. صالح سعديه م م . محاضرات صالح سعديه م م محاضراتالزيني الزيني مهدي مهدي

جامعة / البيطري الطب جامعة / كلية البيطري الطب كليةالكوفة الكوفة

واألدويــة الفسلجــة واألدويــة فــرع الفسلجــة فــرعوسموم أدوية وسموم ماجستير أدوية ماجستير

Drugs affecting the autonomic nervous systemDrugs affecting the autonomic nervous system

Drugs that produce their primary therapeutic effect by altering the function Drugs that produce their primary therapeutic effect by altering the function

of the autonomic nervous system. These autonomic agents act either by of the autonomic nervous system. These autonomic agents act either by

stimulating portions of the ANS or by blocking the action of the ANS.stimulating portions of the ANS or by blocking the action of the ANS.

Anatomic of the CNS:Anatomic of the CNS:

- Efferent fiber the motor portion of the ANS is he major pathway for information transmission from the central nervous system to the involuntary effector tissue (smoth muscle, cardiac muscle and exocrine glands. - Enteric NS is a semiautonomous part of the ANS ,with specific function for the control of the gastrointestinal tract. - Afferent fibers there are sensory fibers,these are of considerable importance for the phsiologic control of the involuntary organs but are directly influenced by only afew drugs 1- 1-spinal roots of origin: The parasympathetic preganglionic motor fibers originate in cranial nerve and sacral segments of the spinal cord. The sympathetic preganglionic fibers originate in the thoracic and lumbar segments of the cord.2- location of ganglia: most of sympathetic ganglia are located in two paravertebral chains that lie alonge the spinal column. A few located on the anterior of column. Most of parasympathetic ganglia are located in the organs innervated, more distant from the spinal cord 3- length of pre-and postganglionic fiber: The preganglionic sympathetic fibers are short and the postganglionic fibers are long. The opposite is true for the parasympathetic system: the preganglionic parasympathetic fibesr are long and the postganglionic fibers are short.4-Uninnervated receptors: These include muscarinic receptorson the endothelium of blood vessels,the adrenoceptors on sweat glands and adrenoceptors in blood vessels.

Sites of actions of cholinergic antagonists.

Neurotransmitter aspects of the ANS:1-Cholinergic transmission2- Adrenergic transmission Cholinergic transmission:Acetylcholine: is the primary transmitter in all autonomic ganglia and at the parasympathetic postganglionic neuron-effecrs cell synapses.- Synthesis and storage: Synthesized from acetyl-CoA and cholin by the enzyme choline acetyltansferase. this transport can be inhibited by hemicholinium. this process can be inhibited by vesamicol.- Ach storage into vesicles.-Release of ACh from vesicles in the nerve ending requires the entry of calcium through calcium channels and triggering of interaction between several proteins associated with the vesicles and the nerve ending membrane. This interaction results in the fusion of the vescular and nerve ending membranes, the opening of a pore to the extracellular space, and the release of the stored transmitter. This release can be blocked by botulinum toxin. In contrast ,the toxin in black widow spider venom causes all the Ach stored in synaptic vesicles to empty into the synaptic gap.- Termination of action of Ach: the action of acetylcholine is normally terminated by metabolism to acetate and choline by the enzyme acetylcholinesterase. The products are not excreted but are recycled in the body. Inhibition of acetylcholinesterase is an important therapeutic effect of several drugs.

- Binding to the receptor: Ach release from the synaptic vesicles diffuses across the synaptic space, and it binds to either of tow postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the Ach.

Synthesis and release of Ach from cholinergic neuron

Cholinergic receptors:Cholinergic receptors: Cholinoceptors are molecules respond to acetylcholine, these divided into classes: Cholinoceptors are molecules respond to acetylcholine, these divided into classes:

1 - muscarinic receptors:1 - muscarinic receptors: has been found for five (subtypes M1,M2,M3,M4,M5), has been found for five (subtypes M1,M2,M3,M4,M5), located on ganglia of the peripheral nervous system and on the surface of the effector located on ganglia of the peripheral nervous system and on the surface of the effector organs. M1 found on gastric cell, M2 found on cardiac cell and smooth muscle, M3 organs. M1 found on gastric cell, M2 found on cardiac cell and smooth muscle, M3 found on bladder, exocrine gland and smoth muscle. found on bladder, exocrine gland and smoth muscle.

2 - nicotinic receptors2 - nicotinic receptors:: (composed of five subunits) are located in the CNS, adrenal (composed of five subunits) are located in the CNS, adrenal medulla, autonomic ganglia and the neuromuscular junction.medulla, autonomic ganglia and the neuromuscular junction.

Direct - action Cholinergic agonists ( parasympathomimetics)Direct - action Cholinergic agonists ( parasympathomimetics) Mimic effects of acetycholine by binding directly to cholinoceptors. These may be Mimic effects of acetycholine by binding directly to cholinoceptors. These may be

classified into tow groups:classified into tow groups:

1 - Choline esters1 - Choline esters,, which include acetylcholine and synthetic esters of choline such as which include acetylcholine and synthetic esters of choline such as

a- Acetylcholinea- AcetylcholinePharmacologic effectsPharmacologic effects: the action include : the action include

1- Decrease in heart rate and cardiac output. 1- Decrease in heart rate and cardiac output.

2- Decrease in blood pressure: Ach cause vasodilation and lowering of blood pressure.2- Decrease in blood pressure: Ach cause vasodilation and lowering of blood pressure.

3- Smooth muscle: increase salivary secretion and motility of intestinal, urinary and uterine 3- Smooth muscle: increase salivary secretion and motility of intestinal, urinary and uterine smooth muscle.smooth muscle.

4- Eye: Ach stimulating ciliary muscle contraction for near vision and in the constriction 4- Eye: Ach stimulating ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle causing miosis. of the pupillae sphincter muscle causing miosis.

b- b- carbachol carbachol has both muscarinic as well as nicotinic action, used to treat has both muscarinic as well as nicotinic action, used to treat glaucoma by causing papillary contraction and decrease in intraocular glaucoma by causing papillary contraction and decrease in intraocular pressure pressure

c- Bethanecholc- Bethanechol directly stimulate muscrinic receptors, causing increased directly stimulate muscrinic receptors, causing increased intestinal motility and used to stimulate the atonic bladder in postoperative.intestinal motility and used to stimulate the atonic bladder in postoperative.

2- Alkaloids 2- Alkaloids a group of naturally occurring such as muscarine, not used a group of naturally occurring such as muscarine, not used thrapeutically but rather important accidental poison. thrapeutically but rather important accidental poison.

- pilocarpine- pilocarpine therapeutic use in glaucoma choice in the emergency lowering of therapeutic use in glaucoma choice in the emergency lowering of intraocular pressure.intraocular pressure.

Indirect – action cholinergic agonists (anticholinesterases)Indirect – action cholinergic agonists (anticholinesterases) The indirect- acting cholinomimetic drugs into two major chemical classes The indirect- acting cholinomimetic drugs into two major chemical classes 1- Reversible (Carbamic acid ester):1- Reversible (Carbamic acid ester): Inhibitors of acetylcholinesteras enzyme indirectly provide a cholinergic Inhibitors of acetylcholinesteras enzyme indirectly provide a cholinergic

action by prolonging the lifetime of acetycholine produce endogenously at the action by prolonging the lifetime of acetycholine produce endogenously at the cholinergic nerve endings. This accumulation of acetycholine in the synaptic cholinergic nerve endings. This accumulation of acetycholine in the synaptic space .these drug can thus provoke a response at all cholinoceptors in the space .these drug can thus provoke a response at all cholinoceptors in the body, including both muscarinic and nicotinic receptors of the ANS as well as body, including both muscarinic and nicotinic receptors of the ANS as well as at neuromuscular junctions and in the brain. such as at neuromuscular junctions and in the brain. such as physostigmine and physostigmine and neostigmineneostigmine the drug increase intestinal and bladder motility. the drug increase intestinal and bladder motility.

2- Irreversible (phosphoric acid esters): A number of synthetic organophosphate compounds have the capacity to bind to acetylcholinesterase and . The resulte is long-lasting increase in Ach at all sites where it is released. Many of these drugs are extremely toxic. Related compound, such as parathion, are employed as insecticides. -Ecothiophate: actions include generalized cholinergic stimulation, paralysis of motor function causing breathing difficulties and convulsion. used for treatment of glaucoma.

Cholinergic antagonists ( anticholinergic drug):Called cholinergic blocker, parasympatholytics. Cholinoceptor antagonists are readily into subclasses: 1-Basis of their spectrum action they block muscarinic and nicotinic receptors2-Special subgroup, the cholinesterase regenerators, are not receptor blockers but rather are chemical antagonists of organophosphate cholinesterase inhibitors

Cholinergic antagonists

Antimuscarinic Antinicotinic

M1 Selective nonselectiveGanglionblockers

neuromuscular blockers

Cholinesterase

regenerators

Chemicalantagonists

Antimuscarinic agents (muscarinic antagonists)Antimuscarinic agents (muscarinic antagonists) muscarinic antagonists can be subdivided according to their selectivity for muscarinic antagonists can be subdivided according to their selectivity for

M1 receptors, only a few receptor-selective antagonists ( pirenzepine, M1 receptors, only a few receptor-selective antagonists ( pirenzepine, telenzepine). All of the drugs in general are nonselective. These agents telenzepine). All of the drugs in general are nonselective. These agents block muscarinic receptors causing inhibition of all muscarinic function.block muscarinic receptors causing inhibition of all muscarinic function.

AtropineAtropine A tertiary amine belladonna alkaliod, has affinity for muscarinic receptors where it A tertiary amine belladonna alkaliod, has affinity for muscarinic receptors where it

binds competitively, preventing acetylcholine from binding to these sites. Atropine binds competitively, preventing acetylcholine from binding to these sites. Atropine acts both centrally and peripherally.acts both centrally and peripherally.

Action Action - Eye:- Eye: mydriasis (dilation of the pupil) and cycloplegia (inability to focus for near mydriasis (dilation of the pupil) and cycloplegia (inability to focus for near

vision)vision)

- Gastrointestinal:- Gastrointestinal: used an antispasmodic to reduce activity of the GI tract used an antispasmodic to reduce activity of the GI tract

- Urinary system:- Urinary system: used to reduce hypermotility states of the urinary blodder and used used to reduce hypermotility states of the urinary blodder and used in enuresis (involuntary voiding urine) among childrenin enuresis (involuntary voiding urine) among children

- Cardiovascular:- Cardiovascular: at low dose decrease cardiac rate, in higher dose of atropine, the M2 at low dose decrease cardiac rate, in higher dose of atropine, the M2 receptors on the sinoatrial node blocker, and cardiac rate increase. Blood pressure is receptors on the sinoatrial node blocker, and cardiac rate increase. Blood pressure is unaffected.unaffected.

- Gland: - Gland: decrease secretion of saliva gland produce a drying effect on the oral mucous decrease secretion of saliva gland produce a drying effect on the oral mucous membranes ( xerostomia). membranes ( xerostomia).

Pharmacokinetic:Pharmacokinetic: Absorbed from GI, metabolized by the liver and eliminated in the urine. It Absorbed from GI, metabolized by the liver and eliminated in the urine. It

has half life of about 4 hourshas half life of about 4 hoursScopolamine:Scopolamine: Is another belladonna alkaloid has longer action and more central effect Is another belladonna alkaloid has longer action and more central effect Action : antimotion sickness, block short term memory causes sedationAction : antimotion sickness, block short term memory causes sedationIpratropium Ipratropium Used in treating asthma in patients who are unable to take adrenergic Used in treating asthma in patients who are unable to take adrenergic

agonists and chronic obstructive pulmonary disease.agonists and chronic obstructive pulmonary disease.

Antinicotinic agents (nicotinic antagonists)1- ganglion blockers: blockers ganglionic specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. used for treatment of hypertension. hexamethonium and mecamylamin used for this disease.2- neuromuscular blocking drugs: These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle, these drugs include agonists (depolarizing) or antagonists (nondepolarizing) of Ach nicotinic receptors at the neuromuscular junction.

1- Nondepolarizing (competitive) blockers1- Nondepolarizing (competitive) blockers These drugs include tubocuarine considered to be the prototype agent in this These drugs include tubocuarine considered to be the prototype agent in this class, compete with Ach at the nicotinic receptor at the neuromuscular junction class, compete with Ach at the nicotinic receptor at the neuromuscular junction without stimulating the receptors, they are called competitive blockers . These without stimulating the receptors, they are called competitive blockers . These agents have increased the safety of anesthesia, because less anesthetic isagents have increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation.required to produce muscle relaxation. Mechanism of action:Mechanism of action:a- At low doses:a- At low doses:

these drugs intract with the nicotinic receptos to prevent the binding of acetylcholine, these drugs intract with the nicotinic receptos to prevent the binding of acetylcholine, prevent depolarization of the muscle cell membrane and inhibit muscular contraction. prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Their action can be overcome by increase concentration of Ach in the synaptic gap- for Their action can be overcome by increase concentration of Ach in the synaptic gap- for example by administration of cholinesterase inhibitors, such as neostigmine.example by administration of cholinesterase inhibitors, such as neostigmine.

b-At higher doses:b-At higher doses: nondepolarizing blockers can block ion channels of the end plate. This leads to further nondepolarizing blockers can block ion channels of the end plate. This leads to further

weakening of neuromuscular transmission and it reduces the ability of cholinesterase weakening of neuromuscular transmission and it reduces the ability of cholinesterase inhibition to reverse. inhibition to reverse.

ActionAction:: Not muscles are equally sensitive to blockade by competitive blockers. Small, rapidly Not muscles are equally sensitive to blockade by competitive blockers. Small, rapidly

contracting muscles of the face and eye are most susceptible and paralyzed first, contracting muscles of the face and eye are most susceptible and paralyzed first, followed by the fingers, thereafter, the limb, neck and trunk muscles are paralyzed. thin followed by the fingers, thereafter, the limb, neck and trunk muscles are paralyzed. thin intercostals muscles are affected and lastly the diaphragm muscles are paralyzedintercostals muscles are affected and lastly the diaphragm muscles are paralyzed

Drug interaction:Drug interaction:a- Cholinesterase:a- Cholinesterase: Drug such as neustigmine ……can overcome the action of nondepolarizing Drug such as neustigmine ……can overcome the action of nondepolarizing

neuromuscular lockers,but with increase dosage, cholinesterase inhibitors can cause a neuromuscular lockers,but with increase dosage, cholinesterase inhibitors can cause a depolarizing block as a result of elevated Ach concentration at the end plate membrane.depolarizing block as a result of elevated Ach concentration at the end plate membrane.

b- Halogenated hydrocarbon anesthetic:b- Halogenated hydrocarbon anesthetic: Drugs such as halothane act t o enhance neuromuscular blocker by exerting a stabilizing Drugs such as halothane act t o enhance neuromuscular blocker by exerting a stabilizing

action at the neuromuscular junction.action at the neuromuscular junction.c- Aminoglycoside antibiotics:c- Aminoglycoside antibiotics: Drug such as gentae rmicin or tobramycin inhibit acetycholine Drug such as gentae rmicin or tobramycin inhibit acetycholine Release from cholinergic nerves by competing with calcium ions.Release from cholinergic nerves by competing with calcium ions.d-Calcium- channel blockess:d-Calcium- channel blockess: These agents may increase the muscular block of tubocuraine and other competitive These agents may increase the muscular block of tubocuraine and other competitive

blockers as well as depolarizing blockers.blockers as well as depolarizing blockers.

2- Depolarizing agents:2- Depolarizing agents: Mechanisme of action:Mechanisme of action:The depolarizing neuromuscular The depolarizing neuromuscular

blocking drug blocking drug (succinylcholine) attaches to the nicotinic receptor(succinylcholine) attaches to the nicotinic receptor and acts like acetylcholine to depolarize the junction.and acts like acetylcholine to depolarize the junction. The depolarizing agent persists at high concentrations The depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptorin the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing a constantfor a relatively longer time and providing a constant stimulation of the receptor. stimulation of the receptor. Phase-Phase-1: The depolarizing agent first causes the opening 1: The depolarizing agent first causes the opening of the sodium channel associated with the nicotinicof the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptors, which results in depolarization of the

receptor.receptor. Phase-2: Phase-2: This leads to transient twitching of the muscle This leads to transient twitching of the muscle (fasciculation). Continued binding of the depolarizing agent(fasciculation). Continued binding of the depolarizing agent renders receptor incapable of transmitting further implses. renders receptor incapable of transmitting further implses. With time continuus depolarization gives way to gradualWith time continuus depolarization gives way to gradual repolarization as the sodium channel closes or is blockd. repolarization as the sodium channel closes or is blockd. This causes resistance to depolarization and a flaccid This causes resistance to depolarization and a flaccid

paralysis. paralysis.

Action: Action: Succinylcholin initially produces short-lasting muscle fasciculation, followed Succinylcholin initially produces short-lasting muscle fasciculation, followed within a few minutes by paralysis because this drug is rapidly broken downwithin a few minutes by paralysis because this drug is rapidly broken down by plasma cholinesterase. The drug does not produce a ganglionic block by plasma cholinesterase. The drug does not produce a ganglionic block except at high doses, but it does have weak histamine-releasing action.except at high doses, but it does have weak histamine-releasing action.

Therapeutic usesUseful when rapid endotracheal intubation is required during the induction of anesthesia and it is also employed during electroconvulsive shock treatment.

Adverse effects:-hyperthermia malignant with halothane (reducing heat production and relaxing muscle ton) because block release of Ca++ - apnea paralysis of diaphragm ( deficient in plasma cholinesterase) - hyperkalemia potassium lost from within cell ( tissue damage )

Cholinesterase regenerators:The cholinesrterase regenerators are not receptor antagonists but belong to a Class of chemical antagonists. These molecules contain an oxime group, which has high affinity for the phosphorus atom in organophosphate insecticides lead to exceeds that of the enzyme active site. Used to treat patients exposed to insecticides such as parathion

Adrenergic transmion: Norepinephrine and epinerphrie: Norepinephrine and epinerphrie is the transmitter, the fiber is termed adrenergic. In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effector organs.- Synthesis: Tyrosin is transported by a Na+ linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase, this is the rate – limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopadecarboxylase to form dopamine in the cytoplasm of the presynaptic neuron. Drugs that block synthesis eg, metyrosine.- Storsge of norepinephrine in vesicle:Dopamine enter vesicle by an amine transporter systme and is converted to norepinephrine by the enzyme dopamine B-hydroxylase. Norepinephrine protected from degradation in the vesicle. Transport dopamine into the vesicle is inhibited by reserpine. In the adrenal medulla, norepinephrine methylated to yield epinephrine, both of which are stored in chromaffin cells.

Release of norepinephrine:Release of norepinephrine: Influx of calciume causes fusion of the vesicle with the cell membrane in a Influx of calciume causes fusion of the vesicle with the cell membrane in a

process known as exocytosis. Release is blocked by guonethidine and process known as exocytosis. Release is blocked by guonethidine and bretylium.bretylium.

Binding to alpha receptors:Binding to alpha receptors: Norepinephrine released from the syneptic vesicles diffuses the syneptic Norepinephrine released from the syneptic vesicles diffuses the syneptic

space and binds to either postsynaptic receptors on the effector organ or to space and binds to either postsynaptic receptors on the effector organ or to presyneptic receptor on the nerve ending. Adrenergic receptors use both presyneptic receptor on the nerve ending. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system,2 the cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the phosphatidylinositol cycle,3 to transduce the signal into an effect.and the phosphatidylinositol cycle,3 to transduce the signal into an effect.

Removal of norepinephrine: Removal of norepinephrine: - diffuse out of the syneptic space and enter the general circulation.- diffuse out of the syneptic space and enter the general circulation. - Metabolizes to o-methylated derivations by postsynaptic cell membrane - Metabolizes to o-methylated derivations by postsynaptic cell membrane

associated catechol o-methyltransferase (COMT) in the syneptic apace. associated catechol o-methyltransferase (COMT) in the syneptic apace. Inactive norepinephrine metabolism are excreted in the urine. Inactive norepinephrine metabolism are excreted in the urine. - Recaptured by uptake system that pumps the norepinephrine back into the - Recaptured by uptake system that pumps the norepinephrine back into the

neuronneuron..

Adrenergic receptors:Adrenergic receptors: Adrenoceptors are divided into several subtype:Adrenoceptors are divided into several subtype:1- Alpha adreoceptors1- Alpha adreoceptors These receptors show a weak response to the synthetic These receptors show a weak response to the synthetic

agonist isoproterenol, but they are responsive to the to the naturally agonist isoproterenol, but they are responsive to the to the naturally occurring catecholamines epinephrine and norepinphrine. These are occurring catecholamines epinephrine and norepinphrine. These are located on, blood platelets, fat cells and neurons in the brain. Alpha receptor located on, blood platelets, fat cells and neurons in the brain. Alpha receptor are subdivided into two subgroups: are subdivided into two subgroups:

a-Alpha-1 receptors:a-Alpha-1 receptors: These are present on the postsynaptic membrane of the effector organs and These are present on the postsynaptic membrane of the effector organs and

mediate many of the classic effects. Activation of alpha-1 receptors initiates mediate many of the classic effects. Activation of alpha-1 receptors initiates a series of reactions through a G protein activation of phospholipase. These a series of reactions through a G protein activation of phospholipase. These receptors subdivided into alpha-1 A,B,C,Dreceptors subdivided into alpha-1 A,B,C,D

b-Alpha-2 receptorsb-Alpha-2 receptors:: These are located on presyneptic nerve endings and other cells, such as the B These are located on presyneptic nerve endings and other cells, such as the B

cell of the pancreas and on some vascular smooth muscles cells. When a cell of the pancreas and on some vascular smooth muscles cells. When a sympathetic adrenergic nerve is stimulated, the releasedsympathetic adrenergic nerve is stimulated, the released norepinephrine norepinephrine traverses the synaptic cleft and interacts with the alpha-1 receptors. A traverses the synaptic cleft and interacts with the alpha-1 receptors. A portion of the releasedportion of the released norepinephrine (circles back) and reacts with alpha -norepinephrine (circles back) and reacts with alpha -2 receptors on the neuronal membrane. The stimulation of the alpha-2 2 receptors on the neuronal membrane. The stimulation of the alpha-2 receptor causes feedback inhibition of the release of norepinephrine from receptor causes feedback inhibition of the release of norepinephrine from the stimulated adrenergic neuron. These receptors subdivided into alpha-2 the stimulated adrenergic neuron. These receptors subdivided into alpha-2 A,B,C,D.A,B,C,D.

2- Beta receptors:2- Beta receptors: These are receptors, characterized by a strong response to isoproterenol with These are receptors, characterized by a strong response to isoproterenol with

less sensitivity to epinephrine and norepinephrine. The B-adrenoceptors can less sensitivity to epinephrine and norepinephrine. The B-adrenoceptors can be subdivided into three major subgroups, B-1, B-2, and B-3, based on their be subdivided into three major subgroups, B-1, B-2, and B-3, based on their affinities for adrenergic agonists and antagonists. affinities for adrenergic agonists and antagonists.

B-1Receptors have approximately equal affinities for epinephrineB-1Receptors have approximately equal affinities for epinephrine and and norepinephrine, whereas B-2 receptors have a higher affinity for epinephrinenorepinephrine, whereas B-2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of B-2 receptors than for norepinephrine. Thus, tissues with a predominance of B-2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrinehormonal effects of circulating epinephrine released by the adrenal medulla. released by the adrenal medulla.

Distribution of receptors:Distribution of receptors: Adrenergically innervated organs and tissues tend to Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. For example, tissues such as have a predominance of one type of receptor. For example, tissues such as the vasculature to skeletal muscle have both alpha-1 and B-2 receptors, but the vasculature to skeletal muscle have both alpha-1 and B-2 receptors, but the B-2 receptors predominate. the B-2 receptors predominate.

Characteristic responses mediated by adrenoceptors:Characteristic responses mediated by adrenoceptors:

It is useful to organize the physiologic responses to adrenergic stimulation It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or according to receptor type, because many drugs preferentially stimulate or block one type of receptor. As ageneralization, stimulation of alpha-1 block one type of receptor. As ageneralization, stimulation of alpha-1 receptors characteristically produces vasoconstriction (particularly in skin receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of B-1 receptors characteristically blood pressure. Conversely, stimulation of B-1 receptors characteristically causes cardiac stimulation, whereas stimulation of B-2 receptors produces causes cardiac stimulation, whereas stimulation of B-2 receptors produces vasodilation (in skeletal vascular beds) and bronchiolar relaxation.vasodilation (in skeletal vascular beds) and bronchiolar relaxation.

Type Tissue ActionsType Tissue Actions

Alpha-1 Most vascular smooth muscle ContractionAlpha-1 Most vascular smooth muscle Contraction Pupillary dilator muscle Contraction (dilates pupil)Pupillary dilator muscle Contraction (dilates pupil) Pilomotor smooth muscle Erects hairPilomotor smooth muscle Erects hair Prostate ContractionProstate Contraction Alpha 2 Adrenergic and cholinergic nerve Inhibition of transmitterAlpha 2 Adrenergic and cholinergic nerve Inhibition of transmitter terminals releaseterminals release Platelets stimulates AggregatioPlatelets stimulates Aggregatio Some vascular smooth muscle ContractionSome vascular smooth muscle Contraction Fat cells Inhibition of lipolysisFat cells Inhibition of lipolysis Beta -1 Heart Increases force and rateBeta -1 Heart Increases force and rate Beta-2 Respiratory, uterine, and vascular smooth relaxationBeta-2 Respiratory, uterine, and vascular smooth relaxation muscle Promotes smooth muscle muscle Promotes smooth muscle liver (human) stimulate glycogenolysisliver (human) stimulate glycogenolysis pancreatic B cell stimulate insulin release pancreatic B cell stimulate insulin release Beta-3 Fat cells Activates lipolysisBeta-3 Fat cells Activates lipolysis

Distribution of Adrenoceptor Subtypes.Distribution of Adrenoceptor Subtypes.

Mechanism of action of the adrenergic agonistsMechanism of action of the adrenergic agonists1- 1- Direct-acting agonists: Direct-acting agonists: These drugs act directly on alpha or beta receptors, producing effects similar to those These drugs act directly on alpha or beta receptors, producing effects similar to those

that occur following stimulation of sympathetic nerves or release of the hormone that occur following stimulation of sympathetic nerves or release of the hormone epinephrineepinephrine from the adrenal medulla. Examples of direct-acting agonists include from the adrenal medulla. Examples of direct-acting agonists include

2- 2- Indirect-acting agonists:Indirect-acting agonists: These agents, which include These agents, which include amphetamine, amphetamine, cocaine and tyramine, may block the cocaine and tyramine, may block the

uptake of norepinephrine or are taken up into the presynaptic neuron and cause the uptake of norepinephrine or are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic vesicles of the adrenergic neuron. release of norepinephrine from the cytoplasmic vesicles of the adrenergic neuron. As with neuronal stimulation, the norepinephrine then traverses the synapse and As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the alph or beta receptors.binds to the alph or beta receptors.

3- 3- Mixed-action agonists: Mixed-action agonists: Some agonists, such as ephedrine, pseudoephedrineSome agonists, such as ephedrine, pseudoephedrine and metaraminol, have the and metaraminol, have the

capacity both to stimulate adrenoceptors directly and to release norepinephrine from capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron.the adrenergic neuron.

Direct-Acting Adrenergic AgonistsDirect-Acting Adrenergic Agonists Direct-acting agonists bind to adrenergic receptors without interacting with the Direct-acting agonists bind to adrenergic receptors without interacting with the

presynaptic neuron. As a group, these agents are widely used clinically.presynaptic neuron. As a group, these agents are widely used clinically. EpinephrineEpinephrine Epinephrine is one of four catecholamines - epinephrine, norepinephrine, Epinephrine is one of four catecholamines - epinephrine, norepinephrine,

dopamine, and dobutamine commonly used in therapy. The first three dopamine, and dobutamine commonly used in therapy. The first three catecholamines occur naturally in the body as neurotransmitters; the latter is a catecholamines occur naturally in the body as neurotransmitters; the latter is a synthetic compound. Epinephrinesynthetic compound. Epinephrine is synthesized from tyrosine in the adrenal is synthesized from tyrosine in the adrenal medulla and released, along with small quantities of norepinephrine, into the medulla and released, along with small quantities of norepinephrine, into the bloodstream. Epinephrinebloodstream. Epinephrine interacts with both alpha and beta receptors. At low interacts with both alpha and beta receptors. At low doses, beta effects (vasodilation) on the vascular system predominate, whereas at doses, beta effects (vasodilation) on the vascular system predominate, whereas at high doses, alpha effects (vasoconstriction) are strongest.high doses, alpha effects (vasoconstriction) are strongest.

Actions:Actions:-Cardiovascular: -Cardiovascular: The major actions of epinephrine are on the cardiovascular system. The major actions of epinephrine are on the cardiovascular system.

Epinephrine strengthens the contractility of the myocardium (positive inotropic: Epinephrine strengthens the contractility of the myocardium (positive inotropic: beta-1 action) and increases its rate of contraction (positive chronotropic: beta-1 beta-1 action) and increases its rate of contraction (positive chronotropic: beta-1 action). Cardiac output therefore increases. With these effects comes increased action). Cardiac output therefore increases. With these effects comes increased oxygen demands on the myocardium.oxygen demands on the myocardium.

EpinephrineEpinephrine constricts arterioles in the skin, mucous membranes, and viscera constricts arterioles in the skin, mucous membranes, and viscera (alpha effects), and it dilates vessels going to the liver and skeletal muscle (beta-2 (alpha effects), and it dilates vessels going to the liver and skeletal muscle (beta-2 effects). Renal blood flow is decreased. Therefore, the cumulative effect is an effects). Renal blood flow is decreased. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolicincrease in systolic blood pressure, coupled with a slight decrease in diastolic

-Respiratory: -Respiratory: EpinephrineEpinephrine causes powerful bronchodilation by acting directly on causes powerful bronchodilation by acting directly on bronchial smooth muscle (beta-2 action). This action relieves all known bronchial smooth muscle (beta-2 action). This action relieves all known allergic- or histamine-induced bronchoconstriction. Epinephrineallergic- or histamine-induced bronchoconstriction. Epinephrine rapidly rapidly relieves the dyspnea and increases the volume of gases inspired and expired. relieves the dyspnea and increases the volume of gases inspired and expired. EpinephrinEpinephrine e also inhibits the release of allergy mediators such as histamines also inhibits the release of allergy mediators such as histamines from mast cells.from mast cells.

-Hyperglycemia: -Hyperglycemia: EpinephrineEpinephrine has a significant hyperglycemic effect because of has a significant hyperglycemic effect because of increased glycogenolysis inthe liver (beta-2 effect), increased release of increased glycogenolysis inthe liver (beta-2 effect), increased release of glucagon (beta-2 effect), and a decreased release of insulin (alpha-2 effect). glucagon (beta-2 effect), and a decreased release of insulin (alpha-2 effect).

-Lipolysis: -Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the beta Epinephrine initiates lipolysis through its agonist activity on the beta receptors of adipose tissue.receptors of adipose tissue.

Therapeutic usesTherapeutic uses-Bronchospasm: -Bronchospasm: EpinephrineEpinephrine is the drug used in the intreatment of acute asthma is the drug used in the intreatment of acute asthma

and anaphylactic shock, epinephrineand anaphylactic shock, epinephrine is the drug of choice; within a few is the drug of choice; within a few minutes after subcutaneous administration. Selective beta-2 agonists, such as minutes after subcutaneous administration. Selective beta-2 agonists, such as albuterol, are presently favored in the chronic treatment of asthma because of a albuterol, are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect.longer duration of action and minimal cardiac stimulatory effect.

-Glaucoma: -Glaucoma: In ophthalmology, a two-percent epinephrine solution may be used In ophthalmology, a two-percent epinephrine solution may be used topically to reduce intraocular pressure in open-angle glaucoma. topically to reduce intraocular pressure in open-angle glaucoma.

-Anaphylactic shock: -Anaphylactic shock: EpinephrineEpinephrine is the drug of choice for the treatment of Type is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens.I hypersensitivity reactions in response to allergens.

-Anesthetics:-Anesthetics: The effect of the drug is to greatly increase the duration of the local The effect of the drug is to greatly increase the duration of the local anesthesia. anesthesia.

Pharmacokinetics: Pharmacokinetics: EpinephrineEpinephrine has a brief duration of action (due to rapid has a brief duration of action (due to rapid degradation). epinephrinedegradation). epinephrine is given intravenously, subcutaneously, by is given intravenously, subcutaneously, by endotracheal tube, by inhalation. Oral administration is ineffective, Only endotracheal tube, by inhalation. Oral administration is ineffective, Only metabolites are excreted in the urine.metabolites are excreted in the urine.

Adverse effects:Adverse effects:- CNS disturbances: - CNS disturbances: adverse CNS effects that include anxiety, fear, tension, adverse CNS effects that include anxiety, fear, tension,

headache, and tremor.headache, and tremor.- Hemorrhage: - Hemorrhage: The drug may induce cerebral hemorrhage as a result of a The drug may induce cerebral hemorrhage as a result of a

marked elevation of blood pressure.marked elevation of blood pressure.- Cardiac arrhythmias- Cardiac arrhythmias, , Pulmonary edema Pulmonary edema Interactions:Interactions:- Hyperthyroidism: - Hyperthyroidism: EpinephrineEpinephrine may have enhanced cardio-vascular actions in may have enhanced cardio-vascular actions in

patients with hyperthyroidism.patients with hyperthyroidism.- Cocaine: - Cocaine: In the presence of cocaine, epinephrineIn the presence of cocaine, epinephrine produces exaggerated produces exaggerated

cardiovascular actions. This is due to the ability of cocaine to prevent cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron reuptake of catecholamines into the adrenergic neuron

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

- Beta Blockers: - Beta Blockers: These agents prevent epinephrine's effects on b- receptors, These agents prevent epinephrine's effects on b- receptors, leaving alpha-receptor stimulation unopposed. This may lead to an increase leaving alpha-receptor stimulation unopposed. This may lead to an increase in peripheral resistance and an increase in blood pressure.in peripheral resistance and an increase in blood pressure.

- Inhalation anesthetics: - Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the Inhalational anesthetics sensitizethe heart to the effects of epinephrine,effects of epinephrine, which may lead to tachycardia.which may lead to tachycardia.

NorepinephrineNorepinephrine Because norepinephrine is the neuromediator of adrenergic nerves, it Because norepinephrine is the neuromediator of adrenergic nerves, it

should theoretically stimulate all types of adrenergic receptors. In practice, should theoretically stimulate all types of adrenergic receptors. In practice, when the drug is given in therapeutic doses to humans, the Alpha- when the drug is given in therapeutic doses to humans, the Alpha- adrenergic receptor is most affected.adrenergic receptor is most affected.

- Cardiovascular Actions:- Cardiovascular Actions:- Vasoconstriction: Vasoconstriction: Norepinephrine causes a rise in peripheral resistance Norepinephrine causes a rise in peripheral resistance

due to intense vasoconstriction (alpha-1), increase blood pressures. The due to intense vasoconstriction (alpha-1), increase blood pressures. The increase heart rate (inotropic) due to beta-1 stimulation increase heart rate (inotropic) due to beta-1 stimulation

- Therapeutic uses: Therapeutic uses: used to treat shock, because it increases vascular used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. It is never used for resistance and, therefore, increases blood pressure. It is never used for asthma or in combination with local anesthetics. asthma or in combination with local anesthetics.

Pharmacokinetics: Pharmacokinetics: Norepinephrine may be given IV for rapid onset of Norepinephrine may be given IV for rapid onset of action. The duration of action is 1 to 2 minutes following the end of the action. The duration of action is 1 to 2 minutes following the end of the infusion period. It is poorly absorbed after subcutaneous injection and is infusion period. It is poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally. Metabolism is similar to that of destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine.epinephrine.

Adverse effects: Adverse effects: These are similar to those of epinephrine. These are similar to those of epinephrine.

IsoproterenolIsoproterenol Isoproterenol is a direct-acting synthetic catecholamine that predominantly Isoproterenol is a direct-acting synthetic catecholamine that predominantly

stimulates both beta-1 and beta-2 adrenergic receptors. stimulates both beta-1 and beta-2 adrenergic receptors. Actions:Actions:- - Cardiovascular:Cardiovascular: Isoproterenol produces intense stimulation of the heart to increase Isoproterenol produces intense stimulation of the heart to increase

its rate and force of contraction, causing increased cardiac output. its rate and force of contraction, causing increased cardiac output. - - Pulmonary:Pulmonary: rapid bronchodilation is produced by the drug (beta-2 action). rapid bronchodilation is produced by the drug (beta-2 action). Therapeutic uses: Therapeutic uses: IsoproterenolIsoproterenol is now rarely used as a broncho-dilator in asthma. It is now rarely used as a broncho-dilator in asthma. It

can be employed to stimulate the heart in emergency situations.can be employed to stimulate the heart in emergency situations.Pharmacokinetics:Pharmacokinetics: Isoproterenol can be absorbed systemically by the sublingual Isoproterenol can be absorbed systemically by the sublingual

mucosamucosa

DopamineDopamine DopamineDopamine the immediate metabolic precursor of norepinephrine, activate alpha and the immediate metabolic precursor of norepinephrine, activate alpha and

beta-adrenergic receptors.beta-adrenergic receptors.- at higher doses (alpha-1 receptors) cause vasoconstriction by activating.- at higher doses (alpha-1 receptors) cause vasoconstriction by activating.- at lower doses, it stimulates beta-1 cardiac receptors. - at lower doses, it stimulates beta-1 cardiac receptors. In addition, D1 and D2 receptors occur in the blood vessels mesenteric and renal. In addition, D1 and D2 receptors occur in the blood vessels mesenteric and renal. - D1- D1 causes vasodilation.causes vasodilation. - D2 receptors are found on presynaptic receptors prevent release norepinephrine. - D2 receptors are found on presynaptic receptors prevent release norepinephrine. These receptors are not affected by alpha or beta blocking drugs and are found in the These receptors are not affected by alpha or beta blocking drugs and are found in the

autonomic ganglia and in the CNS.autonomic ganglia and in the CNS.

Actions:Actions:- Cardiovascular:- Cardiovascular: a stimulatory effect on the beta-1 receptors of the heart, a stimulatory effect on the beta-1 receptors of the heart,

having both inotropic and chronotropic having both inotropic and chronotropic - Renal and visceral:- Renal and visceral: dilatation by activating D1 receptors dilatation by activating D1 receptors Therapeutic uses:Therapeutic uses: - Shock: given by continuous infusion. - Shock: given by continuous infusion. - stimulating heart by beta-1 receptors to increase cardiac output, and alpha- 1 - stimulating heart by beta-1 receptors to increase cardiac output, and alpha- 1

receptors on blood vessels to increase total peripheral resistance. receptors on blood vessels to increase total peripheral resistance. - increased blood flow to the kidney enhances the glomerular filtration rate - increased blood flow to the kidney enhances the glomerular filtration rate Adverse effects:Adverse effects: nausea, hypertension, arrhythmias. nausea, hypertension, arrhythmias.

DobutamineDobutamineActions:Actions: a synthetic, direct-acting catecholamine that is a beta-1-receptor a synthetic, direct-acting catecholamine that is a beta-1-receptor agonist. It increases cardiac rate and output agonist. It increases cardiac rate and output Therapeutic uses:Therapeutic uses: used to increase cardiac output in congestive heart failure used to increase cardiac output in congestive heart failure Adverse effects:Adverse effects: should be used with caution in atrial fibrillation, because the should be used with caution in atrial fibrillation, because the

drug increases atrioventricular conduction.drug increases atrioventricular conduction.

OxymetazolineOxymetazoline is a direct-acting synthetic adrenergic agonist that stimulates both alpha-1 andis a direct-acting synthetic adrenergic agonist that stimulates both alpha-1 and alpha-2 adrenergic receptors.alpha-2 adrenergic receptors. - - usedused locally in the eye or the nose as a vasoconstrictor locally in the eye or the nose as a vasoconstrictor and decrease and decrease

congestion. congestion.congestion. congestion.

PhenylephrinePhenylephrine is a direct-acting, synthetic adrenergic drug that binds to alpha receptors. is a direct-acting, synthetic adrenergic drug that binds to alpha receptors. - It- It is a vasoconstrictor that raises blood pressures. It has no effect on the heart is a vasoconstrictor that raises blood pressures. It has no effect on the heart

itself but cause reflex bradycardia. itself but cause reflex bradycardia. - used topically on the nasal mucous membranes as decongestant. - used topically on the nasal mucous membranes as decongestant. - used to raise blood pressure in hypotension - used to raise blood pressure in hypotension

MethoxamineMethoxamine is a direct-acting, synthetic adrenergic drug that binds to alpha receptors, is a direct-acting, synthetic adrenergic drug that binds to alpha receptors,

causing vasoconstriction. its effects on the vagus nerve by reflex increase causing vasoconstriction. its effects on the vagus nerve by reflex increase blood pressure blood pressure

- used clinically to relieve attacks of paroxysmal supraventricular tachycardia.- used clinically to relieve attacks of paroxysmal supraventricular tachycardia. - used to overcome hypotension during surgery involving halothane- used to overcome hypotension during surgery involving halothane

anesthetics.anesthetics. Adverse effectsAdverse effects include hypertensive headache and vomiting. include hypertensive headache and vomiting.

ClonidineClonidine is an alpha-2 agonist that is used in essential hypertension to lower blood is an alpha-2 agonist that is used in essential hypertension to lower blood

pressure because of its action in the CNS . pressure because of its action in the CNS .

Metaproterenol, Albuterol, pirbuterol, and terbutaline, Metaproterenol, Albuterol, pirbuterol, and terbutaline, Salmeterol and formoterolSalmeterol and formoterol

Beta-2 agonist producing little effect on the heart. ItBeta-2 agonist producing little effect on the heart. It produces dilation of the produces dilation of the bronchioles. The drug is useful as a bronchodilator in the treatment of asthma bronchioles. The drug is useful as a bronchodilator in the treatment of asthma

Indirect-Acting Adrenergic AgonistsIndirect-Acting Adrenergic Agonists Indirect-acting adrenergic agonists cause norepinephrine release from Indirect-acting adrenergic agonists cause norepinephrine release from

presynaptic terminals or inhibit the uptake of norepinephrine. These agents presynaptic terminals or inhibit the uptake of norepinephrine. These agents do not directly affect postsynaptic receptors.do not directly affect postsynaptic receptors.

AmphetamineAmphetamine The marked central stimulatory action of amphetamine is often mistaken The marked central stimulatory action of amphetamine is often mistaken

by drug abusers as its only action. the drug can increase blood pressure by drug abusers as its only action. the drug can increase blood pressure significantly by alpha-agonist action on the vasculature as well as beta significantly by alpha-agonist action on the vasculature as well as beta stimulatory effects on the heart. Its peripheral actions are mediated stimulatory effects on the heart. Its peripheral actions are mediated primarily through the blockade of norepinephrine uptake and cellular primarily through the blockade of norepinephrine uptake and cellular release of stored catecholamines; thus, amphetaminerelease of stored catecholamines; thus, amphetamine is an indirect-acting is an indirect-acting adrenergic drug. It use for treating hyperactivity in children, narcolepsy, adrenergic drug. It use for treating hyperactivity in children, narcolepsy, and appetite control. Its use in pregnancy should be avoided because of and appetite control. Its use in pregnancy should be avoided because of adverse effects on development of the fetus.adverse effects on development of the fetus.

TyramineTyramine Tyramine is not a clinically useful drug, but it is important because it is Tyramine is not a clinically useful drug, but it is important because it is

found in fermented foods, such as ripe cheese and Chianti wine. It is a found in fermented foods, such as ripe cheese and Chianti wine. It is a normal by product of tyrosine metabolism.normal by product of tyrosine metabolism.

CocaineCocaine Cocaine is unique among local anesthetics in having the ability to block the Cocaine is unique among local anesthetics in having the ability to block the

Na+/K+-activated ATPase.Na+/K+-activated ATPase.

Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.

Mixed-Action Adrenergic AgonistsMixed-Action Adrenergic Agonists Mixed-action drugs induce the release of norepinephrine from presynaptic Mixed-action drugs induce the release of norepinephrine from presynaptic

terminals, and they activate adrenergic receptors on the postsynaptic membrane.terminals, and they activate adrenergic receptors on the postsynaptic membrane.

Ephedrine and pseudoephedrineEphedrine and pseudoephedrine Ephedrineand and pseudoephedrine are plant alkaloids, that are now made Ephedrineand and pseudoephedrine are plant alkaloids, that are now made

synthetically. These drugs are mixed-action adrenergic agents. They not only synthetically. These drugs are mixed-action adrenergic agents. They not only release stored norepinephrine from nerve endings but also directly stimulate both release stored norepinephrine from nerve endings but also directly stimulate both alpha and beta receptors. Ephedrine and pseudoephedrinealpha and beta receptors. Ephedrine and pseudoephedrine are not catechols and are not catechols and are poor substrates for COMT (catechol O-methyltransferase) and MAO are poor substrates for COMT (catechol O-methyltransferase) and MAO (adenosine monophosphate); thus, these drugs have a long duration of action. (adenosine monophosphate); thus, these drugs have a long duration of action.

Pharmacokinetics:Pharmacokinetics: excellent absorption orally and penetrate into the CNS. excellent absorption orally and penetrate into the CNS. EphedrineEphedrine is eliminated largely unchanged in the urine, and pseudoephedrine is eliminated largely unchanged in the urine, and pseudoephedrine incomplete hepatic metabolism before elimination in the urine.incomplete hepatic metabolism before elimination in the urine.

Side effect: Side effect: EphedrineEphedrine raises blood pressures by vasoconstriction and cardiac raises blood pressures by vasoconstriction and cardiac stimulation. stimulation.

Therapeutic usesTherapeutic uses: : - Ephedrine used in chronic treatment of asthma to prevent attacks. - Ephedrine used in chronic treatment of asthma to prevent attacks. - Ephedrine improves motor function in myasthenia gravis.- Ephedrine improves motor function in myasthenia gravis. with with

anticholinesterases. anticholinesterases. -Ephedrine stimulation of-Ephedrine stimulation of the CNS produce increases alertness, decreases fatigue, the CNS produce increases alertness, decreases fatigue,

and prevents sleep and improves athletic performance.and prevents sleep and improves athletic performance. -Pseudoephedrine-Pseudoephedrine is primarily used to treat nasal and sinus congestion or is primarily used to treat nasal and sinus congestion or

congestion of thecongestion of the eustachian tubes. eustachian tubes.

Adrenergic AntagonistsAdrenergic Antagonists (blockers or sympatholytic)(blockers or sympatholytic) The adrenergic antagonists bind to adrenoceptors but do not trigger the usual The adrenergic antagonists bind to adrenoceptors but do not trigger the usual

receptor-mediated intracellular effects. These drugs act by either reversibly or receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibleirreversible attaching to the receptor, thus preventing its activation by attaching to the receptor, thus preventing its activation by endogenous catecholamines. These are classified according to affinities for endogenous catecholamines. These are classified according to affinities for alpha or beta receptors. alpha or beta receptors.

Alpha Adrenergic Blocking AgentsAlpha Adrenergic Blocking Agents blockade of these receptors reduces the sympathetic tone of the blood vessels, blockade of these receptors reduces the sympathetic tone of the blood vessels,

This induces a reflex tachycardia resulting from the lowered blood pressure.This induces a reflex tachycardia resulting from the lowered blood pressure.PhenoxybenzaminePhenoxybenzamine is nonselective, noncompetitive, irreversible), linking to both alpha-1 is nonselective, noncompetitive, irreversible), linking to both alpha-1

postsynaptic and Alpha-2 presynaptic receptors. The actions about 24 hours postsynaptic and Alpha-2 presynaptic receptors. The actions about 24 hours after a single administration. after a single administration.

Actions:Actions:a- Cardiovascular effects: a- Cardiovascular effects: By blocking alpha receptors, prevents vasoconstriction. By blocking alpha receptors, prevents vasoconstriction.

Decrease blood pressure but increase cardiac output by reflex tachycardia due Decrease blood pressure but increase cardiac output by reflex tachycardia due to decreased peripheral resistance, inhibitory alpha- 2 receptors in the heart to decreased peripheral resistance, inhibitory alpha- 2 receptors in the heart

b- Epinephrine reversal: b- Epinephrine reversal: All alpha adrenergic blockers reverse the alpha agonist All alpha adrenergic blockers reverse the alpha agonist actions of epinephrine the vasoconstrictive action of epinephrineactions of epinephrine the vasoconstrictive action of epinephrine is interrupted is interrupted but vasodilation of other vascular caused by stimulates beta receptors on the but vasodilation of other vascular caused by stimulates beta receptors on the heart is not blocked .Therefore, the systemic blood pressure decreases in heart is not blocked .Therefore, the systemic blood pressure decreases in response to epinephrineresponse to epinephrine given in the presence of phenoxybenzamine. given in the presence of phenoxybenzamine.

Therapeutic uses: Therapeutic uses: - used in the treatment of pheochromocytoma, before surgery removal- used in the treatment of pheochromocytoma, before surgery removal to to

prevent the hypertensive.prevent the hypertensive. - effective in treating Raynaud's disease. - effective in treating Raynaud's disease. - Autonomic hyperreflexia - Autonomic hyperreflexia .. Adverse effects:Adverse effects: can cause hypotension, nasal stuffiness, nausea, and can cause hypotension, nasal stuffiness, nausea, and

vomiting. vomiting.

PhentolaminePhentolamine competitive block of alpha-1 and alpha-2 receptors. The drug's action lasts for competitive block of alpha-1 and alpha-2 receptors. The drug's action lasts for

4 hours side effect cause tachycardia, arrhythmias and anginal pain. Used 4 hours side effect cause tachycardia, arrhythmias and anginal pain. Used for diagnosis of pheochromocytoma.for diagnosis of pheochromocytoma.

Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosinPrazosin, terazosin, doxazosin, alfuzosin, and tamsulosin are selective competitive blockers of the alpha-1 receptor. The first three are selective competitive blockers of the alpha-1 receptor. The first three

drugs aredrugs are - useful in the treatment of hypertension . - useful in the treatment of hypertension . -Tamsulosin and alfuzosin-Tamsulosin and alfuzosin are indicated for the treatment of prostatic are indicated for the treatment of prostatic

hyperplasia. hyperplasia. -Metabolism leads to inactive products that are excreted in the urine except for -Metabolism leads to inactive products that are excreted in the urine except for

those ofthose of -doxazosin, which appear in the feces. Doxazosin-doxazosin, which appear in the feces. Doxazosin is the longest acting of these is the longest acting of these

drugs.drugs.

- Cardiovascular effects:- Cardiovascular effects: decrease peripheral vascular resistance and lower decrease peripheral vascular resistance and lower arterial blood pressure arterial blood pressure

Therapeutic uses: Therapeutic uses: - hypotensive response that can result in syncope ( first-dose) effect, may be - hypotensive response that can result in syncope ( first-dose) effect, may be

minimized by adjusting the first dose to 1/3 or 1/4 of the normal dose.minimized by adjusting the first dose to 1/3 or 1/4 of the normal dose. - Prostatic hypertrophy decreases tone in the smooth muscle of the bladder - Prostatic hypertrophy decreases tone in the smooth muscle of the bladder

neck and prostate and improves urine flow. neck and prostate and improves urine flow. Adverse effects: Adverse effects: dizziness, a lack of energy, nasal congestion, headache, dizziness, a lack of energy, nasal congestion, headache,

drowsiness,drowsiness, and orthostatic Due to retain sodium and fluid used along with a diuretic. and orthostatic Due to retain sodium and fluid used along with a diuretic.

YohimbineYohimbine is a selective competitive alpha- 2 blocker. It is found as a component of is a selective competitive alpha- 2 blocker. It is found as a component of

the bark of the yohimbe tree.the bark of the yohimbe tree. Uses:Uses: as a sexual stimulant and as a sexual stimulant and used to relieve vasoconstriction associated used to relieve vasoconstriction associated

with Raynaud's disease. with Raynaud's disease.

Beta- Adrenergic Blocking AgentsBeta- Adrenergic Blocking Agents beta blockers are competitive antagonists, divided into nonselective (beta-1 beta blockers are competitive antagonists, divided into nonselective (beta-1

beta- 2 receptors) and cardioselective beta-1 receptors. These drugs also differ beta- 2 receptors) and cardioselective beta-1 receptors. These drugs also differ in in

- intrinsic sympathomimetic activity, - intrinsic sympathomimetic activity, - CNS effects- CNS effects - pharmacokinetics. - pharmacokinetics. Although all beta blockers lower blood pressure in hypertension without Although all beta blockers lower blood pressure in hypertension without

postural hypotension, because the alpha adrenoceptors remain functional. postural hypotension, because the alpha adrenoceptors remain functional. Uses:Uses: angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma and prophylaxis of migraine (headaches). hyperthyroidism, and glaucoma and prophylaxis of migraine (headaches).

Propranolol ( ideral )Propranolol ( ideral ) nonselective beta antagonist, blocks ( beta-1 and beta-2) receptors.nonselective beta antagonist, blocks ( beta-1 and beta-2) receptors.Actions:Actions:- Cardiovascular: - Cardiovascular: Propranolol diminishes cardiac output, having both negative Propranolol diminishes cardiac output, having both negative

inotropic and chronotropic effects. It directly depresses sinoatrial and inotropic and chronotropic effects. It directly depresses sinoatrial and atrioventricular activity, and decreased consumption of oxygen these effects are atrioventricular activity, and decreased consumption of oxygen these effects are useful in the treatment of angina useful in the treatment of angina

- Peripheral vasoconstriction: - Peripheral vasoconstriction: Blockade of beta receptors prevents beta-2 Blockade of beta receptors prevents beta-2 mediated vasodilation. The reduction in cardiac output leads to decreased blood mediated vasodilation. The reduction in cardiac output leads to decreased blood pressure and reduced blood flow to the periphery. pressure and reduced blood flow to the periphery.

- Bronchoconstriction: - Bronchoconstriction: Blocking beta-2 receptors causes contraction of the Blocking beta-2 receptors causes contraction of the bronchiolar smooth muscle (asthma). bronchiolar smooth muscle (asthma).

- Increased Na+ retention: - Increased Na+ retention: Reduced blood pressure causes a decrease in renal Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention, (combined with a diuretic). perfusion, resulting in an increase in Na+ retention, (combined with a diuretic).

- Disturbances in glucose metabolism: - Disturbances in glucose metabolism: beta blockade leads to decreased beta blockade leads to decreased glycogenolysis ( not to be given in case of insulin-dependent diabetic) glycogenolysis ( not to be given in case of insulin-dependent diabetic)

- Blocked action of isoproterenol:- Blocked action of isoproterenol: block the actions of isoproterenol and beta block the actions of isoproterenol and beta blocker of epinephrineblocker of epinephrine but norepinephrine but norepinephrine

Therapeutic effects:Therapeutic effects:- Hypertension: - Hypertension: lowers blood pressure in hypertension by Decreased cardiac lowers blood pressure in hypertension by Decreased cardiac

output and inhibition of renin release from the kidneyoutput and inhibition of renin release from the kidney- Glaucoma:- Glaucoma: used in chronic treatment (timolol) neither affects the ability of the used in chronic treatment (timolol) neither affects the ability of the

eye to focus for near vision nor change pupil size, eye to focus for near vision nor change pupil size, - Migraine:- Migraine: in chronic migraine, the mechanism may depend on the blockade of in chronic migraine, the mechanism may depend on the blockade of

catecholamine-induced vasodilation in the brain vasculature. catecholamine-induced vasodilation in the brain vasculature. - Hyperthyroidism: - Hyperthyroidism: In acute hyperthyroidism (thyroid storm), prevent cardiac In acute hyperthyroidism (thyroid storm), prevent cardiac

arrhythmias.arrhythmias.- Angina pectoris: - Angina pectoris: useful in the chronic management of stable angina, decreases useful in the chronic management of stable angina, decreases

the oxygen requirement of heart muscle and reducing the chest pain the oxygen requirement of heart muscle and reducing the chest pain - Myocardial infarction:- Myocardial infarction: prophylactic use in myocardial infarction reduces infarct prophylactic use in myocardial infarction reduces infarct

size and hastens recovery. The mechanism for these effects may be a blocking of size and hastens recovery. The mechanism for these effects may be a blocking of the actions of circulating catecholamines, which would increase the oxygen the actions of circulating catecholamines, which would increase the oxygen demand, also reduces the incidence of sudden arrhythmic death after myocardial demand, also reduces the incidence of sudden arrhythmic death after myocardial infarction. infarction.

Adverse effects:Adverse effects:Bronchoconstriction: Bronchoconstriction: asthma.asthma.Arrhythmias: Arrhythmias: Treatment with β-blockers must never be stopped quickly Treatment with β-blockers must never be stopped quickly

because of the risk of precipitating cardiac arrhythmias, which may be because of the risk of precipitating cardiac arrhythmias, which may be severe. severe.

Sexual impairment: Sexual impairment: Because sexual function in the male occurs through alpha Because sexual function in the male occurs through alpha adrenergic activation, beta blockers do not affect normal ejaculation or the adrenergic activation, beta blockers do not affect normal ejaculation or the internal bladder sphincter function. internal bladder sphincter function.

Drug interactions: Drug interactions: Drugs that interfere with the metabolism of Drugs that interfere with the metabolism of propranololpropranolol, , such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. Conversely, those that stimulate its metabolism, antihypertensive effects. Conversely, those that stimulate its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.such as barbiturates, phenytoin, and rifampin, can decrease its effects.

Timolol and nadolol: Nonselective beta antagonistsTimolol and nadolol: Nonselective beta antagonists Timolol used in chronic glaucoma and occasionally, hypertension.Timolol used in chronic glaucoma and occasionally, hypertension.Acebutolol, atenolol, metoprolol, and esmolol: Selective beta-1Acebutolol, atenolol, metoprolol, and esmolol: Selective beta-1 antagonistsantagonists - eliminate the unwanted bronchoconstrictor effect (beta-2 effect) in asthma.- eliminate the unwanted bronchoconstrictor effect (beta-2 effect) in asthma. - Cardioselective beta -1 blockers, at low doses (50-100) times than bera-2 - Cardioselective beta -1 blockers, at low doses (50-100) times than bera-2

blockers blockers - - These drugs lower blood pressure in diabetic hypertensive patients. These drugs lower blood pressure in diabetic hypertensive patients. - Esmolol has a very short lifetime due to metabolism of an ester linkage. It - Esmolol has a very short lifetime due to metabolism of an ester linkage. It

is only given intravenously if required during surgery is only given intravenously if required during surgery

Pindolol and acebutolol: Antagonists with partial agonist activityPindolol and acebutolol: Antagonists with partial agonist activityActions:Actions:Cardiovascular:Cardiovascular: have intrinsic sympathomimetic activity (ISA). These partial have intrinsic sympathomimetic activity (ISA). These partial

agonists stimulate the beta receptor, yet they inhibit stimulation by the more agonists stimulate the beta receptor, yet they inhibit stimulation by the more potent catecholamines, epinephrinepotent catecholamines, epinephrine and norepinephrine. and norepinephrine.

-These are effective in hypertensive patients with moderate bradycardia, because -These are effective in hypertensive patients with moderate bradycardia, because decrease effect on heard rate and cardiac output is less pronounceddecrease effect on heard rate and cardiac output is less pronounced

- - Carbohydrate metabolism is less affected (valuable in the treatment of Carbohydrate metabolism is less affected (valuable in the treatment of diabetics)diabetics)

- Not used as antiarrhythmic agents - Not used as antiarrhythmic agents Labetalol and carvedilol: Antagonists of both alpha- and betaLabetalol and carvedilol: Antagonists of both alpha- and beta adrenoceptorsadrenoceptors Actions:Actions: reversible blocke alpha and beta receptors. used in treating the elderly or reversible blocke alpha and beta receptors. used in treating the elderly or

black hypertensive patients for whom increased peripheral vascular resistance is black hypertensive patients for whom increased peripheral vascular resistance is undesirable. They do not alter serum lipid or blood glucose levels. [Note: In undesirable. They do not alter serum lipid or blood glucose levels. [Note: In general, black hypertensive patients are not well controlled with β-blockers.] general, black hypertensive patients are not well controlled with β-blockers.] and used in pregnancy-induced hypertension. and used in pregnancy-induced hypertension.

Adverse effects: Adverse effects: Orthostatic hypotension and dizziness Orthostatic hypotension and dizziness

Drugs Affecting Neurotransmitter Release or UptakeDrugs Affecting Neurotransmitter Release or Uptake They effects indirectly on the adrenergic neuron by causing the release of They effects indirectly on the adrenergic neuron by causing the release of

neurotransmitter from storage vesicles or alter the uptake of the neurotransmitter from storage vesicles or alter the uptake of the neurotransmitter into the adrenergic nerve. neurotransmitter into the adrenergic nerve.

ReserpineReserpine Plant alkaloid, blocks the amines transport system Mg2+/adenosine Plant alkaloid, blocks the amines transport system Mg2+/adenosine

triphosphate (ATP) from the cytoplasm into storage vesicles, has a slow onset, triphosphate (ATP) from the cytoplasm into storage vesicles, has a slow onset, a long durationa long duration

of action, and effects that persist for many days. Decrease blood pressure.of action, and effects that persist for many days. Decrease blood pressure.

GuanethidineGuanethidine blocks the release of stored norepinephrine as well as displaces norepinephrineblocks the release of stored norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure). from storage vesicles (thus producing a transient increase in blood pressure). Side effectSide effect: causes orthostatic hypotension and interferes with male sexual : causes orthostatic hypotension and interferes with male sexual

function. function.

CocaineCocaine Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist. Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist.