d Tetrahydrazoline

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-2 Adrenergic agonists

Salbutamol Terbutaline Salmeterol Reproterol Oxiprenaline Fenoterol Isoxsuprine Rimiterol Ritodrine Bitolterol Isoetharine
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Phenylepherine

Selective, synthetic and direct 1 agonist Administered parenteraly & topically (eye, nose) Long duration of action Resistant to MAO and COMT Peripheral vasoconstriction leads to rise in BP Reflex bradycardia Produces mydriasis and nasal decongestion Used in hypovolaemic shock as pressor agent Sinusitis & Rhinitis as nasal decongestant Mydriatic in the form of eye drops and lowers intraocular pressure Does not cross BBB, so no CNS effects Actions qualitatively similar to noradrenaline ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity
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Ephedrine

Plant alkaloid, indirect sympathomimetic actions resembling adrenaline peripherally Centrally Increased alertness, anxiety, insomnia, tremor and nausea in adults. Sleepiness in children Effects appear slowly but lasts longer (t1/2-4h) achyphylaxis on repeated dosing Used as bronchodilator, mydriatic, in heart block, mucosal vasoconstriction & in myasthenia gravis. Pseudoephedrine is similar Phenylpropanolamine(PPA) on prolonged administration to woman as anorectic causes pulmonary valve abnormality
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What are Mucosal Decongestants?

Nasal and bronchial decongestants are used in allergic rhinitis, colds, coughs and sinusitis as nasal drops Sympathomimetic vasoconstrictors with - effects are used Mucosal ischaemic damage occurs if used excessively (more often than 3hrly) or for prolonged periods (>3weeks) Rebound congestion leads to overuse Use ephedrine, phenylepherine, xylometazoline for only a few days since longer application reduces ciliary action Do not use Naphazoline and Adrenaline Do not use mixtures of vasoconstrictor, antihistaminic, adrenal steroid & antibiotic Oily drops & sprays may cause lipoid pneumonia They lead to failure of antihypertensive therapy Fatal hypertensive crisis in patients on MAOIs
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Clonidine

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Agonist to postsynaptic 2A adrenoceptors in brain, stimulation suppresses sympathetic outflow and reduces blood pressure High dose activates peripheral presynaptic autoreceptors on adrenergic nerve ending mediating negative feedback suppression of noradrenaline release Overdose stimulates peripheral postsynaptic 1 adrenoceptors & cause hypertension by vasoconstriction Clonidine reduces blood pressure

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Clonidine contd.

Abrupt or gradual withdrawal causes rebound hypertension Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days Never use Clonidine with -adrenoceptor blockers

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Clonidine - ADRs

Sedation, dry mouth TCAs antagonize antihypertensive action & increase rebound hypertension of abrupt withdrawal Low dose Clonidine (50-100g/dl) is used in migraine prophylaxis, menopausal flushing and chorea Moxonidine, Rilmenidine Newer Imidazolines
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2 Adrenergic Agonists
Short acting : Salbutamol, Metaproterenol, Terbutaline, pirbuterol Selective for 2 receptor subtype Used for acute inhalational treatment of bronchospasm. Onset of action within 1 to 5 minutes Bronchodilatation lasts for 2 to 6 hours Duration of action longer on oral administration Directly relax airway smooth muscle Relieve dyspnoea of asthmatic bronchoconstriction Long acting: Salmeterol, Bitolterol, colterol Naghman Zuberi

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Uterine Relaxants

Antioxytocics or tocolytic agents 2 agonists relax uterus Used by i.v. infusion to inhibit premature labour Isoxsuprine, Terbutaline, Ritodrine, Salbutamol Tachycardia & hypotension occur Use minimum fluid volume using 5% dextrose as diluents Ritodrine 50 g/min, increase by 50 g/min every 10 minutes until contractions stop or maternal heart rate is 140 beats/minute. Continue for 12-48 hours after contractions stop

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What to Remember ?

Biosynthesis of Catecholamine Distribution of adrenergic receptors Functions of Adrenergic receptors Pharmacological actions of adrenaline Dopamine/Dobutamine actions Nasal decongestants Tocolytic drugs (Uterine Relaxants)
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Alfa-adrenoblockers

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Phentolamine, tropaphen
are synthetic 1, 2-drenoblockers

administration

diagnostics and symptomatic treatment of feochromocytoma disturbances of peripheral blood circulation in case of endarteriitis, Reinos disease, trophic ulcers, decubitus complex treatment of hypertensive crises, acute cardiac insufficiency complex therapy of hypovolemic and cardiogenic shock

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Prasosin
Selective 1- adrenoblocker

Administration
treatment of arterial hypertension Side effects

phenomenon of first dose: sudden decreasing of blood pressure and even development of orthostatic collapse after first administrations of the drug Prophylaxis: administration of half-dose before sleep
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Beta-adrenoblockers

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How do -blockers work?

Mechanism for How It WorksBeta-blockers "block" the effects of adrenaline on your body's beta-receptors. This slows the nerve impulses that travel through the heart. As a result, your heart does not have to work as hard because it needs less blood and oxygen. This decreases heart rate, blood pressure, and lessens the need for nitrates. Beta-blockers also block the impulses that can cause an arrhythmia (abnormal heart beat). Beta-blockers generally work by affecting the response to some nerve impulses. Your body has 2 main beta-receptors: beta 1 and beta 2. Some beta-blockers are selective, which means that they block beta 1 receptors more than they block beta 2 receptors. Beta 1 receptors are responsible for heart rate and the strength of your heartbeat. Nonselective beta-blockers block both beta 1 and beta 2 receptors. Beta 2 receptors are responsible for the function of your smooth muscles (muscles that control body functions but that you do not have control over). This class of drugs may decrease the sympathetic outflow from the central nervous system and/or suppress the release of renina substance that is elevated in some patients with high blood pressure and is involved in a cascade of events leading to constriction of blood vessels. In addition, some speculate that beta-blockers may have possible antioxidant and cholesterol lowering effects.

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Adrenergic Blockers (antagonists/sympatholytics)

Block alpha & beta receptor sites (nonselective) direct or indirect acting on the release of norepinephrine and epinephrine Uses - Cardiac arrthymias ( HR), HTN ( cardiac output), angina ( O2 demand) Side Effects - CHF, bronchospasm, bradycardia, wheezing
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Nonselective vs Selective Beta blockers

Nonselective have an equal inhibitory effect on B1 & B2 receptors - Drugs have lots of interactions due to lots of alpha/beta receptor sites throughout body - use with caution on clients with cardiac failure or asthma Selective B1 helpful in asthma clients

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Anaprilin
Is a 1- 2-adrenoblocker

Administration
ischemic heart disease arterial hypertension cardiac tachyarrhythmias acute myocardium infarction

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Talinolol or cordanum
is a cardioselective -adrenoblocker

Administration

(extrasystolies, paroxysmal tachycardia, fibrillation and scintillation of atria)

disorders of cardiac rhythm

ischemic heart disease arterial hypertension

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.
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Atenolol (tenormin)
Indications for administration

cardioselelctive -adrenoblocker with long duration of action

ischemic heart disease arterial hypertension cardiac arrhythmias acute myocardium infarction
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Acebutolol (sectral)
1-adrenoblocker with inner sympathomimetic activity

Indications
disorders of cardiac rhythm (tachyarrhythmias) hypertension ischemic heart disease

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Labetolol
-, -adrenoblocker. The drug blocks 1, 2, 1 and 2-adrenoreceptors

Administration
treatment of patients with arterial hypertension hypertensive crisis

Contraindications
Atrio-ventricular blockade, cardiac insufficiency
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CARVEDILOL, NEBIVOLOL
increase the production of Nitric Oxide in blood vessels. They are used now for chronic cardiac insufficiency (congestive heart failure)

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 Nebivolol

Nebilet

Stimulates Nitric OXide synthesis in endothelium

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Sympatholytics

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Reserpine

Adelfan - sidrex Rauwolfia Serpentina

(Reserpine, dihydralazine, hydrochlorothiazide)
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is a sum of Rauvolfia (plant) alkaloids. Maximal hypotensive action develops after 5-7 days of regular administration of the drug. After the treatment coarsed effect can still stay for two weeks.

Reserpin

treatment of different forms of essential hypertension (drugs of a second row, second line) (combined drugs trirezid, cristepin, adelfan, brinerdin)

Administration
Side effects

manifestations of parkinsonism fatigue, somnolence, depression, bradycardia increasing of motor and secretory activity of gastrointestinal tract, acute attacks of ulcer disease, diarrhea swelling of nose mucous membrane with complication of nose breathing

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Octadin
Is a sympatholytic with strong hypotensive effect. During administration of the drug decreasing of blood pressure develops gradually, after 2-3 days. After abolition of drug administration the effect still stays for 2 weeks.

Administration
heavy forms of arterial hypertension

Side effects
general weakness, nausea, vomiting, swelling of nose mucous membrane, diarrhea, liquid retention in the organism, orthostatic collapse
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