pharmacology autonomous nervous system s.pptx

C hapter two 1 AUTONOMIC PHARMACOLOGY

Introduction The nervous system is divided into two parts: Central nervous system (CNS) Peripheral nervous system ( PNS ) The CNS consists of the brain and spinal cord The PNS consists of Afferent (sensory) neurons Efferent (motor) neurons 2

The peripheral efferent system is further divided into Somatic nervous system Effector cells are skeletal muscle cells Controls voluntary movement of skeletal muscles Respiration , body movements Autonomic nervous system The effector cells are Smooth muscle cells, cardiac cells & exocrine glands Mainly controls involuntary body functions Cardiac functions, visceral organ functions 3

Nervous System Peripheral nervous Central nervous system (PNS) system (CNS) Afferent Efferent Brain Spinal (sensory) (motor) cord Somatic nervous Autonomic nervous system (SNS) system (ANS) Sympathetic Parasympathetic Enteric nervous system ( thoraco -lumbar) ( Cranio -sacral) 4

Difference between Somatic NS and ANS Somatic NS concerned with consciously controlled functions e.g . Movement , Respiration Innervate skeletal muscle consist of a single motor neuron Has no peripheral ganglia Effect is always excitation Autonomic NS activities are not under conscious control *concerned primarily with visceral functions: Regulation of the heart, temp., secretary glands, digestion, metabolism Innervate visceral organs consist of two motor neurons in series Has ganglia b/n pre-synaptic and post synaptic Effect is both excitatory & inhibitory 5

Autonomic nervous system(ANS) ANS is autonomic Its actions are involuntary, unconscious & automatic by their nature Anatomic aspects of the ANS Autonomic nerves are composed of two neurons The preganglionic neurons (myelinated) The postganglionic neurons (not myelinated) 6

C lassification of ANS ANS is further classified as: Sympathetic NS Cell bodies of the preganglionic neurons arise from thoracic and lumbar areas of spinal cord Also called as thoracolumbar division of ANS Parasympathetic NS Cell bodies of the preganglionic neurons arise from cranial and sacral regions of the spinal cord Also called as craniosacral division of ANS 7

Enteric nervous system is sometimes considered a third division of the ANS. is a collection of nerve fibers that innervate the gastrointestinal tract, pancreas, and gallbladder, constitutes the brain of the gut . Functions independently of the CNS and controls the motility, exocrine and endocrine secretions and microcirculation of the gastrointestinal tract. is modulated by both the sympathetic and parasympathetic nervous systems. 8

Locations of autonomic ganglia Sympathetic ganglia is found near to vertebral column preganglionic fibers are generally short post ganglionic fibers are generally long Exceptions : few sympathetic ganglia lie near the organs innervated e.g. urinary bladder & rectum Parasympathetic ganglia lie very close to the effector/organs innervated preganglionic neurons are long post ganglionic neurons are short 9

ANS Functions Sympathetic nervous system functions 1) Regulating the cardiovascular system Increase cardiac output Causes vasoconstriction 2) Regulate body temperature By regulating blood flow to the skin By promoting secretion of sweat , thereby helping the body to cool By inducing piloerection (erection of hair) can promote heat conservation 10

Sympathetic nervous system functions…….. 3. Implementing the “ fight – or – flight ” reaction which consists Increasing heart rate and blood pressure Shunting blood away from the skin and viscera into skeletal muscles Dilating the bronchi to improve oxygenation Dilating the pupil to enhance visual acuity Mobilizing stored energy thereby providing glucose for the brain and fatty acids for muscles 11

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Parasympathetic nervous system functions maintains essential bodily functions such as digestive processes, elimination of wastes and is required for life usually acts to oppose or balance the actions of the sympathetic division Is dominant over the sympathetic in “rest and digest” situations 13

Functions of parasympathetic nervous system Slowing the heart rate Increase gastric secretion Emptying of the bladder Emptying of the bowel Focusing the eye for near vision Constricting the pupil Contracting bronchial smooth muscle So that, the PsNS is concerned primarily with what might be called “ the housekeeping ” chores of the body (digestion of food and excretion of wastes) In addition, the system helps, control vision & conserve energy (by reducing cardiac work) 14

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Patterns of autonomic innervations Dual innervations Opposite action Complementary actions Single innervation 16

Dual innervations Opposite action : refers that the organ/tissue receives innervations from both PsNS & SNS and: the influence of sympathetic nerves opposes that of parasympathetic nerves e.g. heart rate II. Complementary actions : in some tissues/organs the two divisions supplement each other E.g. In the male reproductive system, 17

Patterns of autonomic innervations….. Single innervation A few structures under autonomic control receive innervations from only one division E.g. adrenal medulla arrector pili muscles sweat glands and Most blood vessels : are innervated by sympathetic division only Exceptions : some blood vessels of the face, tongue & penis are innervated by PsNS 18

Neurotransmission Neurotransmission in the peripheral NS occurs at 3 major sites: Preganglionic synapses in both PsNS & SNS Postganglionic neuroeffector junctions of PsNS & SNS All somatic motor end plates on skeletal muscles Most PsNS postganglionic neurons are cholinergics Significant number of PsNS postganglionic neurons utilize NO or peptides for transmission All preganglionic efferent autonomic fibers are cholinergic 19

Only a few of SNS postganglionic neurons are cholinergic (i.e. those innervate sweat gland) All efferent somatic fibers are cholinergic Most of the postganglionic SNS fibers are adrenergic 20

Cholinergic neurons are neurons which synthesis, store & release Ach Cholinomimetics are those agents which mimic the activity of Ach Are also called parasympathomimetics Chlinoreceptors are binding site for Ach & cholinomimetics Cholinoreceptor antagonists are agents which antagonize the actions of Ach 21

Adrenergic neurons are neurons which synthesis, store & release NE Adrenomimetics are agents which mimic the activities of NE Are also called sympathomimetics Adrenoceptors are binding sites for NE, EP & adrenomimetics Adrenoceptor antagonists are agents which antagonize the activities of NE are also called sympatholytics/sympathoplegics 22

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Regardless of the type of neuron under consideration the fundamental steps in chemical transmission are the same Each of these steps is a potential site for pharmacological intervention in the normal transmission process 24

Steps in neurotransmission includes: Synthesis of the transmitter Storage of the transmitter Release of the transmitter by a nerve action potential Interaction of the released transmitter with receptors on the effector cell membrane and the associated change in the effector cell Rapid removal of the transmitter from the vicinity of the receptors Recovery of the effector cell to the state that preceded transmitter action 25

Cholinergic neurotransmission Synthesis of Acetylcholine (Ach) Ach is synthesized in cholinergic neurons from Acetyl CoA & Choline by the enzyme Choline acetyltransferase (ChAT) Acetyl-coA is synthesized in the mitochondria Choline is found in the extracellular fluid Transported into the neuron by sodium-dependent carrier protein (Carrier A) Can be inhibited by drugs called Hemicholiniums Acetyl CoA + Choline Choline acetyl transferase ( ChAT ) Ach 26

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Degradation of Acetylcholine After release, Ach binds & activates cholinoceptors Eventually, all of Ach molecules will be degraded by AchE (Acetyl cholinesterase) Ach AchE Choline + acetate Choline is recycled 29

Cholinesterase Rapidly metabolizes Ach into Choline & acetate Choline is recycled into the neuron Highly accumulated in the neuron & effector cells Two types True cholinesterase Found in the neurons & effectors Specifically metabolizes Ach Pseudo cholinesterase Found in the plasma, liver, glia & other tissues Also called butyrylcholinesterase Non specific (also metabolizes other ester compounds) 30

Adrenergic neurotransmission Transmission in noradrenergic neurons is somewhat more complex steps of synthesis and removal mechanisms Synthesis of norepinephrine (NE) begins with the amino acid tyrosine Enters the neuron by Na+/tyrosine symporter In the neuronal cytosol, tyrosine is changed into dihydroxyphenylalanine ( DOPA ) by tyrosine hydroxylase ( rate limiting step ) Inhibited by tyrosine analog, metyrosine 31

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DEGRADATION OF NE/EP For terminating the actions of NE/EP, there are three mechanisms Neuronal reuptake NE/EP is transported back to the neuronal cytoplasm by carrier 1 Commonly called uptake 1 or reuptake 1 Can be inhibited by cocaine & TCAs NE/EP can be metabolized or stored in the vesicle is the most important mechanism for removing NE/EP 33

II. Diffusion into the circulation NE/EP escapes from the junctional space to circulation Ultimately metabolized by liver & kidney enzymes Catechol-O-methyl transferase ( COMT ) & monoamine oxidase ( MAO ) 34

Catechol O-methyl transferase (COMT) Very specific enzyme to substances with catechol ring Cathecol is a substance with two adjacent OH groups on unsaturated six member ring Reduces the activity of NE/EP by at least 100 times 35 Catechol ring

Monoamine oxidase (MAO) Less specific enzyme as compared to COMT Metabolizes an amine group from varieties of substances Metabolizes NE, EP, dopamine, serotonin, tyramin etc Two types MAO-A and MAO-B Although either COMT or MAO may act first on circulating NE/EP COMT is the more rapidly acting enzyme Therefore, more molecules are O- methylated and then deaminated 36

Autonomic receptors 37

Types of receptors Receptors can be divided into four families Ligand gated ion channels G-protein coupled receptors Enzyme linked receptors Intracellular receptors 38

Ligand gated ion channels are responsible for regulation of the flow of ions across cell membrane The activity of these channels is regulated by the binding of a ligand to the channel Binding of a ligand to the receptor results in the opening of the ion channel and the subsequent flow of ions Response to these receptors is very rapid, having duration of a few milliseconds e.g. nicotinic Ach receptors GABA receptors 39

G-protein coupled receptors Consists of a single peptide that has seven membrane spanning regions These receptors are linked to a G-protein having three subunit Binding of the appropriate ligand to the extracellular region of the receptor activates the G-protein so that GTP replaces GDP on the α - subunit Dissociation of the G-protein occurs and both the a- subunit and the B subunit subsequently interacts with other cellular effectors that produces secondary messengers 40

Secondary messengers Includes cAMP, IP3 and DAG They are formed by the activation of enzymes by G- protein coupled receptors cAMP by adenylcyclase IP3 and DAG by phospholipase C These secondary messengers in turn activates kinases that phosphorylate proteins at specific amino acid residue The observed effect of a ligand binding to a G-protein coupled receptors is the consequence of increase in intracellular concentration of secondary messengers 41

Autonomic receptors Includes cholinergic and adrenergic receptors Cholinergic receptors Two types: muscarinic & nicotinic cholinoceptors Muscarinic receptors All are GPCRs Are activated by muscarine (plant alkaloid) Found in many visceral organs such as smooth muscle cells, cardiac cells, exocrine glands, CNS, Autonomic ganglia Further classified into M1, M2, M3, M4 & M5 M1, M3 & M5 Activate the IP3 & DAG pathway Activate adenylcyclase pathway 42

So, the M1, 3 & 5 receptors are involved in Increasing glandular secretion Smooth muscle contraction M2 & M4 Are coupled to Gi /Go So inhibit the activity of adenylyl cyclase 43

Cholinergic receptors ……….. Nicotinic receptors Are ligand – gated ion channels Activated by nicotine (tobacco alkaloid) Formed by five subunits arranged around a central pore The pore becomes permeable to Na+ and Ca +2 when the receptor is activated by Ach Resulting in depolarization and excitation of the cell 44

Based on their location nicotinic Ach receptors are grouped into two types Nn (at ganglia) Nm (at neuromuscular junction) 45

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Adrenoceptors Interact with NE, EP & other related drugs Two types based on agonist selectivity α -adrenoceptors ( α -1, α -2) β -adrenoceptors ( β -1, β -2) α -affinity: Norepinephrine ≥ epinephrine >> isoproteranol β - affinity: Isoproteranol >epinephrine >> norepinephrine Isoproteranol is synthetic adrenomimetic agent 47

α -1 are found on post junctional or post synaptic neurons α -2 are mostly found presynaptically involved in feedback inhibition of NE (autoreceptors) Other NTs (hetroreceptors) β -1 are mainly found in heart & fat cells β -2 are mainly found in Bronchial smooth muscles, brain, liver, kidney Skeletal muscle blood vessels Activation causes vasodilatation of vessels of skeletal muscle 48

Pharmacology of ANS 49

Cholinomimetic drugs Similar effects to acetylcholine (Ach) Elicit all or some of the effects of Ach Classified as Direct acting Cholinergic receptor agonists Indirect acting acetyl cholinesterase enzyme inhibitors (AchEIs) also called anticholinesterase 50

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Choline esters Activate either muscarnic or nicotinic receptors or both Are Polar compounds and poorly cross GIT and BBB Differ in duration of action Ultra short action ……Ach Intermediate action……methacholine Long action……Bethanecole and carbacol 52

Synthetic Choline Esters Includes methacholine, Carbachol & Bethanechol Are derivatives of acetylcholine These drugs have the following advantages over acetylcholine: longer duration of action effective orally as well as parenterally, and relatively more selective in their actions 53

Pharmacogocal properties of choline esters Heart: negative chronotropic effect negative dromotrpic effect negative inotropic effect 54

Gastrointestinal System : Choline esters causes: Increase in amplitude of contractions Increase peristaltic activity of the stomach and intestine Enhanced secretory activity of GIT 55

G enitourinary tract: Cholinesters can cause: Increase urethral peristalsis Contraction of detruser muscle of the urinary bladder increase voluntary voiding pressure Decrease capacity of the bladder Relaxation of trigone and sphincters Carbachol and Bethanechol stimulate GIT and urinary tract selectively, unlike Ach and methacholine. 56

Respiratory system Muscarinic stimulants : Contract smooth muscles of the bronchial tree Increase secretion of the glands of the trachiobronchial mucosa. These combination effects can occasionally cause symptoms, especially in individuals with asthma. 57

Eye: The iris has two types of muscles Circular papillary constrictor smooth muscle ( has M 3 receptor) At the papillary margin, the sphincter smooth muscle is organized in a circular band with parasympathetic innervations, which when stimulated causes miosis (constriction). Radial papillary dilator smooth muscle( α -1 receptor) Anterior to the pigmented epithelium, the dilator smooth muscle is oriented radially and is innervated by the sympathetic nervous system which causes mydriasis ( dilation ). 58

The eye has also ciliary body which has two main parts : Ciliary process secretion of aqueous humor by the epithelial bilayer( has B- 2 receptor ) Ciliary muscles : has only M3 receptor Coordinated contraction of this smooth muscle apparatus by the parasympathetic nervous system causes the suspending ligament of the lens to relax, allowing the lens to become more convex and to shift slightly forward. 59

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The pharmacological effects of cholinomometic drugs on the eye include Miosis due to stimulation of papillary constrictor smooth muscle ……… M 3 receptor Accommodation to near objects due to constriction of ciliary muscles …………… M 3 receptors 61

Cholinomimetic alkaloids Includes Pilocarpine ……use externally muscarine arecoline not clinically used due to toxicity nicotine 62

Pilocarpine Alkaloid obtained from pilocarpus microphyllus and pilocarpus japorandi. A tertiary amine compound Can cross the cornea of the eye & BBB more easily & faster Pure muscarinic agonist A natural alkaloid Not affected by cholinesterase 63

Pharmacologic effects Increase in GIT smooth muscle tone & peristalsis Dilates blood vessels Decreases heart activity Miosis, accommodation for near vision Decrease intraocular pressure 64

Therapeutic uses Pilocarpine is mainly used for topical uses b/c of muscarinic systemic toxicity Used in the treatment of Glaucoma To reverse mydriatic (dilating) effects of atropine Xerostomia (dry mouth) Fever Works by increasing sweatin g Adverse effects Similar to ach Reversed by atropine 65

Glaucoma accumulation of fluid in the eye & increased intraocular pressure Could be Open angle glaucoma Porosity of the trabecular meshwork is not adequate to permit movement of fluid into the canal of Schlemn Treated with pilocarpine, Carbachol Angle closure glaucoma Abnormal positioning of the peripheral iris blocking the access of fluid to the trabecular meshwork Treated with pilocarpine or by surgical removal of part of the iris ( iridectomy ). 66

Contraindication to cholinomimetics Bronchial asthma GIT hyper-motility Peptic ulcer disease Coronary artery disease Hypotension Bradycardia 67

Adverse effects Choline esters can cause: Nausea Abdominal cramps Salivation Diarrhea Hypotension Reflex tachycardia Bronchoconstriction Sweating Flushing 68

Indirectly acting cholinomimetic agents Reversible inhibitors of AchE Irreversible inhibitors of AchE 69

Reversible inhibitors of AchE Noncovalent Inhibitors Edrophonium Tacrine Donepezil Carbamate Inhibitors Physostigmine Neostigmine Pyridostigmine 70

Irreversible Acetylecholinesterase Inhibitors (organophosphates) Diisofluorophosphate (DFP) Insecticides Malathione Parathion Nerve gases Sarin Tabun Soman Echothiophate iodide 71

Tacrine / Donepezil synthetic tertiary ammonium compound higher affinity to AchE readily cross the blood brain barrier to inhibit AChE in the CNS longer duration of action useful in patients with Alzheimer’s disease 72

Carbamate Esters covalent binding bind reversibly with the esteratic site increase relative conc. of Ach does not alter enzyme function 73

Physostigmine an alkaloid obtained from Physostigma venenosum tertiary amine activates both muscarinic and nicotinic receptor can easily enter the CNS 2-4 hours duration of action 74

Neostigmine synthetic quaternary ammonium compound more polar – do not pass through the BBB directly stimulates Nicotinic Receptor at the motor end plate 2-4 hrs duration of action 75

Neo….. dual action reversible Achase inhibitor direct activation of nicotinic receptor at the motor end plate beneficial in Myasthenia Gravis Antidote for toxicity to Non-depolarizing Neuromuscular blocker 76

Pyridostigmine synthetic quaternary ammonium compound used for long term treatment of Myasthenia gravis longer duration of action (4-6 hrs) 77

Irreversible Acetylcholinesterase Inhibitors Organophosphates covalent binding cause inhibition of physiologic function of enzyme Phosphorylate enzyme complex undergo “aging” 78

LOSS OF AN ALKYL GROUP FROM PHOSPHORYLATED AChE “AGES” THE ENZYME 79 AChE, phosphorylated and inhibited by DFP “Aged” AChE

Pharmacological Properties Organophosphates highly lipid soluble except Echothiophate effectively absorbed from all routes endogenous Ach stimulates all cholinergic receptors (peripheral and CNS) 80

Parathion/ Malathion low volatility and stability in aqueous solutions widely used as insecticides employed for home, garden and agricultural use also use in suicide attempts or deliberate poisoning also used topically in the treatment of Pediculosis (lice infestations ) converted to active metabolites by CYPs 81

Nerve Gases most potent synthetic toxins known used in warfare and terrorism attacks 82

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Victims of the Sarin attack taken from the Tokyo subways on March 20, 1995 84

Therapeutic uses of '' Reversible '' carbamate inhibitors'' Glaucoma- Physostigmine Myasthenia gravis- Neostigmine, Pyridostigmine Edrophonium is used for diagnosis. Post operative paralytic ileus-atony or paralysis of the stomach or bowel following surgical manipulation. neostigmine 85

CHOLINESTERASE REACTIVATORS The drugs which reactivate acetyl cholinesterase are oximes like pyridone-2-aldoxime(2- PAM )-SC, IM, PO diacetyle monoxime , obidoxime (more potent than 2-PAM)-cross BBB especially useful in reversing neuromuscular effects of organophosphorous compounds which cannot be inhibited by atropine ( muscarnic antagonist ) 86

Cholinoceptor Antagonists Or Parasympatholytics 87

Cholinoceptor antagonists Muscarinic receptor antagonists Nicotinic receptor antagonists Naturally occurring alkaloids : atropine & scopolamine Semisynthetic derivatives of the alkaloids : differ in PKs Homatropine , ipratropium , tropicamide , methylatropine & tiotropine Synthetic antagonists : receptor selectivity Pirenzepin e, tolterodine & oxybutinin , Clidinium Ganglionic antagonists : Trimethaphane mecamylamine Neuromuscular blockers : gallamine tubocurarine pancuronium vecuronium succinyl choline 88

Muscarinic receptor antagonists Prevent the effects of Ach on muscarinic receptors of Smooth muscles Cardiac muscle & gland cells In the CNS No antagonist, including pirenzepine , is completely selective 89

Pharmacological effects of muscarinic antagonists Muscarinic antagonists have no intrinsic activity T he magnitude of the response produced by muscarinic antagonists depends on The existing level of cholinergic activity or on the presence of muscarinic agonists The organ’s pattern of innervations E.g. some organs receive dual innervation from adrenergic and cholinergic pathways At these locations, block of muscarinic receptors can increase the activity of the adrenergic input 90

Heart Higher doses produce tachycardia due to direct inhibitory effect on the parasympathetic input to SA node Gastrointestinal tract ↓amplitude & frequency of peristaltic contraction, ↓gastric acid secretion, ↓salivation, dry mouth Higher doses are needed to inhibit acid production 91

Eye dilation of the pupil ( mydriasis ) and paralysis of accommodation ( cycloplegia ) responses Causes photophobia & inability to focus on nearby objects 92

Urinary bladder Inhibit cholinergic activity on the detrusor muscle & cause urinary retention Lung Muscarinic antagonists inhibit secretions and relax smooth muscle in the respiratory system 93

Clinical uses of antimuscarinic drugs Cardiovascular Uses Atropine can be useful in Carotid sinus syncope Results from excessive activity of afferent neurons whose stretch receptors are in the carotid sinus By reflex mechanisms, this excessive afferent input to the medulla oblongata causes pronounced bradycardia which is reversible by atropine 2. S-A node dysfunction If sinus bradycardia is due to extracardiac causes, atropine can generally elicit a tachycardic response Whereas it cannot elicit tachycardia if the bradycardia results from intrinsic causes 94

Uses in Anesthesiology To block excessive salivary and respiratory secretions induced by certain inhalation anesthetics (e.g. diethyl ether) E.g. atropine and scopolamine Use With Cholinesterase Inhibitors Atropine or another muscarinic antagonist should be given to prevent the stimulation of muscarinic receptors that accompanies excessive inhibition of AchE in two cases During reversal of competitive NM blockade by using AchEIs When managing myasthenia gravis with AchEIs 95

Uses in Ophthalmology widely used to produce mydriasis & cycloplegia permit an accurate determination of the refractive state of the eye have aesthetic value 96

are also useful in treating specific ocular diseases the antimuscarnic drugs used in ophthalmology include Atropine scopolamine long duration of action cyclopentolate tropicamide short duration of action 97

Uses in Digestive system disorders For the therapy of peptic ulcers Pirenzipine 100-150 mg/day as adjunctive therapy in the treatment of irritable bowel syndrome (IBS) Decrease pain associated with spasm of intestinal smooth muscles, by blocking contractile responses to Ach 98

Genitourinary Tract Overactive urinary bladder disease can be successfully treated with antimuscarinics lower intravesicular pressure, increase capacity & reduce the frequency of contractions Are also useful in treating urinary incontinence, enuresis Uses in cholinomimetic poisoning Atropine is used as an antidote in poisoning by an overdose of a cholinesterase inhibitor 99

Uses in respiratory disorders For a long time, muscarinic receptor blocking drugs occupied a major place in the therapy of asthma But they have been largely replaced by the adrenergic drugs Have low therapeutic index Cause impaired expectoration Consequence of their inhibition of mucous secretion, ciliary activity & mucous transport Ipratropium bromide Is a synthetic quaternary muscarinic blocking drug Gained widespread use in recent years for the treatment of respiratory disorders It is applied topically to the airways through the use of a metered-dose inhaler Has minimal systemic side effects 100

Uses in Parkinsonism Antimuscarinic agents have beneficial effects in the treatment of parkinsonism Especially, drug induced parkinsonism Benztropine mesylate, biperiden, procyclidine and trihexyphenidyl hydrochloride Uses in Motion Sickness Scopolamine is useful for prevention of motion sickness when the motion is very stressful and of short duration When the motion is less stressful & lasts for longer period of time, antihistamines are used than antimuscarinics Promethazine, meclizine, dimenhydrinate A transdermal preparation with a 72-hour duration of action has been marketed for this purpose Blockade of cholinergic sites in the vestibular nuclei & reticular formation may account for the e ffectiveness of this agent 101

Adverse effects Constipation Abdominal distension Retention of urine Photophobia as result of mydriasis Glaucoma Near vision blurred Flushed skin Dry mouth CNS side effects 102

Contraindications Muscarinic blockers are contraindicated in Glaucoma Cardiac diseases Hyperthyroidism Reflux esophagitis Prosthete hypertrophy 103

Nicotinic receptor antagonists Ganglionic blocking drugs Neuromuscular junction blockers (NMBs) 104

GANGLIONIC BLOCKERS Depolarizing ganglion blockers These blocking agents are actually ganglionic stimulants Thus, for nicotine, small doses give an action similar to that of the neutral neuroeffector ACh , an action known as the “Nicotinic effect of ACh ” 105

… However larger amounts of the nicotine bring about a ganglion block characterized initially by depolarization, followed by a typical competitive antagonism. This depolarization of the membrane of the muscle end plate is quite similar to that produced by Ach itself at ganglia and NMJ . Chemicals that cause this type of ganglionic block are not of therapeutic significance 106

Non-depolarizing competitive ganglionic blocking agents Compounds in this class possess the necessary affinity to attach to the nicotinic receptor sites that are specific for Ach but lack the intrinsic activity necessary for impulse transmission. 107

Non-depolarizing non-competitive ganglionic Blocking agents These blocking agents produce their effect, not at the specific Ach receptor site, but at some point further along the chain of events that is necessary for transmission of the nerve impulse. 108

When the block has been imposed, increase of the concentration of Ach has no effect: thus apparently, Ach does not act competitively with the blocking agent at the same receptor. 109

Neuromuscular junction blockers ( NMBs ) Based on their MOA, NMBs are grouped into two Depolarizing NMBs E.g. Succinylcholine Non depolarizing NMBs d - tubocurarine Atracurium Mivacurium Pancuronium Vecuronium Rocuronium Rapacuronium 110

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Depolarizing NMBs (Leptocurares) Succinylcholine Structurally, equivalent to two Ach molecules attached to each other back to back 112

MOA Produces NMB by overstimulation of nicotinic acetylcholine receptors in the NMJ Neuromuscular blockade occurs in two sequential events Phase I (depolarization block) Initial depolarization of the motor end plate producing muscle action potentials & fasciculation As result of maintained depolarization, Na+ channels become inactivated Muscle action potentials can’t be generate d 113

Phase II (desensitization block) In continued presence of Succinylcholine, membrane potential becomes repolarised Na+ channels inactivation is reversed Muscle membrane excitability is restored But NMB persists b/s of desensitization of nicotinic acetylcholine receptors 114

Pharmacokinetics of Succinylcholine Is positively charged & highly polar drug, given parentrally Metabolized by plasma cholinesterase to succinyl monocholine Pharmacologically inactive The response to Succinylcholine may be prolonged in Patients with renal or liver diseases (the enzyme synthesis decreases in such patients) In individuals with a genetic defect Atypical plasma cholinesterase is produced This enzyme has reduced affinity for substrates like succinylcholine About 10% of the active drug is excreted unchanged in the urine 115

Pharmacological actions Succinylcholine Primarily acts at nicotinic Ach receptors of the skeletal NMJ Has little effect on nicotinic Ach receptors of the autonomic ganglia Has no direct effect on the uterus or other smooth muscles Doesn’t enter to the CNS & doesn’t cross the placental barrier Increases histamine release from mast cells The effect of Succinylcholine is not reversible by AchEIs, and may prolong the block 116

Clinical uses Succinylcholine is used to produce paralysis of the skeletal muscles for surgical procedures It has fast onset & short duration of action Makes it suitable for short term surgical procedures, like Endotracheal intubation Setting of fractures Prevention of injury during electroconvulsive therapy Adverse effects Results in fasciculation & myoglobinuria Postoperative pain, transient elevation of intraocular pressure Hyperkalemia Cardiac arrhythmias 117

Non depolarizing blockers ( Pachycurares ) Curare (1516) and tubocurarine Curare was first identified when Spanish soldiers in South America found themselves the unwilling victims of poisoned arrows. It was discovered that the Indians were putting a poison on to the tips of their arrows. This poison was a crude, dried extract from a plant called Chondrodendron tomentosum and caused paralysis as well as stopping the heart. 118

curare is a mixture of compounds. The active principle, however, is an antagonist of acetylcholine which blocks nerve transmissions from nerve to muscle. Can be used medically if they are taken at the right dose levels and under proper control. 119

The main application is in the relaxation of abdominal muscles in preparation for surgery. (This allows the surgeon to use lower levels of general anesthetic) Curare, as mentioned above, is actually a mixture of compounds, and it was not until 1935 that the active principle ( Tubocurarine ) was isolated. 120

Classification according to duration of action Short Intermediate Long Mivacurium Vecuronium Pancuronium Atracurium Rocuronium Classification based on structure 121 Aminosteroids Pancuronium Vecuronium Rocuronium Rapacuronium Piperacuronium Benzylisoquinolines Atracurium Mivacurium d- Tubocurarine Doxacurium Metocurine

MOA These agents work by acting as reversible competitive inhibitors to Ach at nicotinic Ach receptors in the NMJ Their effect can be reversed by AchEIs , since the blockade is competitive 122

d-tubocurarine Is has a quaternary ammonium group, poorly crosses cells Doesn’t cross BBB Has moderate onset of action (3-4 minutes), followed by progressive flaccid paralysis Different muscles have differential sensitivity Head & neck muscles---->limb muscles---- >muscles of respiration Recovery from blockade occurs in the reverse order 123

Sensitive individuals Newborns Patients with myasthenia gravis but resistant to depolarizing agents These altered responsiveness is probably due to fewer functional nicotinic Ach receptors at the muscle end plate 124

Drug interactions Certain inhalational anesthetics like isoflurane, enflurane, halothane & nitrous oxide potentiate the action of non depolarizing blockers Modifying end plate responsiveness Alteration of local blood flow So, doses of these muscle relaxants should be reduced when used with these anesthetics Some antibiotics such as aminoglycosides, macrolides, polymyxins & lincomycin enhances NMB Decreasing Ach release Blocking postjunctional response Procainamide & phenytoin also increases the effects of non depolarizing NMBs Dose of the NMBs should be adjusted accordingly 125

Adrenomimetics & Adrenergic antagonists 126

Adrenomimetics Drugs w hich mimic the effects of adrenergic SN stimulation Also c alled sympathomimetics Have a wide range of effects Can be classified into different groups, based on Chemical structure Mechanism of action Receptor selectivity 127

Based on chemical structure Adrenomimetics can be divided into two: Catecholamines Have catechol ring in their structure E .g. NE, EP, DA, Isoproternol, Dobutamine, Colterol, ethyl NE, Metaproternol Non Catecholamines Don’t have catechol ring E.g. ephedrine, phenylephrine, albuterol, metaraminole, tyramine, amphetamine, terbutalin, methamphetamine, ritodrine, salmiterol, methoxamine 128

Catecholamines 129

Non Catecholamines 130

Based on mechanism of action Adrenomimetics can be classified into three groups 1. Direct acting adrenomimetics Directly interact & stimulate adrenoceptors Exhibit receptor selectivity Examples: NE, EP, DA, IP, Dobutamine, phenylephrine, albuterol, salmiterol, metaraminole, terbutalin, clonidine, oxymethazoline 131

2. Indirect acting adrenomimetics Don’t interact with the adrenoceptors Increase availability of NE/EP to stimulate the adrenoceptors Their action emanates from one of the following Displace stored neurotransmitters from the vesicles E.g. amphetamine , tyramine, methamphetamine Inhibit reuptake of neurotransmitters into the neuron E.g. cocaine, TCAs Inhibit the metabolizing enzymes ( MAO & COMT) E.g. pargyline, entacapone 132

3. Mixed acting adrenomimetics Work by both direct & indirect mechanisms Increase release of NE & also activate adrenoceptors E.g. ephedrine 133

Based on selectivity to adrenoceptors Grouped into many classes a. Non selective b/n α & β adrenoceptors NE, EP b. α 1 selective adrenomimetics Phenylephrine , methoxamine , metaraminole , midodrine , mephentermine c. α 2 selective adrenomimetics clonidine , methyldopa, guanfacine , guanbenz d. non selective α 1 & α 2 adrenomimetics oxymethazoline , xylomethazoline , naphazoline e. β 1 selective adrenomimetics Dobutamine 134

f . β 2 selective adrenoceptor agonists Albuterol, terbutalin, salmeterol , metaproternol, bitolterol, ritodrine, isoetharine g. β 1 β 2 nonselective adrenoceptor agonists Isoproternol, EP 135

The main effect of adreno receptor activation α 1 - vasoconstriction( BLOOD VESSEL ) GUT → contraction of the sphincter tone of the bladder →contraction of uterus in non pregnant women ↓salivary secretion( SALIVARY GLANDS ) increase force of contraction of heart ( HEART ) contraction of pupillary dilator muscle ( EYE ) Hepatic glycogenolysis and g luconeogenesis ( liver ) Sweat glands → sweat secretion 136

II. α 2 - On pre-synaptic : Inhibition of transmitter release (auto receptor) Post-synaptic platelet aggregation ( platelates ) decrease sympathetic outflow in CNS Inhibition of insulin release ( B-cell of pancreas) Decrease aqueous humor secretion 137

III. B 1 - Increased cardiac rate and force Increased rennin secretion in kidney juxtaglomerular cells III. Β 2 - Bronchodilation and vasodilatation Relaxation of visceral smooth muscle of GIT GUT : Bladder relaxes Uterus (in pregnant women) relaxes hepatic glycogenolysis mast cell decrease histamine secretion ↑ ed secretion of aqueous humour ( ciliary epithelium) IV. β 3 - Lipolysis (fat cell) 138

Pharmacologic responses of NE, EP & Isoproternol 1. Vascular effects Blood vessels of skin & Mucus membranes Predominantly contain α -adrenoceptors So, both NE & EP can produce potent constriction b/s both NE & EP are non selective adrenomimetics IP has very low affinity for α -adrenoceptors & so produce no effect on these vessels Blood vessels of visceral organs Predominantly contains α -adrenoceptors & some β -adrenoceptors NE & EP produce vasoconstriction Isoproternol produces minor vasodilation 139

Blood vessels of skeletal organs Contain both α & β adrenoceptors So, NE produces vasoconstriction through its effect on α -adrenoceptors IP dilates the vessels by its effect on β adrenoceptors EP has complex effect depending on its dose 140

2. Cardiovascular System Increased sympathetic neural activity produces Increased heart rate, force of contraction Increased stroke volume & cardiac output Constricts most of blood vessels, so increases TPR Increased blood pressure 141

3. Vascular Smooth Muscles Postjunctional α 1 & α 2 adrenoceptors mediate constriction of vascular smooth muscles Prejunctional & endothelial α 2 adrenoceptors mediate vasodilation 142

4. Nonvascular Smooth Muscles Bronchial smooth muscles Predominantly β 2 receptors are found Bronchodilation by EP & IP due to β 2 action NE has very low affinity & so weaker effects GIT smooth muscles Motility of the gut is reduced Due to activation of the α 2 hetroreceptors (inhibit Ach) GI sphincters are contracted Through an action on α1 adrenoceptor s 143

Eye Radial muscle of the iris contain a 1 adrenoceptors NE/EP cause contraction of this muscle & lead to mydriasis The epithelium of ciliary muscle contains β 2 adrenoceptors So, EP & IP ↑ ed secretion of aqueous humour α-2--------????? Urinary system Detrusor muscle contains β 2 adrenoceptors So, EP & IP relax the detrusor muscle Trigon & sphincter muscles contain α 1 adrenoceptors Contracted by NE & EP, w/h inhibits the voiding of urine 144

Uterine muscle Contains both α 1 & β 2 adrenoceptors NE causes uterine contraction EP/IP cause uterine relaxation 5. CNS effects Though catecholamines minimally cross the BBB, they cause CNS stimulation ( mechanism not well known ) Apprehension, restlessness & increased respiration 145

6. Metabolic Effects Increases skeletal muscle glycogenolysi s IP>EP>NE Mediated by β - adrenoceptors Increases blood lactic acid level than blood glucose level b/s skeletal muscle lacks glucose-6- phosphatase enzyme which converts G-6-P to glucose Increased lipolysis Increases blood free fatty acid levels Mediated by β3 adrenoceptors IP>EP>NE 146

K + homeostasis Catecholamines play an important role in the short term regulation of plasma K + levels Stimulation of hepatic α - adrenoceptors will result in the release of K+ from the liver In contrast, stimulation of β 2 adrenoceptors , particularly in the skeletal muscles, will lead to uptake of K+ into the tissue β2 adrenoceptors are linked to Na+/K+ ATPase 147

Clinical uses of catecholamines Is based on their actions on bronchial smooth muscles, blood vessels & the heart Allergic reactions EP is mainly used in allergic reactions which are due to histamine release So , EP is used in the treatment of Anaphylactic shock Urticaria Angioneuretic edema Serum sickness 148

Open-angle glaucoma EP has been used to lower IOP in open-angle glaucoma Works by increasing outflow of aqueous humor EP is C/I in closed-angle glaucoma b/s it reduces the filtration angle further & hinders outflow of fluid in this case Used with local anesthetics NE/EP is coadministered with LAs, to Prolong duration of action of the LAs Prevent systemic absorption & toxicity of the LAs 149

Control of bleeding EP is used as topical hemostatic agent for the control of local hemorrhage Management of hypotension NE is infused IV to combat systemic hypotension during spinal anesthesia NE is also useful in controlling hypotension in which TPR is low But NE is not used to combat hypotension due to most types of shock 150

Side effects of Catecholamines Tachycardia Reflex bradycardia By NE, but not with EP or IP Headache & tremor Anxiety, fear & nervousness Primarily by EP Tissue sloughing & necrosis Local ischemia from extravasation of NE at site of injection Arrhythmia Hypertension Pulmonary edema 151

Other adrenomimetic agents A number of adrenomimetics aren’t catecholamines Resistant to enzymatic degradation(COMT) have longer action Are orally active α1-selective adrenomimetic agents Phenylephrine, metaraminole & methoxamine Are all directly acting adrenomimetics Exert their effect primarily by α 1- adrenoceptor activity Has no/little direct effect on the heart They have vasoconstrictor effect Increase both the systolic & diastolic blood pressure They don’t precipitate cardiac arrhythmias & don’t stimulate CNS 152

Their vasoconstrictor effect is accompanied by Reflex increment in the vagal input to the heart Reflex bradycardia No change in the contractile forces Have considerably longer duration of action than NE Phenylephrine resistant to COMT metabolism Metaraminole & methoxamine are resistant to both COMT & MAO 153

Clinical uses Associated with their potent vasoconstrictor effects They are used to restore or maintain Bp during spinal anesthesia & certain other hypotensive states Phenylephrine is commonly used As nasal decongestant As mydriatic agent With local anesthetics in dental procedures 154

α 2 selective adrenomimetics Includes: methyldopa, clonidine, guanfacine Methyldopa Is a centrally acting adrenomimetic agent Is a prodrug & produces its effects via active metabolite In adrenergic neurons, it is metabolized by DOPA decarboxylase enzyme to α -methyl dopamine α -methyl dopamine is then converted to α -methyl NE α -methyl NE, by activating α 2 adrenoceptors in the brainstem attenuates further release of NE Produces its vasodilatory effects Uses: it is preferred drug for treatment of HTN during pregnancy b/s it is safe for both the mother & infant 155

Adverse effects Sedation Occasional depression Dryness of mouth Reduction in libido Hyperprolactinemia Gynacomasteia, galactorrhea Serious but rare hepatotoxicity C/I in patients with hepatic disease Can also cause hemolytic anemia 156

Clonidine, guanbenze & guanfacine Are all α 2 selective agonists MOA: they stimulate presynaptic α 2A receptors in the brainstem reducing sympathetic outflow from the CNS Reduce arterial pressure by an effect on both CO & peripheral resistance At higher doses, these drugs can stimulate postsynaptic α 2B receptors (found on the vascular smooth muscles) causing vasoconstriction This explains the initial vasoconstriction that is seen when overdoses of these drugs are taken Uses: they are mainly used in the treatment of essential hypertension 157

Adverse effects Sedation & Xerostemia Postural hypotension & erectile dysfunction Sleep disturbances & night mares Depression Sudden withdrawal of clonidine & other α 2 agonists may cause withdrawal syndrome consisting of: Headache, sweating, tremors, abdominal pain, tachycardia & rebound HTN 158

β1-selective adrenomimetics Dobutamine Acts directly on β1-adrenoceptors in the heart Exerts a greater effect on the contractile force of the heart relative to its effect on the heart rate At higher doses, it produces vasodilation of the renal & mesenteric blood vessels Has a fast onset & short half life (2mins) Therapeutic uses Indicated for short term treatment of cardiac decompensation that may occur After surgery In patients with CHF In patients with acute MI 159

Dobutamine increases the SV & CO in such patients, usually without marked increase in the heart rate It is also useful in the treatment of cardiogenic shock Adverse effects May increase the size of myocardial infarct By further increasing the O2 demand Increased risk of atrial fibrillation 160

β2-selective adrenomimetic agents Are agents used in the management of asthma Main difference in the available β2 adrenomimetics is their pharmacokinetic profiles So, in the management of asthma, β2 agonists Work by activating pulmonary β2 adrenoceptors & relax the bronchial smooth muscles & decrease airway resistance Recent studies suggest that β2 adrenomimetics may Suppress release of leukotrenes & histamine in lung tissue Enhance mucociliary function Decrease microvascular permeability Possibly inhibit PLA2 activity Relative importance of these effects in the treatment of asthma remains to be determined 161

Terbutaline Is β 2 selective Belongs to resorcinol bronchodilators class Resistant to COMT Effective when given by oral, Sc or inhalational routes Onset of action is rapid from inhalational & Sc routes Uses: terbutaline is used for Long term treatment of obstructive airway disease Treatment of acute bronchospasm Emergency treatment of status asthmaticus Albuterol β2 selective, given by inhalational or oral route Has similar therapeutic indications as terbutaline Oral albuterol has the potential to delay preterm labor 162

Salmeterol Is a β 2 selective agent with the longest duration of action (>12hours) At least 50 times more β 2 selective than albuterol Highly lipophilic & has sustained action Metabolized by CYP3A4 to α -OH-salmeterol Excreted by faces Has slow onset of action Not suitable monotherapy for acute attacks of asthma Due to its sustained duration of action, salmeterol Is drug of choice for treatment of nocturnal asthma Shouldn’t be used more than twice daily Shouldn’t be used for to treat acute asthma 163

Formoterol Is another long acting, β 2 selective agonist It is highly lipophilic, resulting in storage in adipocytes Responsible for sustained action It is an alternative to salmeterol for treatment of nocturnal asthma Ritodrine Selective β 2 agonist, developed specifically for use as uterine relaxant Up to 30% absorbed after oral dose 90% of drug excreted in urine as inactive conjugate Uses: given IV in selected patients to arrest premature labor 164

Adverse effects of β 2 selective adrenomimetics Tremor Feeling of restlessness, apprehension & anxiety Tachycardia, which may result from β 1 stimulation β 2 receptor stimulation in the heart Reflex response to peripheral vasodilation Cardiac arrhythmias or myocardial ischemia Less likely to in patients without pre-existing cardiac disease High risk of occurrence in patients with underlying coronary artery disease or pre-existing arrhythmia Pulmonary edema In women who receive ritodrine or terbutaline for preterm labor 165

Larger doses of β 2 adrenomimetics may Increase plasma glucose level Increase lactate & free fatty acids level in plasma Lower plasma concentration of K+ Note: All the adverse effects are far less likely with inhalational therapy than with parentral or oral therapy 166

Indirect acting adrenomimetics Includes: amphetamine, methamphetamine, cocaine, methylphenidate, TCAs Amphetamine Indirectly acting agent Works by displacing NE/EP from its storage vesicles Pharmacological effects CVS effects Increases both systolic & diastolic blood pressure Heart rate is reduced reflexively L-isomer of amphetamine is more potent than the d-isomer in producing CVS effects 167

CNS effects It is one of the most potent sympathomimetic amines in stimulating the CNS The d-isomer is more potent than the l-isomer in producing CNS stimulant effects Amphetamine: Stimulates medullary respiratory centres Lessens degree of central depression caused by various drugs Alters psyche of individuals 168

Therapeutic uses Amphetamine is used chiefly for its CNS effects Dextroamphetamine, with more CNS actions than peripheral actions Was used for reducing obesity Due to its anorexic effects No more approved by FDA for this purpose Is approved by FDA for treatment of Narcolepsy Attention deficient hyperactivity disorder 169

Toxic & adverse effects of amphetamines Are extensions of pharmacological actions of amphetamine CNS effects Restlessness, dizziness, tremor, hyperactive reflexes, insomnia, talkativeness & euphoria If dose is large enough or in mentally ill patients Confusion, aggressiveness, changes in libido, anxiety, suicidal or homicidal tendencies may occur Fatigue & depression usually follow central stimulation CVS effects Pallor or flushing, palpitations, cardiac arrhythmias, anginal pain, hypertension/hypotension, circulatory collapse Excessive sweating GI effects: dry mouth, metallic taste, anorexia, nausea, vomiting & abdominal cramps 170

Treatment of acute amphetamine toxicity Acidification of urine with ammonium chloride Increases the excretion of amphetamine Sedatives may be required for CNS effects Severe hypertension may require administration of Sodium nitroprusside or α 1 antagonists 171

Mixed acting adrenomimetic drugs Ephedrine Naturally occurring plant alkaloid Can cross BBB Has strong CNS stimulating effect, in addition to its peripheral actions CNS stimulatory effect is less, compared to amphetamine Has longer duration of action than NE Very resistant to both COMT & MAO Unlike NE/EP, ephedrine is effective when taken orally Less potent compared to NE/EP Tachyphylaxis develops after repeated use 172

MOA Actions mainly depend on release of NE/EP Has also some direct receptor stimulatory effects Particularly in its bronchodilating effects Clinical uses Ephedrine is useful in Relieving bronchoconstriction & mucosal congestion associated with bronchial asthma prevention of asthmatic attacks Nasal decongestion Producing mydriasis Terbutaline & albuterol are replacing ephedrine for treatment of asthma Less side effects, effective bronchodilation 173

Adverse effects Tachycardia Insomnia Nervousness, nausea, vomiting Emotional disturbances 174

Adrenoceptor antagonists 175

Are drugs that inhibit responses mediated by adrenoceptor activation Have affinity for adrenoceptors Lack intrinsic activity, so won’t initiate receptor responses Works by competing with adrenomimetics for access to adrenoceptors Reduce effects produced by both sympathetic nerve stimulation & exogenous adrenomimetics Adrenoceptor antagonists Don’t prevent release of NE/EP from adrenergic neurons Are not catecholamine depleting agents Are also called, sympathoplegics, sympatholytics 176

Classification of Adrenoceptor antagonists 1.α- Adrenoceptor antagonists a) Non selective α 1 , α 2 - Adrenoceptor antagonists Phentolamine, Phenoxybenzamine, Tolazoline b) α 1 - selective adrenoceptor antagonists Prazosin, Terazosin, Doxazosin, Tamsulosin, Alfuzosin c) α 2 - selective adrenoceptor antagonists: Yohimbine 2.β- Adrenoceptor antagonists a) Non selective β 1 , β 2 adrenoceptor antagonists Propranolol , Pindolol, Nadolol, Timolol b) β 1 - selective adrenoceptor antagonist Atenolol , acebutolol, Metoprolol , Esmolol, Bisoprolol C) β 2 - selective adrenoceptor antagonists Butoxamine 177

3. Nonselective α, β-Adrenoceptor antagonists Labetalol, Carvedilol, Bucindolol Pharmacological effects of α -blockers 1. Cardiovascular system : (  1 receptors on blood vessels ) Dilatation of arteries & veins   BP 2. Eye: Radial muscle of iris (  1 receptors) - > relaxes -> m iosis 3. Nose: Dilatation of blood vessels  n asal congestion 4. Genitourinary system:  resistance to urine flow Inhibition of ejaculation 178

Non-selective α -blockers Block both α 1 & α 2 adrenoceptors E.g. Phenoxybenzamine, Phentolamine, Tolazoline Phenoxybenzamine Is a haloalkylamine that blocks both α 1 & α 2 receptors irreversibly Major pharmacological effect (vasodilation) occurs from blockade of α -receptors in blood vessels Causes reduced TPR (due to α 1 & α 2B blockade) Increased CO (due to reflex sympathetic nerve stimulation) Tachycardia Reflex to hypotension, enhanced release of NE/EP 179

Therapeutic uses Treatment of pheochromocytoma Tumors of the adrenal medulla & sympathetic neurons Secrete enormous amounts of NE/EP, w/h leads to hypertension Phenoxybenzamine, by antagonizing α -receptors is used to treat symptoms of pheochromocytoma Treatment of benign prostatic hyperplasia (BPH) Used to reduce obstructive symptoms of BPH It is no more used for treatment of BPH Adverse effects Reflex tachycardia, postural hypotension, inhibit ejaculation 180

Phentolamine & tolazoline Are competitive antagonists at α adrenoceptors Antagonism is reversible So, have short duration of action Nonselective antagonist b/n α1 & α2 adrenoceptors Tolazoline is less potent than phentolamine Pharmacological action ↓BP by blocking α-receptors (α1 & α2B) Reflex increase in HR, CO ↑ Mechanism for increase in HR & CO ① BP↓ as result of vasodilation → reflex excited heart ② block presynaptic α 2A receptors →release of NE/EP ↑ → activate β 1 R 181

Therapeutic uses Benign prostetic hyperplasia Hypertensive emergencies Local vasoconstrictor excess Pheochromocytoma Side effects Postural hypotension Reflex tachycardia GI stimulation Abdominal pain Nausea Exacerbation of peptic ulcer 182

Selective α 1 -antagonists Includes: prazosin , terazosin, doxazosin , tamsulosin Are highly selective for α 1 receptors Exhibit greater clinical utility than the non-selective blockers Replaced the non-selective blockers clinically Leads to relaxation of both arterial and venous smooth muscle due to blockade of α 1 receptors Leads to fall in TPR which leads to lowered preload as well as after load They generally differ in their pharmacokinetics Well absorbed after oral use, highly bound to plasma proteins 183

Therapeutic uses Treatment of essential hypertension Congestive heart failure b/s reduce both preload & afterload Benign prosthetic hyperplasia Produces symptomatic urethral obstruction in a significant number of older men Urinary frequency, nocturia α1 antagonists have efficacy in treating BPH, owing to Relaxation of smooth muscles in the bladder neck, prostate capsule & prostatic urethra Rapidly improve urine flow 184

Side effects Major adverse effect is 1 st dose phenomenon Marked postural hypotension & syncope are seen 30-90 minutes after patient takes the 1 st dose of α1 blockers Can be minimized by limiting initial dose & gradually increasing the dose Headache, dizziness Asthenia (abnormal loss of strength) 185

Selective α 2 -antagonists Yohimbine Is an alkaloid obtained from plants Readily enters to CNS Is competitive α 2 -selective antagonist Increases sympathetic outflow Increases blood pressure & heart rate Produces opposite effects to clonidine Therapeutic uses The treatment of male erectile dysfunction (ED)??? Not widely used due to availability of effective agents 186

 -Blockers A. N on selective - Blockers Are also called 1 st generation  -blockers Propranolol , Timolol Nadolol, Pindolol B. Cardio selectives [  1 Blockers ] Are called 2 nd generation  -blockers Atenolol, Acebutolol, Bisoprolol Esmolol, Metoprolol Non-selective adrenergic blockers( &  Blockers) Carvedilol, Labetalol , Bucindolol, Nebivolol Are also called 3 rd generation  -blockers 187

Some of the β -blockers have some intrinsic activity & membrane stabilizing activity May be considered as partial antagonists Examples Pindolol Acebutolol Bucindolol 188

Pharmacological actions of -blockers A . Heart (  1 receptors )  myocardial contraction  HR  AV-conduction & automaticity B . CNS/Neurological Sedation ( with Propranolol, Carvedilol) C. Respiratory system Bronchoconstriction Little effect on pulmonary functions of normal individuals Can cause life-threatening bronchospasm in patients with COPD  1 selective blockers or those with intrinsic sympathomimetic activity are less likely than propranolol to cause severe bronchoconstriction 189

D. EYE:  IOP by reducing production of aqueous humor E. Liver Decrease glycogenolysis & lipolysis Can aggravate hypoglycemia in diabetic patients treated with insulin or oral hypoglycemic agents  1 selective blockers are less likely to produce hypoglycemic effects F. Adipose tissue Non selective  - blockers reduce lipolysis Reduce HDL, increase LDL & increase triglycerides F. Kidney Reduce renin release 190

Therapeutic uses of β -blockers Hypertension Coronary heart disease  Angina Pectoris  Myocardial infarction Cardiac arrhythmias Anxiety : to  sympathetic manifestations Hyperthyroidism: to  sympathetic manifestations Migraine headache Blockade of cranial beta receptors reduce vasodilation Glaucoma Reduce the production of aqueous humor Timolol is applied topically to treat glaucoma 191

Adverse effects of β -blockers 1. CVS Bradycardia hypotension AV block 2. Bronchoconstriction 3. Hypoglycemic effect 4. Affect lipid profile 5. Muscle pain & fatigue 6. Sleep disturbances, nightmares 192 More pronounced with  1 selectives Produced by non-selective blockers

Contraindications to β -blockers Heart failure Slow AV-node conduction Asthma & COPD Diabetes mellitus Hypothyroidism Combination with Ca-channel blockers 193

Non selective  &  antagonists Includes: Labetalol, Carvedilol, Bucindolol Are called 3 rd generation, vasodilatory β -blockers Labetalol Possess both  &  blocking activity  blocking activity is more potent than  blocking activity Non selective b/n 1 & 2 receptors Have some intrinsic activity at 2 receptors Responsible for vasodilatory effect of the drug At  receptors, labetalol Is more selective to  1 receptors Causes vasodilation (another mechanism for vasodilation) 194

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