ANS Pharmacology - Adrenergic transmission

ADRENERGIC TRANSMISSION

·         Adrenergic transmission is conducted mainly by three closely related catecholamines in different parts of the body.

·         These catecholamine substances are noradrenaline (NA), adrenaline and dopamine.

Noradrenaline (NA) / Norepinehrine (NE)

·         NA is the important neurotransmitter in most sympathetic post-ganglionic nerve fibers (except sweat glands, hair follicles and some blood vessels) and in some parts of CNS.

·         It is responsible for most sympathetic nervous system activities in the body.

·         Neurons that release NA are called adrenergic neurons and the neurotransmission is called adrenergic neurotransmission.

Dopamine

·         It is a major neurotransmitter in the CNS and it has minor role in peripheral nervous system.

Adrenaline

·         It is a major hormone of adrenal medulla.

·         Adrenal medulla does not contain post synaptic neuronal cells but instead secretory chromaffin cells are present, which liberate adrenaline mainly and some NA directly into the blood.

Synthesis, storage, release and fate of catecholamines

Phenylalanine

Phenylalanine hydroxylase (liver)

Tyrosine

                     Tyrosine hydroxylase (cytosol)

Dopa

                     Dopa-decarboxylase (Cytosol)

Dopamine

     Dopamine β – hydroxylase (synaptic vesicle)

Noradrenaline

        Phenylalanine – N – methyltransferase (cytosol

                                                                                                                            in adrenal medulla)

Adrenaline

·         Tyrosine is an essential amino acid synthesized from phenylalanine in the liver.

·         Tyrosine is taken up from circulation by an active transport process (Rate limiting step) into adrenergic neuron and chromaffin cells.

·         Dopamine is taken up by an active process from cytoplasm into storage vesicles.

·         In adrenal medulla, chromaffin cells contain an additional cytoplasmic enzyme which converts most of the noradrenaline into adrenaline. This enzyme is absent in adrenergic nerve terminals, as a result adrenaline is not synthesized in adrenergic nerve fiber.

Storage

·         Noradrenaline is then stored in storage vesicle as a complex of noradrenaline, adenosine triphosphate (ATP), a specific protein chromagranin and some peptides (enkephaline and neuropeptide Y)

Release

·         When nerve impulse arrives at nerve terminal, the noradrenaline is released by the process called exocytosis.

Action and fate

·         Nor adrenaline released from the storage vesicles, diffuse across the junctional cleft and binds to post junctional receptors present on the effector cells or to the prejunctional receptors. This interaction triggers a cascade of events within the effector cell and results in appropriate effector response.

·         After its action noradrenaline is removed from the junctional cleft either by reuptake mechanism or by metabolic degradation.

·         Some also diffuses out of the junctional space and enters general circulation.

Reuptake

·         75 to 90% of noradrenaline released is rapidly taken back into nerve terminal by an active process called uptake I.

·         This uptake is energy dependant and it is against the concentration gradient.

·         There is higher affinity for noradrenaline than adrenaline

·         Up taken noradrenaline is metabolized by monoamine oxidase (MAO) and partly stored in vesicles (reused).

·         Some neurotransmitters are also taken up by non neuronal tissues (Eg: Cardiac muscle, smooth muscles of blood vessels and intestine) by a process called uptake II.

·         This uptake is energy independent and it is along the concentration gradient.

·         Affinity for adrenaline is more when compared to noradrenaline in this reuptake II and rapidly metabolized in the non neuronal tissues by  Catechol – O– Methyl transferase (COMT)

Receptors

·         Two families of membrane bound receptors are

a.       α – Alpha receptors – The subtypes are α₁ and α₂

b.      β – Beta receptors – The subtypes are β₁, β₂, and β₃.

Receptor	Agonists (order of potency) and Effector System	Tissue	Responses
α1	Epi ≥NE >> Iso	Vascular smooth muscle	Contraction
	IP3 , DAG	GU smooth muscle	Contraction
		Liver	Glycogenolysis; gluconeogenesis
		Intestinal smooth muscle	Hyperpolarization and relaxation
α2	Epi ≥ NE >> Iso	Pancreatic islets ( cells)	Decreased insulin secretion
	cAMP ↓	Platelets	Aggregation
		Nerve terminals	Decreased release of NE
		Vascular smooth muscle	Contraction
β1	Iso > Epi = NE	Juxtaglomerular cells	Increased renin secretion
	cAMP ↑	Heart	Increased force and rate of contraction and AV nodal conduction velocity
β2	Iso > Epi >> NE cAMP ↑	Smooth muscle (vascular, bronchial, GI, and GU)	Relaxation
		Skeletal muscle	Glycogenolysis; uptake of K+
		Liver	Glycogenolysis; gluconeogenesis
β3	Iso = NE > Epi	Adipose tissue	Lipolysis
	cAMP ↑

 

ABBREVIATIONS: Epi, epinephrine; NE, norepinephrine; Iso, isoproterenol; GI, gastrointestinal; GU, genitourinary.

Sympathomimetics / Adrenoreceptor agonist

             Adrenergic agonists are drugs which produce actions similar to that of noradrenaline, either by directly interacting with adrenergic receptors or by increasing the availability of noradrenaline at its receptor site.

Classification

I. Direct acting sympathomimetics -   Act directly as agonist of alpha and beta receptors.

1.      Non – Selective adrenergic receptor agonist – Noradrenaline, Adrenaline, Isoprenaline,    

                                                                          Dopamine

2.      Selective adrenergic receptor agonist

a.       α₁ agonist -  Phenylephrine

b.      α₂ agonist – Clonidine, Xylazine

c.       β₁ agonist – Dobutamine

d.      β₂ agonist - Salbutamol, Terbutaline, Clenbuterol, Albuterol

II. Indirect acting sympathomimetics – These drugs increase the availability of norepinephrine 

                                                                          to stimulate adrenergic receptors

1.      By releasing or displacing norepinephrine from sympathetic nerve (e.g., Amphetamine)

2.      By blocking the transport of norepinephrine into sympathetic neurons (e.g., cocaine)

3.      By blocking the metabolizing enzymes, monoamine oxidase (MAO) (e.g., Tranylcypramine, Pargyline) or Catechol-O-methyltransferase (COMT) (e.g., Pyrogallol).

II. Mixed acting sympathomimetics - Drugs that indirectly release norepinephrine and also directly 

                                                                activate receptors are referred to as mixed-acting

                                                                sympathomimetic drugs (e.g., ephedrine, dopamine).

   

Direct acting sympathomimetics

Non – Selective adrenergic receptor agonist

Epinephrine (Adrenaline)

·         It is an endogenous catecholamine and major hormone secreted by the adrenal medulla of most animals. It also occurs commercially.

·         It activates all the subtypes of adrenergic receptors (α₁ and α₂ / β₁, β₂, and β₃)

Cardiac effects

·         Cardiac effects of adrenaline are mediated by direct activation of β₁ receptors in myocardial cells and pacemaker cells in SA node.

·         It is a powerful cardiac stimulant.

·         It increases heart rate, force of contraction and cardiac output but cardiac efficiency (work done relative to oxygen consumption) is reduced.

Vascular smooth muscle effects

·         Depending on the vascular beds both vasoconstriction (α₁) and dilatation (β₂) can occur.

·         Vasoconstriction predominates in cutaneous, mucus membrane, mesenteric and renal beds primarily through α₁ receptors. Thus decreased blood flows to these regions occur.

·         Vasodilatation predominates in skeletal muscles, liver and coronaries primarily through activation of β₂ receptors.

·         But β₂ is more sensitive to adrenaline than α₁ receptors thereby causing an increase in blood flow in therapeutic doses to skeletal muscle. But large doses of adrenaline results in vasoconstriction in skeletal muscle by α₁ mediated action overriding β₂ mediated relaxation.

Blood pressure

·         The effect depends on the dose and rate of administration.

·         On slow intravenous infusion or subcutaneous injection causes reduced peripheral resistance because vascular β₂ receptors are more sensitive than α receptors.

·         Rapid intravenous injection produces marked increase in both systolic and diastolic pressure. At higher concentration α response predominates and vasoconstriction occurs even in skeletal muscles. The blood pressure returns to normal within a few minutes and a secondary fall in mean blood pressure follows. This is because the concentration of adrenaline is reduced due to its rapid uptake and dissipation. Low concentrations are not able to act on α receptors but continue to act on β₂ receptor.

·         When α blocker has been given only fall in blood pressure is seen – Vasomotor reversal of Dale.

Respiratory system

·         Adrenaline is a potent bronchodilator by β₂ action.

·         Adrenaline given by aerosol additionally decongests bronchial mucosa by α action.

Eye

·         Mydriasis occurs due to contraction of radial muscle of iris (α₁ action) but this is minimal after topical application because adrenaline penetrates cornea poorly.

·         The intraoccular pressure tends to fall slightly upon local instillation of adrenaline.

Smooth muscles

·         GI tract – GI smooth muscle is relaxed by adrenaline through activation of both α and β receptors. Gastric juices secretions are decreased but salivary glands are activated in response to sympathetic activity. The saliva produced is scant and viscous.

·         Uterus - The response to uterine smooth muscle varies according to species

Non pregnant                Pregnant

Cat                      Relaxation                 Contraction

Sheep                 Contraction                 Relaxation

Human               Contraction                 Relaxation (at term only)

·         Bladder - Relaxation of detrusor muscle (β₂) and contraction of trigone vesicle (α₁) results in urinary retention.

Metabolic effects

·         Adrenaline has significant hyperglycemic effect by increasing glycogenolysis in liver (β₂ action), increased release of glucagon (β₂ action) and decreased release of insulin (α₂ action)

·         Increase the concentration of free fatty acids in blood by stimulating β₃ receptors.

Other actions

·         Spleen – contraction (α₁ receptor)

·         Contraction of piloerector muscle, hair becomes erect. Noticed in animals during fear.

·         Facilitates neuromuscular transmission.

·         Poorly penetrates blood brain barrier and little CNS effects.

Clinical uses

·         Used in the treatment of cardiac arrest, cardiac insufficiency and hypotension associated with anaphylactic shock.

·         Used with local anaesthetics to cause vasoconstriction (to retard systemic circulation)

Norepinehrine

·         It is an endogenous catecholamine neurotransmitter released by postganglionic sympathetic neurons.

·         Limited stimulation of β₂ receptors, therefore no bronchial smooth muscle relaxation.

·         Stimulates only α and β₁ receptors.

·         Only vasoconstriction noticed and the blood pressure rises (α receptor).

·         When blood pressure rises markedly, reflex bradicardia occurs.

·         Limited metabolic responses.

·         Less potent than adrenaline

·         Rarely used therapeutically.

Dopamine

·         It is an endogenous catecholamine.

·         It is a dopamine receptor (D₁ and D₂) and adrenergic receptor (α and β₁) agonist. It also indirectly induces the release of noradrenaline.

·         Very sensitive to dopaminergic receptor – Renal vessels dilates and urinary output increases.

·         Have positive inotropic effect by acting through β₁ receptors.

·         Vasoconstriction noticed only at high concentration.

Clinical use

·         Cardiogenic shock, severe Congestive heart failure (CHF), renal failure and oliguria.

Isoprenaline or Isoproterenol

·         It is a direct acting synthetic catecholamine.

·         Predominantly stimulates β₁ and β₂ receptors and no appreciable α activity at therapeutic dose.

·         It produces positive inotropic and chronotropic action. However, because of β₂ stimulation, total peripheral resistance decreases and blood pressure decreases. It was used as antihypertensive but not used now because of cardiac effects.

·         It relaxes bronchial smooth muscles by acting through β₂ receptors. It relieves bronchoconstriction from allergies, drugs or asthma. But now not used clinically because of its effect on heart (tachycardia).

Selective adrenergic receptor agonist

Selective α₁ adrenergic receptor agonist

Phenylephrine

·         Powerful α₁ adrenergic receptor agonist

·         Causes vasoconstriction and increase in blood pressure, which results in reflex bradicardia

·         It reduces intraocular pressure and produces mydriasis.

Clinical use

·         Used as mydriatic in dogs

·         Occasionally used as nasal decongestant.

Selective α₂ adrenergic receptor agonist

Clonidine

·         Predominantly utilized in human beings with hypertension and tachycardia

·         Limited therapeutic use in Veterinary medicine.

·         Rapid intravascular injection of clonidine raises blood pressure transiently due to activation of post junctional α₂ adrenoreceptor in peripheral vascular smooth muscles. This effect is followed by a more prolonged hypotensive response mediated through activation of α₂ receptor in the lower brain stem that causes decrease in central sympathetic outflow.

Xylazine

·         It has sedative action by acting on the α₂ receptors in the brain and decrease the sympathetic outflow.

·         It has analgesic and muscle relaxant property.

·         Mainly used as a sedative.

·         Other drugs – Detomidine and Medetomidine.

Selective β₁ adrenergic receptor agonist

Dobutamine

·         It enhances cardiac contractility and cardiac output without significant change in heart rate, peripheral resistance and blood pressure.

·         Dobutamine is more effective positive inotropic agent than dopamine although it does not dilate renal vascular beds.

·         Primarily used as an inotropic agent for short term treatment of severe congestive heart failure / heart failure.

Selective β₂ adrenergic receptor agonist

·         Salbutamol, Clenbuterol, Terbutaline, Albuterol, Metaproterenol, Ritodine and Isoxsuprine.

·         They relax smooth muscles of bronchi and uterus and blood vessels of skeletal muscles (β₂) without affecting the heart (β₁ action).

·         Used as bronchodilators in asthma.

·         It can be administered through intravenous or inhalation route.

·         It has long duration of action and no CNS stimulation.

·         Used as uterine relaxant to delay premature labour. Eg; Ritodine and Isoxsuprine

·         In addition to β₂ adrenoreceptor sitmulation, some of these drugs may also suppress the release of leukotrienes and histamine from mast cells in the lung tissue. It also enhances mucociliary function and decrease microvascular permeability

·         Long term use of β₂ adrenergic receptor agonist may result in down regulation of β₂ adrenergic receptor in some tissues and subsequent decreased pharmacological response noticed.

Indirect acting sympathomimetics

·         These drugs increase release of noradrenaline from sympathetic neurons or block reuptake of released noradrenaline.

Amphetamine

·         It is a synthetic sympathomimetic compound that has powerful CNS stimulant action, in addition to peripheral α and β adrenergic actions (No activation of β₂ receptors).

·         Due to its structural resemblance to NA, amphetamine on its administration is transported into adrenergic nerve terminal by uptake I mechanism.

·         Inside the nerve terminal, it displaces NA from storage vesicles into the cytosol. In the cytosol, some of the NA is metabolized by intraneuronal MAO while rest escapes by carrier mediated diffusion into junctional cleft to act on adrenergic receptors.

·         Has minimal peripheral sympathetic effects.

·         Central action due to release and blockage of reuptake of dopamime in limbic regions of brain.

·         Rarely used therapeutically for CNS stimulant action.

Ephedrine

·         Chemically related to adrenaline

·         Ephedrine is not a substrate for COMT and MAO; hence it has long duration of action.

·         It stimulates a mainly β₂   receptors and also it stimulates α and β₁ receptors.

·         Occasionally used to treat mild cases of asthma and also as decongestant.

·         As it lacks selectivity and has low efficacy it is not widely used therapeutically.

Pseudoephedrine and Phenylpropanolamine

·         It is a stereoisomer of ephedrine and stimulates release of NA.

·         Has fewer CNS and cardiac effects and is also a poor bronchodilator.

·         Used orally as a decongestant to provide symptomatic relief in upper respiratory tract problems associated with profuse secretions. Used for symptomatic relief of hay fever and rhinitis.

·         Prolonged use or excessive dosing frequency can deplete NA from its storage site causing tachyphylaxis.

Clinical uses of adrenergic agonist

Pressor agent                           – NA, Phenylephrine, Ephedrine

Cardiac stiumulants                – Adrenaline, Isoprenaline, Dobutamine

Bronchodilators                      – Isoprenaline, Salbutamol, Terbutaline

Nasal decongestants               – Pseudoephedrine, Phenylpropanolamine, phenylephrine

CNS stimulants                       – Amphetamine, Methamphetamine

Uterine relaxant                      – Ritodine, Isoxuperine.

Glaucoma                                - Phenylephrine

Sympatholytics / Antiadrenergic drugs

·         Drugs that decrease the sympathetic neuronal activity.

Classification

I. Indirect acting - Drugs that interfere with sympathetic neuronal function by inhibiting

    a. Synthesis of NA

    b. Storage of NA

    c. Release of NA

II. Direct acting - These drugs are adrenergic receptors antagonist. These drugs are classified into,

a.       Non - Selective adrenergic receptor antagonist – α blockers and β blockers

b.      Selective adrenergic receptor antagonist – α₁ and α₂ blockers

                                                  β₁ and β₂ blockers

Indirect acting sympatholytics

Drugs interfere with the synthesis of NA

α –Methyl tyrosine

·         It is the structural analogue of tyrosine, the precursor of NA. On administration it is taken up by adrenergic neurons and adrenal medulla where it blocks the enzyme tyrosine hydroxylase. This results in depletion of catecholamines (NA, Adrenaline and Dopamine) both peripherally and centrally.

·         Used in the treatment of pheochromocytoma as an adjunct to phenoxybenzamine and other adrenoreceptor blockers.

Carbidopa

·         It inhibits dopa decarboxylase activity and inhibits the synthesis of NA and dopamine.

·         Acts only peripherally and not centrally as it cannot cross blood brain barrier.

·         It is used to decrease the side effects (motor symptoms) due to dopamine formation in peripheral tissues of patients with Parkinson’s disease treated with L-dopa.

α –methyl dopa

·         It is an analogue of L- dopa, precursor of dopamine and NA.

·         On administration it is taken up by adrenergic neurons and false neurotransmitter (α –methyl noradrenaline) is produced. α –methyl noradrenaline is a potent agonist of α₂ adrenergic receptor located presynaptically which leads to decreased sympathetic out flow from the brain.

·         It decreases total peripheral resistance and decrease blood pressure.

Drugs interfere with storage of NA

Reserpine

·         Reserpine is obtained from the plant Rauwolfia serpentina (Indian snake root), the first drug found to interfere with the sympathetic nervous system.

·         It blocks the transport of NA and other biogenic amines into storage vesicles, by binding to transport protein.

·         The NA accumulates instead in the cytoplasm, where it is degraded by MAO enzyme.

·         Effects are decreased peripheral resistance, cardiac output and blood pressure

·         It has long duration of action and not widely used. Rarely used in low doses with diuretics to treat mild hypertension.

·         Occasionally used as experimental tool to study effects of drugs on adrenergic nerve terminal.

Drugs interfere with release of NA

Guanethidine

·         On administration it is taken up by uptake I into peripheral adrenergic neurons. It acts by blocking nerve impulse coupled release of stored NA.

·         It decreases sympathetic tone to all organs.

·         The side effects are decreased blood pressure, cardiac output, heart rate and postural hypotension. Also increases gut motility and nasal stuffiness.

·         Because of side effects, only used for moderate to severe hypertension in humans and not used in veterinary medicine.

(Postural / orthostatic hypotension – It is fall in blood pressure associated with dizziness, syncope and blurred vision occurring upon standing.)

Bretylium

·         Accumulates in sympathetic neurons and release NE.

·         In addition to adrenergic neuron blocking effects, bretylium has effect on potassium channels in heart and has antiarrythmic effect. 

·         Currently it is used exclusively as an alternative drug for emerging control of serious ventricular arrhythmias.

Direct acting Sympatholytics

α - receptor blocking drugs

General Pharmacological effects of α - receptor blockade

·         α₁ - receptor blockade causes vasodilation and it results in decreased peripheral resistance and blood pressure.

·         Fall in blood pressure results in postural hypotension and reflex tachycardia

·         α₂ blockade enhance this reflex tachycardia because the inhibitory effect on NE release is blocked. Therefore more NE is released to stimulate the β₁receptors in heart.

·         Nasal stuffiness and miosis noticed.

·         Intestinal motility increased, which results in diarrhea.

·         Smooth muscle tone in bladder trigone and sphincter decreased which results in increased urine flow.

Classification

1.      Non selective α blockers: Phenoxybenzamine, Phentolamine

2.      Selective β blockers:

a.       α ₁ blockers – Prazosin

b.      α ₂ blockers – Yohimbine, Atipamizole

Phenoxybenzamine

·         It irreversibly blocks α₁ and α₂ receptor by binding covalently to the receptor.

·         It causes postural hypotension and tachycardia and it also acts centrally to cause nausea, vomiting, sedation and weakness.

·         Used to diagnose and treat pheochromocytoma(Tumor of adrenal gland which secretes norepinephrine and epinephrine)

Phentolamine

·         It is a potent competitive reversible α₁ and α₂ receptor blocker.

·         It causes postural hypotension and tachycardia

·         Major clinical use is in the treatment of pheochromocytoma and used to treat episodes that occur during surgical removal of this tumor.

Ergot alkaloids

·         Ergot alkaloids were the first adrenergic blocking drugs to be discovered and with which Dale demonstrated the vasomotor reversal phenomenon. Ergot is a fungus (Claviceps purpurea) contains 12 alkaloids (6 isomeric pairs) like Ergotamine and Ergocryptine.

·         Cause direct peripheral vasoconstriction which persist for a fairly long time. Still larger doses cause intense and persistent peripheral vasoconstriction leading to stasis of blood, thrombosis, obliterative endarteritis causing gangrene and sloughing of extremities (ergotism).

·         Not used clinically due to their non specific action on a variety of organs.

·         Primarily used to stimulate postpartum uterine contraction and to relive pain of migrane in humans.

·         Contraindicated in pregnancy and hypertension.

Selective α₁ blockers

Prazosin

·         Potent selective α₁ receptor antagonist (Reversible).

·         It causes dilatation of both arterial (more prominent) and veins.

·         It causes less tachycardia because α₂ receptors are not blocked.

·         Effective in management of chronic hypertension.

·         In Veterinary practice, it is occasionally used for therapy of CHF (Chronic Heart Failure).

·         Terazosin, Doxazosin and Trimazosine are newer selective α₁ antagonist used primarily in human medicine.

Selective α₂ blockers

Yohimbine

·         It is used in animals primarily to reverse the effects of xylazine overdosage.

·         Used as an antitode for Amitraz insecticide poisoning.

Atipamezole

·         It is used for the reversal of medetomidine, Xylazine and amitraz poisoning.

β - receptor blocking drugs

·         These drugs inhibit adrenergic responses mediated through β receptor.

·         All β blockers are competitive antagonists.

Classification

1.      Non selective β blockers: Propranolol, Pindolol, Timolol

2.      Selective β blockers:

a.       β₁ blockers – Atenolol, Metoprolol, Esmolol, Acebutolol

b.      β₂ blockers – Butoxamine

Propranolol

·         It is a prototype of β blocking drug and a potent reversible β₁ and β₂ receptor blocker.

·         In addition it has powerful local anaesthetic action and also antiarrythmic action.

·         It decreases heart rate, force of contraction and cardiac output.

·         Cardiac automaticity is suppressed. At higher dose, a direct depressant and membrane stabilizing effect is also exerted on myocardium.

·         Blockade of β₂ receptor results in higher total peripheral resistance.

·         No effect on blood pressure on short term administration.

·         But on prolonged administration, blood pressure gradually falls in hypertensive but not in normotesive patients. This is due to

1.               Inhibition of rennin form JG cells of kidney which is stimulated by β agonist   

           (Renin angiotensin system is inhibited)

2.               Block β₁ receptor – Bradicadia

3.               Inhibition of prejunctional β₂  receptor causes reduced NE release

4.               Central action reduces sympathetic outflow from CNS.

·         In respiratory tract increases airway resistance due to bronchoconstriction. This is more marked in patients with asthma.

·         Blocks lipolysis and glycogenolysis.

·         It increases uterine activity, decrease aqueous humor formation and decrease platelet aggregation.

Side effects

·         Few in normal individuals but occur in disease states.

·         Diabetes – Blocks metabolic effects of β₂ receptor i.e., inhibits lipolysis, glycogenolysis and increase insulin secretion which results in hypoglycemia.

·         Contraindicated in patients with asthma, bradicardia, partial heart block and congestive heart failure.

·         Withdrawal symptoms – Rebound hypertension, angina, even sudden death.

Timolol

·         It is a non selective β blocker used orally for hypertension, angina and in prophylaxis of myocardial infarction.

·         Used topically for the treatment of glaucoma.

Pindolol

·         Used primarily as antihypertensive and in patients who develop marked bradicardia with propranolol

·         Chances of rebound hypertension on withdrawal are also less.

Selective β blockers

·         β₁ blockers – Atenolol, Metoprolol, Esmolol, Acebutolol

·         It is less likely to increase the bronchoconstriction in patients with asthma

·         Useful in treatment of hypertension and angina.

·         Longer duration of action – once daily dose is often sufficient.

·         Preferred in diabetics receiving insulin or oral hypoglycemic.

·         Atenolol – has no deleterious effect on lipid profile and one of the most commonly used β blocker for hypertension and angina

Clinical uses of β blockers

·         Hypertesion

·         Angina

·         Cardiac arrhythmias

·         Prophylaxis in myocardial infarction

·         Glaucoma – Timolol.

α + β blocker - Labetalol

·         First adrenergic antagonist capable of blocking both α  and β receptors.

·         Use in pheochormocytoma

·         Most important side effect is postural hypotension but significant only in some patients.

β₁ + β₂ + α₁ blocker - Carvedilol – Used in hypertension.