the autonomic nervous system israa omar. autonomic drugs autonomic drugs : drugs that produce their...

The Autonomic Nervous System

ISRAA OMAR

Autonomic drugs

• Autonomic drugs : Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the autonomic nervous system .

• The autonomic nervous system is composed of efferent neurons

• These innervate smooth muscle, cardiac muscle and the exocrine glands, thereby controlling digestion, cardiac output, blood flow, and glandular secretions.

Activity of the Sympathetic Nervous System

• Prepares body for physical action• Fight or Flight– Increased heart rate– Increased blood pressure–Redistribution of blood flow - ↑ flow to

skeletal muscle, ↓ flow to skin and organs–↓ GI activity–Dilation of pupils and bronchioles–↑ blood glucose

Activity of the Parasympathetic Nervous System

• Opposite effects to SNS• Prepares the body for feeding and digestion– Slows heart rate– Lowers blood pressure–Promotes GI secretions– Stimulates GI movement–Constricts the pupil– Empties bladder and rectum

In general, the parasympathetic division and the sympathetic division of the ANS are antagonistic in their effects on organ systems.

The enteric division of the ANS

• It is a very large and highly organized collection of neurons located in the walls of the gastrointestinal (GI) system.

• It regulates and coordinates the motor activity and secretory functions of the GI system.

Anatomy of the ANSAfferent nerve fibers (sensory nerves): Non-myelinated; information is carried to the CNS by the

vagus, pelvic, splanchnic and somatic nerves.

Efferent nerve fibers (motor nerves):a) Sympathetic division

Thoracolumbar divisionb) Parasympathetic division

Craniosacral division

Consists of 2 neurons arranged in series: Preganglionic nerve fiber Postganglionic nerve fiber

Adrenal Medulla is the exception to the 2 neuron arrangement (a modified ganglion that mainly secretes adrenaline hormone)

The Peripheral Nervous System

PRE-GANGLIONICPRE-GANGLIONIC

GANGLIAGANGLIA

POST-GANGLIONICPOST-GANGLIONIC

Cholinergic Agonists The cholinergic drugs act on receptors that are

activated by acetylcholine. • Location of cholinergic neurons (releases Ach): 1 - preganglionic fibers terminating in the adrenal

medulla, 2- preganglionic fibers terminating in autonomic

ganglia (both parasympathetic and sympathetic), 3- the postganglionic fibers of the parasympathetic

division .

4- cholinergic neurons innervate the muscles of the somatic nervous system

5- also found in the central nervous system (CNS).

Neurotransmission at cholinergic neurons

Involves sequential six steps. • The first four steps: synthesis, storage,

release, and binding of acetylcholine to a receptor

• fifth step, degradation of the neurotransmitter in the synaptic gap by acetylcholinesterase enzyme to choline and acetic acid.

• and the sixth step, the reuptake of choline by the cholinergic neurons for synthesis of new ACh.

Synthesis of acetylcholine

• Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form acetylcholine.

choline + acetyl coenzyme A (CoA) ↓ Choline acetyltransferase acetylcholine

Release of acetylcholine:

• When an action potential arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium.

• Elevated calcium levels promote the release of acetylcholine into the synaptic space.

• This release can be blocked by botulinum toxin.

Cholinergic Receptors (Cholinoceptors)

• The postsynaptic cholinergic receptors on the surface of the effector organs are divided into two classes muscarinic and nicotinic.

Muscarinic receptors

• There are five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5;

• Only M1, M2 and M3, receptors have been functionally characterized.

Mechanisms of acetylcholine signal transduction

• Activation of the M1 or M3 receptors: the receptor undergoes a conformational change and interacts with Gq protein, which in turn activates phospholipase C. This leads to an increase in intracellular Ca2+.

• Ca2+ can then interact to produce the response (e.g. Secretion, contraction, etc.)

• Activation of M2 subtype on the cardiac muscle stimulates Gi protein,

• Gi protein inhibits adenylyl cyclase and increases K+ conductance, to which the heart responds with a decrease in rate and force of contraction.

Selective Muscarinic antagonists:

• Pirenzepine, a tricyclic anticholinergic drug, selective M1 muscarinic receptor antagonist (such as those of the gastric mucosa).

• Darifenacin is a competitive muscarinic receptor antagonist at M3 receptor. The drug is used in the treatment of overactive bladder.

Nicotinic receptors

• The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel.

• Binding of two acetylcholine molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell.

• Nicotine (or high doses of acetylcholine) initially stimulates and then blocks the receptor.

• Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction.

• The nicotinic receptors of autonomic ganglia ( called nicotinic neuronal ) differ from those of the neuromuscular junction (which are called nicotinic muscular) .

I. Direct-Acting Cholinergic Agonists

• Cholinergic agonists (also known as parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors.

• Classified into two groups: 1) Choline esters, which include acetylcholine and

synthetic esters of choline, such as carbachol and bethanechol.

2) Naturally occurring alkaloids, such as pilocarpine constitue the second group .

• All direct-acting drugs have longer durations of action than acetylcholine.

• Drugs (e.g. pilocarpine and bethanechol) which bind to muscarinic receptors are also referred to as muscarinic agents.

1. Acetylcholine

• Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes.

• It is not useful therapeutically because of its multiplicity of actions and its rapid inactivation by the cholinesterases (unstable).

Major Actions of Acetylcholine

• Acetylcholine has both muscarinic and nicotinic activity. Its actions include:

1.CVS: –Decrease in heart rate (negative

chronotropic effect) and cardiac output– The actions of acetylcholine on the heart

mimic the effects of vagus nerve stimulation.

• Decrease in blood pressure: –Acetylcholine activates M3 receptors found

on endothelial cells lining the smooth muscles of blood vessels. This results in the production of nitric oxide from arginine.– [Note: nitric oxide is also known as

endothelium-derived relaxing factor and is a vasodilator]

2. Other actions:– In the gastrointestinal tract, acetylcholine

increases salivary secretion and stimulates intestinal secretions and motility. –Bronchiolar secretions are also enhanced. – In the genitourinary tract, the tone of the

detrusor urinae muscle is increased, causing expulsion of urine.

– In the eye, acetylcholine is involved in stimulating ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle (circular muscle), causing miosis (marked constriction of the pupil).

2. Bethanechol

• Bethanechol is not hydrolyzed by acetylcholinesterase

• It posses strong muscarinic activity, but lacks nicotinic activity.

• It is used to treat urinary retention. as well as megacolon.

• Adverse effects: sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.

3. Carbachol • Carbachol has both muscarinic as well as

nicotinic actions . • Is a poor substrate for acetylcholinesterase• Therapeutic uses: carbachol is rarely used

therapeutically except in the eye as a miotic agent to treat glaucoma by causing pupillary constriction and a decrease in intraocular pressure.

4. Pilocarpine

• The alkaloid pilocarpine is a tertiary amine and is stable to hydrolysis by acetylcholinesterase .

• Pilocarpine is the drug of choice in both narrow-angle (also called closed-angle) and wide-angle (also called open-angle) glaucoma.

II. Indirect-Acting Cholinergic Agonsists(Anticholinesterases)

• These drugs can provoke a response at all cholinoceptors in the body, including:

- both muscarinic and nicotinic receptors of the autonomic nervous system,

- nicotinic receptors of skeletal muscle - and muscarinic and nicotinic receptors in the

brain.

A. Reversible anticholinesterases 1. Physostigmine

- Used in treatment of atony of intestine and bladder as it increases motility of either organ.

- It is used to treat glaucoma - Used in the treatment of overdoses of drugs

with anticholinergic actions, such as atropine, phenothiazines, and tricyclic antidepressants.

• Adverse effects (shown by high doses): - Convulsions .- Bradycardia and a fall in cardiac output - Accumulation of acetylcholine and,

ultimately, paralysis of skeletal muscle.

2. Neostigmine

• Similar actions to that of physostigmine.• Unlike physostigmine, neostigmine has a

quaternary nitrogen; hence, it is more polar and does not enter the CNS.

• Neostigmine is used to stimulate the bladder and GI tract, and it is also used as an antidote for tubocurarine

• Also used in symptomatic treatment of myasthenia gravis ( an autoimmune disease caused by antibodies to the nicotinic receptor at neuromuscular junctions. This causes their degradation and, thus, makes fewer receptors available )

• Adverse effects include salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.

3. Pyridostigmine and ambenomium

• Cholinesterase inhibitors that are used in the chronic management of myasthenia gravis.

• Their durations of action are longer than that of neostigmine.

• Adverse effects of these agents are similar to those of neostigmine.

4. Demecarium

• Cholinesterase inhibitor used to treat chronic open-angle glaucoma (primarily in patients refractory to other agents) and closed-angle glaucoma after irredectomy.

• Mechanism of actions and side effects are similar to those of neostigmine.

5. Edrophonium

• Prototype short-acting agent (duration of action is 10 to 20 minutes).

• The actions are similar to those of neostigmine, except that it is more rapidly absorbed and has a short duration of action

• Edrophonium is used in the diagnosis of myasthenia gravis. Intravenous injection of edrophonium leads to a rapid increase in muscle strength.

6. Other reversible anticholinesterases

Tacrine, donepezil, rivastigmine, and galantamine

• Are useful in patients with Alzheimer's disease ( they have a deficiency of cholinergic neurons in the CNS). Gastrointestinal distress is their primary adverse effect.

B. Irreversible Anticholinesterases

• Some synthetic organophosphate compounds have the capacity to bind covalently to acetylcholinesterase. The result is a long-lasting increase in acetylcholine at all sites where it is released.

• Many of these drugs are extremely toxic and were developed by the military as nerve gases (sarin, soman, tabun).

• Related compounds, such as parathion, are employed as insecticides.

1. irreversible anticholinesterases Echothiophate

• Echothiophate is an organophosphate.• It is an irreversible anticholinesterase• The enzyme becomes permanently inactivated,

and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules.

• Echothiophate is used in treatment of open-angle glaucoma..

• Atropine in high dosage can reverse many of the muscarinic and some of the central effects of echothiophate.

• Pralidoxime can reactivate inhibited acetylcholinesterase enzyme.

2. Other irreversible anticholinesterases

• Nerve gases: sarin, soman, tabun These are organophosphorus compounds Used as chemical warfare• Malathion and ParathionThese are organophosphorus compounds Used as insecticides• Toxic effects could be treated with immediate

administration of pralidoxime and atropine

Cholinergic Antagonists

• The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to cholinoceptors. Include:

• Antimuscarinic Agents: block muscarinic synapses of the parasympathetic nerves.

• The ganglionic blockers, which block the nicotinic receptors of the sympathetic and parasympathetic ganglia.

• The skeletal neuromuscular blocking agents

A. Antimuscarinic Agents

• Antimuscarinic drugs have little or no action at skeletal neuromuscular junctions or autonomic ganglia.

1. Atropine

• Atropine, a tertiary amine belladonna alkaloid, that binds competitively to muscarinic receptors , preventing acetylcholine from binding to those sites.

• Atropine acts both centrally and peripherally.

Pharmacological action: •Eye: – persistent mydriasis and cycloplegia (inability to

focus for near vision).– In patients with narrow-angle glaucoma intraocular

pressure may rise dangerously.•Gastrointestinal (GI): – antispasmodic, gastric motility is reduced but

hydrochloric acid production is not significantly affected.

•Urinary system: – reduces hypermotility states of the urinary bladder.

• Cardiovacular:–With higher doses of atropine, the M2 receptors

on the sinoatrial node are blocked, and the cardiac rate increases (tachycardia).

• Secretions: –Atropine blocks the salivary glands, producing a

drying effect on the oral mucous membranes (xerostomia). – Sweat and lacrimal glands are also affected.

[Note: Inhibition of secretions by sweat glands can cause elevated body temperature.]

Therapeutic uses of atropine•Ophthalmic: for eye examination. Atropine may induce an acute attack of eye pain due to sudden increases in eye pressure in individuals with narrow-angle glaucoma.•Antispasmodic: to relax the GI tract and bladder.•for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning (muscarine poisoning). •As preanesthetic medication to block secretions in the upper and lower respiratory tracts prior to surgery.

Pharmacokinetics: •Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in the urine. It has a half-life of about 4 hours.Adverse effects: •dry mouth, blurred vision, tachycardia, and constipation. •Effects on the CNS include restlessness, confusion, hallucinations, and deliriumContraindications: •In older individuals, the use of atropine may exacerbate an attack of glaucoma and / or urinary retention.

2. Scopolamine

• Tertiary amine belladonna alkaloid, • Used prophylactically for treatment of

motion sickness. • Produces sedation (atropine causes

excitation). • Scopolamine may produce euphoria and is

subject to abuse.

3. Ipratropium

• Inhaled ipratropium, a quaternary derivative of atropine, is useful in treating asthma.

• Ipratropium is also useful in chronic obstructive pulmonary disease(COPD).

4. Tropicamide and cyclopentolate

• Used as ophthalmic solutions as mydriatics. • Their duration of action is shorter than that of

atropine.

B. Ganglionic Blockers

• Ganglionic blockers act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.

• These drugs are not effective as neuromuscular blockers

1. Nicotine• A component of cigarette smoke and a poison

with many undesirable actions. • Nicotine is available as patches, lozenges,

gums, and other forms. • The drug is effective in reducing the craving

for nicotine in people who wish to stop smoking.

Pharmacological action•Nicotine initially stimulates, then blocks all sympathetic and parasympathetic ganglia.• The stimulatory effects include increased blood pressure and cardiac rate (due to release of noradrenaline from adrenergic terminals and adrenaline hormone from the adrenal medulla) •Nicotine causes increased peristalsis and secretions

2. Mecamylamine and trimethaphan

• These are ganglion blockers.• They are used to lower blood pressure in

emergency situations.

Drugs affecting the sympathetic nervous system

• Drugs that act directly on the adrenergic receptor (adrenoceptor) and activate them are said to be sympathomimetics.

• Blockers of adrenoceptors are called sympatholytics

• There are drugs which affect presynaptic adrenergic function.

Adrenergic neurons

• Adrenergic neurons synthesize, store and release norepinephrine (noradrenalin).

• Adrenergic neurons are found in the sympathetic nervous system (postganglionic sympathetic neurons) and in the central nervous system (CNS).

Neurotransmission at adrenergic neurons

• The process involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic cleft.

Synthesis of norepinephrine• Tyrosine is transported into the axoplasm of the adrenergic

neuron, where it is hydroxylated to DOPA by tyrosine hydroxylase.

• This is the rate-limiting step in the formation of norepinephrine. • DOPA is then decarboxylated by dopa decarboxylase to form

dopamine.• Dopamine is hydroxylated to form norepinephrine by the

enzyme, dopamine β-hydroxylase. • In the adrenal medulla, norepinephrine is methylated to yield

epinephrine (adrenaline).

Binding with adrenoceptors

• Binding of norepinephrine to the membrane receptors triggers a cascade of events, resulting in the formation of intracellular second messengers.

• Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system, and the phosphatidylinositol cycle, to transduce the signal into an effect.

Termination of norepinephrine actionsNorepinephrine may 1.Diffuse out of the synaptic space and enter the general circulation, 2.Be metabolized by catechol o-methyltransferase (COMT) in the synaptic space, 3.Be recaptured by an uptake system that pumps the norepinephrine back into the neuron. Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine's effects.

Fate of reuptaken norepinephrine

• Norepinephrine may be released by another action potential, or it may stored,

• Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria.

Adrenergic receptors (adrenoceptors)

• Adrenoceptors are designated α and β.

• For α receptors, the rank order of potency is epinephrine >norepinephrine >> isoproterenol (isoprenaline).

• For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine.

α adrenoceptors• The α adrenoceptors are subdivided into two

subgroups, α1 and α2

α1 Receptors: • Found on the postsynaptic membrane of the effector

organs .• Activation of α1 receptors initiates a series of

reactions through a G protein resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol.

• IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell.

• The α 1 receptors are further divided into α 1A, α 1B, α 1C, and α 1D

α2 Receptors:

•are located primarily on presynaptic nerve endings.• The stimulation of α2 receptor causes inhibition of further release of norepinephrine.• α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine can diffuse and interact with these receptors, inhibiting acetylcholine release. • The effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular c-AMP.• α 2 receptors are further divided into α 2A, α 2B, α 2C, and α

2D.

Tamsulosin– is a selective α 1A antagonist – is used to treat benign prostate hyperplasia.

The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland.

2. β-adrenoceptors• The β-adrenoceptors can be subdivided into

three major subgroups, β1, β2, and β3,. β1 Receptors :• have approximately equal affinities for

epinephrine and norepinephrine (mainly found in the heart)

β2 receptors • have a higher affinity for epinephrine than for

norepinephrine (mainly found in the bronchioles)β3 receptors • are involved in lipolysis.

• Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell.

Distribution of receptors

• Tissues such as the vasculature & skeletal muscle have both β1 and β2 receptors, but the β2 receptors predominate.

• The heart contains predominantly β1 receptors.

Effects mediated by the adrenoceptors

• Stimulation of β1 receptors characteristically causes cardiac stimulation,

• Stimulation of β2 receptors produces vasodilatation (in skeletal vascular beds) and bronchiolar relaxation.

• Desensitization of receptors: Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization.

Catecholamines• Sympathomimetic amines that contain the 3,4-

dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines.

• These compounds share the following properties:–High potency–Rapid inactivation: by COMT and by MAO . –Poor penetration into the CNS because they

are polar

Adrenergic agonists

• Classification of the adrenergic agonists• Direct-acting agonists include: – epinephrine, norepinephrine, isoproterenol, and

phenylephrine.• Indirect-acting agonists include – amphetamine, cocaine and tyramine.

• Mixed-action agonists include – ephedrine, pseudoephedrine and metaraminol,

may act directly and indirectly.

A. Direct-Acting Adrenergic Agonists

1. Epinephrine• Is a catecholamine.• Interacts with both α and β receptors. At low

doses, β effects (vasodilatation) predominate, whereas at high doses, α effects (vasoconstriction) are strongest.

Pharmacological effects•Epinephrine strengthens the contractility of the myocardium (positive inotropic: β1 action) and increases the heart rate (positive chronotropic: β1 action). •Epinephrine increases systolic blood pressure, coupled with a slight decrease in diastolic pressure.•Epinephrine causes powerful bronchodilation (β2 action).

• Epinephrine inhibits the release of allergy mediators such as histamines from mast cells.

• Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect).

• Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue

Metabolism of Epinephrine

• Epinephrine is metabolized by two enzymatic pathways: MAO, and COMT.

• The final metabolites found in the urine are metanephrine and vanillylmandelic acid.

Therapeutic uses– Treatment of acute asthma and anaphylactic shock,

epinephrine is the drug of choice;. – Glaucoma: in open-angle glaucoma. It reduces the

production of aqueous humor. – Cardiac arrest: Epinephrine may be used to restore

cardiac rhythm.– Anesthetics: Local anesthetic solutions usually contain

1:100,000 parts epinephrine. The effect of the drug is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the site of injection.

Adverse effects

• CNS disturbances: include anxiety, fear, tension, headache, and tremor.

• Cerebral hemorrhage: as a result of a marked elevation of blood pressure.

• Cardiac arrhythmias• Pulmonary edema.

Interactions:

• Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in patients with hyperthyroidism.

• Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions.

• Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased.

2. Norepinephrine• Cardiovascular actions:–Vasoconstriction: Both systolic and

diastolic blood pressures increase• Norepinephrine is used to treat shock,

because it increases vascular resistance and, therefore, increases blood pressure. However, metaraminol is favored.

3. Isoproterenol

• Isoproterenol is a direct-acting synthetic catecholamine that predominantly stimulates both β1- and β2-adrenergic receptors

Therapeutic uses:• It can be employed to stimulate the heart in

emergency situations.

4. Dobutamine

• Dobutamine is a synthetic, selective β1 agonist.

• Dobutamine is used to increase cardiac output in congestive heart failure.

5. Oxymetazoline

• Oxymetazoline is a direct-acting synthetic adrenergic agonist that stimulates both α1- and α2-adrenergic receptors.

6. Phenylephrine

• Phenylephrine is a direct-acting, synthetic α 1 receptors agonist.

• It is not a catechol derivative and, therefore, not a substrate for COMT.

• Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures.

• Phenylephrine acts as a nasal decongestant and produces prolonged vasoconstriction.

7. Methoxamine and clonidine

• Methoxamine is a direct-acting, synthetic α1 receptor agonist.

• Clonidine is an α2 agonist that prevents further release of noradrenaline.

• It is used in hypertension as it acts on α2 receptors in the CNS..

• It can be used in withdrawal from opiates or benzodiazepines.

8. Metaproterenol•The drug is an agonist at β2 receptors, producing little effect on β1 receptors of the heart. •The drug is useful as a bronchodilator in the treatment of asthma 9. Albuterol, pirbuterol, and terbutaline •are short-acting β2 agonists used primarily as bronchodilators .10. Salmeterol and formoterol •are selective β2-agonists, long-acting bronchodilators. •These agents are highly efficacious when combined with a corticorsteroid.

B. Indirect-Acting Adrenergic Agonists

• They potentiate the effects of norepinephrine produced endogenously, but these agents do not directly affect postsynaptic receptors.

1. Amphetamine

• Central stimulant, abused drug • Its peripheral actions are mediated primarily

through the release of stored norepinephrine and the blockade of norepinephrine uptake.

2. Tyramine

• It is not a clinically useful drug, but it is important because it is found in fermented foods, such as cheese.

• Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can precipitate a hypertensive crisis in him.

3. Cocaine

• Cocaine is a local anesthetic (sodium channel blocker) and is a CNS stimulant (blocks the reuptake of norepinephrine, thus potentiating NA effects).

• Drug of abuse.

C. Mixed-Action Adrenergic Agonists

• Mixed-action drugs induce the release of norepinephrine, and they activate postsynaptic adrenergic receptors.

• Ephedrine, and pseudoephedrine are plant alkaloids, that are now made synthetically.

• Ephedrine produces bronchodilation • Pseudoephedrine is used to treat nasal and

sinus congestion.

D. Adrenergic Antagonists (also called blockers or sympatholytic agents)

α-Adrenergic Blocking Agents • The α-adrenergic blocking agents,

phenoxybenzamine and phentolamine, have limited clinical applications, they are nonselective α blockers

1. Phenoxybenzamine•is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of the adrenal medulla.•Adverse effects: Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. 2. Phentolamine•Phentolamine is also used for the short-term management of pheochromocytoma.

3. Prazosin terazosin, doxazosin, and tamsulosin •are selective competitive blockers of the α1 receptor. •The first three drugs are useful in the treatment of hypertension. •Tamsulosin is indicated for the treatment of benign prostatic hyperplasia. •Doxazosin is the longest acting of these drugs.

• The first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action, termed first-dose effect.

• Tamsulosin is a more potent inhibitor of the α1A receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect on blood pressure.

4. Yohimbine• Is a selective α2 blocker.

• It is found as a component of the bark of the yohimbe tree and is sometimes used as a sexual stimulant (aphrodisiac) or cardiovascular stimulant.

β-Adrenergic Blocking Agents

• Nonselective β-blockers act at both β1 and β2 receptors, whereas cardioselective β antagonists block β1 receptors

• [Note: There are no clinically useful β2 blockers].

• Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the α-adrenoceptors remain functional.

β-Blockers are also effective in treating – angina, – cardiac arrhythmias, –myocardial infarction, – congestive heart failure, –hyperthyroidism, – glaucoma, as well as serving in the

prophylaxis of migraine headaches.

1. Propranolol• A nonselective β blocker• Sustained-release preparations for once-a-day

dosing are available.• Actions:• Cardiovascular: Propranolol diminishes cardiac

output, having both negative inotropic and chronotropic effects.

• Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina.

• The reduction in cardiac output leads to decreased blood pressure.

• Bronchoconstriction: Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle.

• Non-selective β-blockers, are contraindicated in patients with COPD or asthma.

• β-blockade leads to decreased glycogenolysis and decreased glucagon secretion, thus pronounced hypoglycemia may occur after insulin injection in a patient using propranolol.

• β-Blockers also mask the normal physiologic response to hypoglycemia.

Mechanisms of action

• Propranolol lowers blood pressure in hypertension by:– Decreased cardiac output is the primary

mechanism, – inhibition of renin release from the kidney

and decreased sympathetic outflow from the CNS also contribute to propranolol's antihypertensive effects .

• Adverse effects:–Bronchoconstriction–Arrhythmias: Treatment with β-blockers

must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. – Sexual impairment

• Drug interactions: –Drugs that interfere with the metabolism of

propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. –Conversely, those that stimulate its metabolism,

such as barbiturates, phenytoin, and rifampin, can decrease its effects.

2. Timolol and nadolol: •Nonselective β blockers, •are more potent than propranolol. 3. Acebutolol, atenolol, metoprolol, and esmolol: •Selective β1 blockers•Esmolol has a very short lifetime. It is only given intravenously if required during surgery or management of poisoning.4. Pindolol and acebutolol: •blockers with partial agonist activity

5. Labetalol and carvedilol: •blockers of both α- and β- adrenoceptors •Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure.•Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. •Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure.

Drugs Affecting Neurotransmitter Release or Uptake

• Some agents act on the adrenergic neuron, either to interfere with neurotransmitter release or to alter the uptake of the neurotransmitter.

1. Reserpine• Reserpine, a plant alkaloid that causes the

depletion of biogenic amines. • Sympathetic function, in general, is impaired

because of decreased release of norepinephrine.

2. Guanethidine• Guanethidine blocks the release of stored

norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure).

• This leads to gradual depletion of norepinephrine in nerve endings except for those in the CNS.

• Guanethidine commonly causes orthostatic hypotension and interferes with male sexual function.

3. Alpha methyl dopa• Antihypertensive• Mechanism: Transformed to alpha methyl

noradrenaline in adrenergic neuron,• When released, alpha methyl noradrenaline

acts as agonist on presynaptic alpha2 receptors. Thus further release of transmitter is inhibited.

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