Autonomic pharmacology-Nervous System module.pptx

Central NS
Functions: Integrates sensory information, coordinates bodily functions, and generates thoughts, emotions, and memories
Sympathetic NS
Although continually active to some degree (for example, in maintaining tone of vascular beds),
the sympathetic division is responsible for adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, and exercise
Prepares the body for "fight-or-flight" responses during stressful situations
Mobilize energy
Parasympathetic NS
It is involved with maintaining homeostasis within the body
It is required for life, since it maintains essential bodily functions, such as digestion and elimination
Generally predominates the sympathetic system in “rest-and-digest” situations
Usually acts to oppose or balance the actions of the sympathetic division
Conserve energy
Enteric NS
Functions independently of the CNS and controls motility, exocrine and endocrine secretions, and microcirculation of the GI tract
It is modulated by both the sympathetic and parasympathetic nervous systems
Somatic NS: Involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion


Footnotes for Table 1: …
gSympathetic cholinergic neurons cause vasodilation in skeletal muscle beds, but this is not involved in most physiological responses.
hThe endothelium of most blood vessels releases NO, which causes vasodilation in response to muscarinic stimuli. However, unlike the receptors innervated by sympathetic cholinergic fibers in skeletal muscle blood vessels, these muscarinic receptors are not innervated and respond only to exogenously added muscarinic agonists in the circulation
iWhile adrenergic fibers terminate at inhibitory β receptors on smooth muscle fibers and at inhibitory β receptors on parasympathetic (cholinergic) excitatory ganglion cells of the myenteric plexus, the primary inhibitory response is mediated via enteric neurons through NO, P2Y receptors, and peptide receptors.
jUterine responses depend on stages of menstrual cycle, amount of circulating estrogen and progesterone, and other factors.
kPalms of hands and some other sites (“adrenergic sweating”).
lThere is significant variation among species in the receptor types that mediate certain metabolic responses. All three β adrenergic receptors have been found in human fat cells. Activation of β3 receptors produces a vigorous thermogenic response as well as lipolysis. The significance is unclear. Activation of β receptors also inhibits leptin release from adipose tissue.
Footnotes for Table 1:
aResponses are designated + to +++ to provide an approximate indication of the importance of sympathetic and parasympathetic nerve activity in the control of the various organs and functions listed.
bAdrenergic receptors: α1, α2 and subtypes thereof; β1, β2, β3.
Cholinergic receptors: nicotinic (N); muscarinic (M), with subtypes 1–4. When a designation of subtype is not provided, the nature of the subtype has n

1. Taklo S. (BPharm, MSc, Assistant professor in pharmacology) Nervous System Module for PC II Medicine Autonomic Pharmacology

2. Objectives At the end of this unit, students are expected to: Identify the different classes of autonomic drugs Discuss the therapeutic uses of various autonomic drugs Identify side effects and contraindications of commonly used autonomic drugs Evaluate the rational of autonomic drugs in clinical practice

3. Brain storming questions Think-pair-share How nervous system execute its function? What is autonomic nervous system? How autonomic dysfunction be treated?

4. Outline Overview of autonomic neurotransmission Cholinergic agonists Cholinergic antagonists Adrenergic agonists Adrenergic antagonists

5. Classification of Nervous system Anatomical CNS: Brain and spinal cord PNS: Efferent & Afferent Functional Efferent: Somatic & ANS ANS includes: Sympathetic NS (adrenergic) Parasympathetic NS (cholinergic) Enteric NS

6. Central NS Functions: Integrates sensory information, coordinates bodily functions, and generates thoughts, emotions, and memories Sympathetic NS Although continually active to some degree (for example, in maintaining tone of vascular beds), the sympathetic division is responsible for adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, and exercise Prepares the body for "fight-or-flight" responses during stressful situations Mobilize energy

7. Parasympathetic NS It is involved with maintaining homeostasis within the body It is required for life, since it maintains essential bodily functions, such as digestion and elimination Generally predominates the sympathetic system in “rest-and-digest” situations Usually acts to oppose or balance the actions of the sympathetic division Conserve energy Enteric NS Functions independently of the CNS and controls motility, exocrine and endocrine secretions, and microcirculation of the GI tract It is modulated by both the sympathetic and parasympathetic nervous systems Somatic NS : Involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion

8. Differences between somatic and autonomic nervous system

9. A natomy of the autonomic nervous system

10. The autonomic nervous system Is distributed widely throughout the body Regulates autonomic functions In the periphery, it consists of nerves, ganglia, and plexuses that Innervate the heart, blood vessels, glands, other visceral organs, and smooth muscle in various tissues They give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia Autonomic nerves are actually composed of two neuron systems, termed: preganglionic and postganglionic

11. Innervation by the ANS Most organs have dual innervation Usually one dominates in controlling the system activity E.g. Vagus nerve dominates in controlling HR over sympathetic innervation The dual innervation of organs is dynamic, and fine-tuned continually to maintain homeostasis Some organs receiving only sympathetic innervation Adrenal gland Kidney Sweat gland

12. Table 1. Responses of effector organs to autonomic nerve impulses

13. Responses of effector organs to autonomic nerve impulses Footnotes for Table 1 : a Responses are designated + to +++ to provide an approximate indication of the importance of sympathetic and parasympathetic nerve activity in the control of the various organs and functions listed. b Adrenergic receptors: α1, α2 and subtypes thereof; β1, β2, β3. Cholinergic receptors: nicotinic (N); muscarinic (M), with subtypes 1–4. When a designation of subtype is not provided, the nature of the subtype has not been determined unequivocally. Only the principal receptor subtypes are shown. Transmitters other than ACh and NE contribute to many of the responses. c In the human heart, the ratio of β1 to β2 is about 3:2 in atria and 4:1 in ventricles. While M2 receptors predominate, M3 receptors are also present. d The predominant α1 receptor subtype in most blood vessels (both arteries and veins) is α1A, although other α1 subtypes are present in specific blood vessels. The α1D is the predominant subtype in the aorta e Dilation predominates in situ owing to metabolic autoregulatory mechanisms. f Over the usual concentration range of physiologically released circulating EPI, the β receptor response (vasodilation) predominates in blood vessels of skeletal muscle and liver; β receptor response (vasoconstriction) predominates in blood vessels of other abdominal viscera. The renal and mesenteric vessels also contain specific dopaminergic receptors whose activation causes dilation.

14. Responses of effector organs to autonomic nerve impulses Footnotes for Table 1 : … g Sympathetic cholinergic neurons cause vasodilation in skeletal muscle beds, but this is not involved in most physiological responses. h The endothelium of most blood vessels releases NO, which causes vasodilation in response to muscarinic stimuli. However, unlike the receptors innervated by sympathetic cholinergic fibers in skeletal muscle blood vessels, these muscarinic receptors are not innervated and respond only to exogenously added muscarinic agonists in the circulation i While adrenergic fibers terminate at inhibitory β receptors on smooth muscle fibers and at inhibitory β receptors on parasympathetic (cholinergic) excitatory ganglion cells of the myenteric plexus, the primary inhibitory response is mediated via enteric neurons through NO, P2Y receptors, and peptide receptors. j Uterine responses depend on stages of menstrual cycle, amount of circulating estrogen and progesterone, and other factors. k Palms of hands and some other sites (“adrenergic sweating”). l There is significant variation among species in the receptor types that mediate certain metabolic responses. All three β adrenergic receptors have been found in human fat cells. Activation of β3 receptors produces a vigorous thermogenic response as well as lipolysis. The significance is unclear. Activation of β receptors also inhibits leptin release from adipose tissue.

15. Neurotransmitters Communication between nerve cells, and between nerve cells and effector organs, Occurs through the release of specific chemical signals (neurotransmitters) from the nerve terminals Although many signal molecules in the nervous system have been identified, NE, E, ACh, dopamine, serotonin, histamine, glutamate, and γ- aminobutyric acid are most commonly involved in the actions of therapeutically useful drugs Neuroeffector transmitter For sympathetic: Major-NA; Minor: ATP, NPY, DA, ACh For parasympathetic: Major-ACh; Minor: VIP, NO

16. Each of these chemical signals binds to a specific family of receptors Acetylcholine and norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of neurotransmitters function in the CNS

17. Autonomic receptors Major autonomic receptor types: Cholinergic receptors are receptors that mediate responses to acetylcholine Adrenergic receptors are receptors that mediate responses to noradrenaline and adrenaline Dopamine receptors are receptors that mediate responses to dopamine

18. Signal Transduction in the Effector Cell A neurotransmitter can be thought of as a signal and a receptor as a signal detector and transducer The receptors in the ANS effector cells are classified as adrenergic or cholinergic based on the neurotransmitters that bind to them Postsynaptic cholinergic nicotinic receptors in skeletal muscle cells, are directly linked to membrane ion channels Ionotropic receptors All adrenergic receptors and cholinergic muscarinic receptors are G protein–coupled receptors (metabotropic receptors) G protein coupled receptor

19. A. Receptor coupled to ion channel E.g. β 1 R, β 2R, β 3R Na ion Na ion

20. E.g. α 1R, M1R, M3R, M5R G α i /G α o M2R, M4R, α2 R Couples by Gi/Go M2R, M4R Inhibition of AC, ↓ cAMP Activation of inwardly rectifying K+ channels Inhibition of voltage-gated Ca2+ channels Hyperpolarization α2 R ↓ AC-cAMP-PKA pathway

21. Neurotransmission at cholinergic neurons involves six sequential steps:

22. Cholinergic drugs (Cholinomimetic, Parasympathomimetic) Produce actions similar to that of ACh, either by Directly interacting with cholinergic receptors (cholinergic agonists) or Increasing availability of ACh at the vicinity of receptors (anticholinesterases) Direct cholinergic agonists: Choline esters Alkaloids Acetylcholine Muscarine Methacholine Pilocarpine Carbachol Arecoline Bethanechol Nicotine, lobeline

23. Structure of choline esters

24. Structure of some cholinomimetic alkaloids

25. B/c it is toxic when ingested and even has CNS effects The β- methyl group (methacholine, bethanechol) reduces the potency of these drugs at nicotinic receptors

26. Absorption, Distribution, and Elimination Muscarine and the choline esters are quaternary amines Are poorly absorbed following oral administration and have a limited ability to cross the blood-brain barrier Even though choline esters resist hydrolysis, they are Short-acting agents due to rapid elimination by the kidneys Pilocarpine and arecoline, being tertiary amines, are Readily absorbed and can cross the blood-brain barrier

27. Cholinergic agonists can also be classified as: A. Direct acting ACh, carbachol, bethanechol, and pilocarpine B. Indirect acting (anti-cholinesterase agents) 1. Reversible Edrophonium, Physostigmine, Neostigmine, Rivastigmine, Donepezil, Galantamine 2. Irreversible Echothiophate, malathion, sarin, soman

28. Therapeutic Uses of Muscarinic Receptor Agonists Used in the treatment of Urinary bladder disorders Xerostomia Glaucoma Used in the diagnosis of bronchial hyper reactivity Also used in ophthalmology as miotic agents

29. Therapeutic Uses of Muscarinic Receptor Agonists… ACh is used topically for the induction of miosis during ophthalmologic surgery Methacholine for the Dx of bronchial airway hyperreactivity in patients who do not have clinically apparent asthma Bethanechol has utility in treating urinary retention and inadequate emptying of the bladder in postoperative urinary retention, diabetic autonomic neuropathy, and certain cases of chronic hypotonic, myogenic, or neurogenic bladder Carbachol -glaucoma & miosis during surgery Pilocarpine hydrochloride-xerostomia, glaucoma and as a miotic agent Cevimeline -a long­ lasting sialogogic action on lacrimal and salivary glands

30. Anticholinesterase agents Acetylcholinesterase (AChE) Used to terminate the action of ACh at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites Drugs that inhibit AChE are called anti-cholinesterase (anti- ChE) agents They cause ACh to accumulate in the vicinity of cholinergic nerve terminals Thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems

31. [1]= Structure of carbamate; [2]= Quaternary ammonium

32. Therapeutic uses Current use of anti- AChE agents is limited to four conditions in the periphery: Atony of the smooth muscle of the intestinal tract and urinary bladder Glaucoma Myasthenia gravis Reversal of the paralysis of competitive neuromuscular blocking drugs Alzheimer's disease

33. Reversible indirect acting cholinergic agonists Edrophonium Binds reversibly to the active center of AChE, preventing hydrolysis of ACh It has short duration of action A quaternary amine, and its actions are limited to the periphery Used in the diagnosis of myasthenia gravis (2mg IV) Reversal of weakness and short lasting improvement in the strength of affected muscles occurs Only in myasthenia gravis and not in other muscular dystrophies

34. In case edrophonium is not available, the test Can be performed with 1.5 mg IV neostigmine Atropine pretreatment may be given To block the muscarinic effects of neostigmine Edrophonium has been used for terminating attacks of paroxysmal supraventricular tachycardia

35. Physostigmine It is considered an intermediate-acting agent It is a tertiary amine that enter to CNS Therapeutically used to: Treat atony of intestine and bladder As antidote for anticholinergic overdose Physostigmine (0.1%) is used only to supplement pilocarpine as miotic agent Reverse the effects of nondepolarizing NMJBs Adverse effects: convulsion, bradycardia, hypotension, miosis, excess accumulation of ACh results in paralysis of skeletal muscle Physostigmine is absorbed readily from the GI tract, SC tissues, and mucous membranes It is destroyed by hydrolytic cleavage by plasma esterases

36. Neostigmine Has a quaternary nitrogen which makes it more polar, Absorbed poorly from the GI tract, does not enter the CNS Has an intermediate duration of action Used to stimulate the bladder and GI tract An antidote for competitive neuromuscular-blocking agents Also used to manage symptoms of myasthenia gravis Not used to overcome toxicity of centrally-acting antimuscarinic agents such as atropine Pyridostigmine, and edrophonium are also used to reverse neuromuscular blockage Neostigmine is destroyed by plasma esterases

37. Pyridostigmine and ambenonium Are used in the chronic management of myasthenia gravis Their durations of action are intermediate (4 to 6 hours and 4 to 8 hours, respectively)

38. Rivastigmine, donepezil and galantamine Alzheimer’s disease Characterized by progressive dementia Neurodegenerative disorder, primarily affecting cholinergic neurons in the brain These agents are orally active, have adequate penetration into the central nervous system The relatively cerebroselective anti-ChEs, rivastigmine, donepezil and galantamine are now commonly used

39. Irreversible indirect acting cholinergic agonists A number of synthetic organophosphate compounds Have the capacity to bind covalently to AChE The result is a long-lasting increase in ACh at all sites where it is released Many of these drugs are extremely toxic and were developed by the military as nerve agents (e.g. sarin , soman ) Related compounds, such as parathion and malathion , are used as insecticides Following their absorption, most organophosphates are excreted almost entirely as hydrolysis products in the urine Plasma(carboxylesterases) and liver esterases(paraoxonase) are responsible for hydrolysis Parathion and malathion are thiophosphate (sulfur-containing phosphate) prodrugs that are inactive as such; they are converted to the phosphate derivatives in animals (paraoxon and malaoxon by CYPs, respectively) Malathion is detoxified by plasma carboxylesterases

40. Echothiophate An organophosphate that covalently binds via its phosphate group at the active site of AChE The enzyme AChE is permanently inactivated So how is AChE activity restored? Following covalent modification of AChE, the phosphorylated enzyme slowly releases one of its alkyl groups (aging)

41. Aging makes it impossible for chemical reactivators, such as pralidoxime , to break the bond between the remaining drug and the enzyme A topical ophthalmic solution of the drug is available for the treatment of open-angle glaucoma But rarely used due to its side effect profile (cataracts, motor function paralysis, convulsion)

42. Cholinesterase reactivation Dephosphorylation of enzyme can be effected by strong nucleophilic cpds like the oximes (pralidoxime, obidoxime) Used in organophosphate poisoning but They should be used within few hours following exposure Once aging has occurred, reactivation of cholinesterase is practically impossible Pralidoxime (2-PAM) has a positively charged nitrogen Attaches to the anionic site of the enzyme which remains unoccupied in the presence of organophosphate inhibitors Its oxime end reacts with the phosphorus atom attached to the esteratic site: the oxime-phosphonate so formed diffuses away leaving the reactivated ChE

43. Cholinesterase reactivation… The general formula of carbamates and organophosphates shown below: The R1 in carbamate s may have a nonpolar tertiary amino , e.g. in physostigmine, rendering the compound lipid soluble. In others, e.g. neostigmine , R1 has a quaternary – rendering it lipid insoluble All organophosphates are highly lipid soluble except echothiopate which is water soluble

44. Schematic representation of reaction of acetylcholine (A-D)

45. Schematic representation of reaction of carbamate anti ChE (E, F), or organophosphate anti ChE (G) with cholinesterase enzyme; and reactivation of phosphorylated enzyme by oxime (G, H), Ser- Serine; His-Histidine; Glu-Glutamic acid.

46. Contraindications of muscarinic agonists Asthma, chronic obstructive pulmonary disease (COPD), urinary or GI tract obstruction, acid-peptic disease Cardiovascular disease accompanied by bradycardia, hypotension Hyperthyroidism (muscarinic agonists may precipitate atrial fibrillation in hyperthyroid patients) Unusual effect of muscarinic agonists, why?

47. Common adverse effects of muscarinic agonists Diaphoresis, diarrhea, abdominal cramps, nausea/vomiting A sensation of tightness in the urinary bladder Difficulty in visual accommodation Hypotension, which can severely reduce coronary blood flow, especially if it is already compromised

48. Cholinergic antagonists Parasympatholytics Cholinoceptor antagonists are divided into muscarinic and nicotinic subgroups on the basis of their specific receptor affinities Ganglion blockers and neuromuscular junction blockers make up the antinicotinic drugs Cholinergic antagonist is a general term for agents that bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists Antimuscarinic agents, Ganglion blockers, Neuromuscular junction blockers

49. Antimuscarinic agents Block muscarinic receptors In addition, these drugs block the few exceptional Sympathetic neurons that are cholinergic, such as those innervating the salivary and sweat glands In general, muscarinic antagonists cause little blockade of nicotinic receptors

50. Atropine (prototype) Is tertiary amine bind competitively to muscarinic receptor and prevent ACh binding Acts both centrally and peripherally Neuroeffector organs have varying sensitivity to atropine The greatest inhibitory effects are seen in bronchial tissue, salivary and sweat glands Secretion of acid by the gastric parietal cells is the least sensitive Atropine blocks all subtypes of muscarinic receptors Its effect on nicotinic receptor is not detected clinically Readily absorbed, partially metabolized by liver, primarily eliminated via urine

51. Effect of Atropine on different organs CNS At therapeutic doses, atropine can cause mild CNS excitation. Toxic doses can cause hallucinations and delirium , which can resemble psychosis. Extremely high doses can result in coma, respiratory arrest, and death Heart Increases heart rate (block M2R on sinoatrial node) Exocrine Glands Decreases secretion from salivary glands, bronchial glands, sweat glands, and the acid secreting cells of the stomach Smooth muscle Causes relaxation of the bronchi, decreased tone of the urinary bladder detrusor, and decreased tone and motility of the GI tract Eye Block MR on the iris sphincter causes mydriasis (dilation of the pupil); the ciliary muscle produces cycloplegia (relaxation of the ciliary muscle), thereby focusing the lens for far vision

52. Fig. Autonomic control of pupil (A); and site of action of mydriatics (B) and miotics (C)

53. Therapeutic Uses Preanesthetic Medication Procedures that stimulate baroreceptors of the carotid body can initiate reflex slowing of the heart, Resulting in profound bradycardia Because this reflex is mediated by MRs on the heart, pretreatment with atropine can prevent a dangerous reduction in heart rate Certain anesthetics irritate the respiratory tract If secretions are sufficiently profuse, they can interfere with respiration By blocking muscarinic receptors on secretory glands, atropine can help prevent excessive secretions

54. Disorders of the Eyes By blocking muscarinic receptors in the eyes, atropine can cause mydriasis and paralysis of the ciliary muscle Both actions can be of help during eye examinations and ocular surgery Phenylephrine or similar α-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not required Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to The prolonged mydriasis observed with atropine (7–14 days versus 6–24 hours)

55. Bradycardia Atropine can accelerate heart rate in certain patients with bradycardia Heart rate is increased because blockade of cardiac muscarinic receptors Reverses parasympathetic slowing of the heart Intestinal Hypertonicity and Hypermotility Atropine can decrease both the tone and motility of intestinal smooth muscle This can be beneficial in conditions characterized by excessive intestinal motility, such as mild dysentery and diverticulitis Muscarinic Agonist Poisoning By blocking muscarinic receptors, atropine can reverse all signs of muscarinic poisoning

56. Adverse effects Dry mouth (xerostomia) Blurred Vision and Photophobia Elevation of Intraocular Pressure Urinary Retention Constipation Anhidrosis (deficiency/absence of sweat), Tachycardia

57. Scopolamine Produces peripheral effects similar to those of atropine However, scopolamine has greater action on the CNS and a longer duration of action as compared to atropine At recommended dose, scopolamine produces sedation, but at higher doses, it can produce excitement Scopolamine may produce euphoria and is susceptible to abuse

58. Therapeutic uses Motion sickness Scopolamine is one of the most effective anti–motion sickness drugs available It is much more effective prophylactically than for Treating motion sickness once it occurs Postoperative nausea and vomiting Used for the prevention of postoperative nausea and vomiting Pharmacokinetics and adverse effects Similar to those of atropine, with the exception of longer half-life

59. Aclidinium, glycopyrrolate, ipratropium, and tiotropium Ipratropium, and tiotropium are quaternary derivatives of atropine Glycopyrrolate and aclidinium are synthetic quaternary compounds Ipratropium is a short-acting muscarinic antagonist while glycopyrrolate, tiotropium, and aclidinium are long-acting muscarinic antagonists

60. Therapeutic uses All are used for maintenance treatment of bronchospasm associated with COPD Ipratropium and tiotropium are also used in the Acute management of bronchospasm in asthma & chronic management of asthma, respectively All of these agents are delivered via inhalation Because of the positive charge, these drugs do not enter the systemic circulation or the CNS, restricting effects to the pulmonary system

61. Homatropine, Tropicamide and cyclopentolate These agents are used as ophthalmic solutions for mydriasis and cycloplegia Their duration of action is shorter than that of atropine Tropicamide produces mydriasis for about 6 hours and cyclopentolate for about 24 hours For homatropine mydriasis lasts 1-3 days

62. Oxybutynin and other antimuscarinic agents Oxybutynin, darifenacin, fesoterodine, solifenacin , tolterodine, and trospium are synthetic atropine-like drugs with antimuscarinic actions By competitively b locking M3 receptors in the bladder, Intravesical pressure is lowered , bladder capacity is increased, and the frequency of bladder contractions is reduced Darifenacin and solifenacin are relatively more selective M3 receptor antagonists However, the other drugs are mainly nonselective muscarinic antagonists, binding to other muscarinic receptor subtypes may contribute to adverse effects

63. Pharmacokinetics All of the agents are available in oral dosage forms These drugs are hepatically metabolized by the CYP P450 system (primarily CYP 3A4 and 2D6), With the exception of trospium, which is thought to undergo ester hydrolysis Therapeutic uses These agents are used for management of Overactive bladder and urinary incontinence Trospium is a quaternary compound that minimally crosses the BBB Has fewer CNS effects than do other agents, making it a preferred choice in treating overactive bladder in patients with dementia

64. Benztropine and trihexyphenidyl These agents are centrally acting antimuscarinic agents Benztropine and trihexyphenidyl are useful as adjuncts With other antiparkinsonian agents to treat all types of parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms These drugs may be helpful in geriatric patients who cannot tolerate stimulants

65. Contraindication of muscarinic antagonists Contraindications to the use of antimuscarinic drugs are relative, not absolute Contraindicated to urinary tract obstruction, GI obstruction Contraindicated in patients with glaucoma Especially angle-closure glaucoma In elderly men, antimuscarinic drugs should always be used with Caution and should be avoided in those with a history of prostatic hyperplasia Nonselective antimuscarinic agents should never be used to treat acid-peptic disease

66. Case Study JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension, and during the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed the signs of benign prostatic hypertrophy, which eventually required prostatectomy to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate?

67. Drugs acting on autonomic ganglia Bind Nn cholinergic receptors on autonomic ganglia Muscle-type: ( α1)2β1δε or ( α1)2β1δγ Ganglion-type: ( α3)2(β4)3 Heteromeric CNS-type: ( α4)2(β2)3 Homomeric CNS-type: ( α7)5 It includes: Ganglionic Stimulating Agents Ganglionic Blocking Agents

68. Ganglionic-stimulating drugs The first group consists of drugs with specificities similar to nicotine: Fig: Postsynaptic potentials recorded from an autonomic postganglionic nerve cell body after stimulation of the preganglionic nerve fiber Intensely fluorescent (SIF) cells

69. Ganglionic-stimulating drugs The first group consists of drugs with specificities similar to nicotine: lobeline, epibatidine, tetramethylammonium, and dimethylphenylpiperazinium Nicotine’s excitatory effects on ganglia are rapid in onset, are blocked by ganglionic nicotinic-receptor antagonists, and mimic the initial EPSP The second group consists of muscarinic receptor agonists such as muscarine, and methacholine; their excitatory effects on ganglia are delayed in onset, blocked by atropine-like drugs, and mimic the slow EPSP Both sympathetic and parasympathetic ganglia are stimulated, so effects are complex No therapeutic uses, except some ( e.g. nicotine, varenicline to assist giving up smoking)

70. Ganglionic-stimulating drugs…. Nicotine Primarily act prejunctional in the CNS causing the release of other transmitters Can both stimulate and desensitize receptors-complex and unpredictable effect Effect PNS-Small dose stimulation and large dose a more persistent depression of all autonomic ganglia &NMJ CNS-Nicotine markedly stimulates the CNS Low doses produce weak analgesia; higher doses cause tremors, leading to convulsions at toxic doses. Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration (due to peripheral & central paralysis CVS-In general, the cardiovascular responses to nicotine are due to stimulation of sympathetic ganglia and the adrenal medulla, together with the discharge of catecholamines from sympathetic nerve endings GIT-increased tone and motor activity of the bowel, nausea, vomiting, Exocrine Glands-Nicotine causes an initial stimulation of salivary and bronchial secretions that is followed by inhibition ADME-Readily absorbed via PO, skin (patch), lung Metabolized mainly in liver but also in kidney & lung Nicotine and its metabolites are eliminated rapidly by the kidney

71. Ganglion-blocking drugs Hexamethonium, Mecamylamine, trimetaphan, nicotine Block all autonomic ganglia and enteric ganglia Were the 1st effective therapy for the treatment of hypertension Limited due to many undesirable effect Clinically obsolete, except for some Mecamylamine, is available as an antihypertensive agent with good oral bioavailability for moderate to severe hypertension

72. Ganglion-blocking drugs… Effect of ganglionic blockers

73. Drugs acting on autonomic ganglia

74. Neuromuscular blocking agents Neuromuscular blocking agents prevent acetylcholine from activating nicotinic (N M ) receptors on skeletal muscles, thereby cause muscle relaxation These drugs are given to produce muscle relaxation during Surgery Endotracheal intubation Mechanical ventilation

75. Neuromuscular Blockers…

76. Neuromuscular Blockers… Structures of steroid neuromuscular blocking drugs (steroid nucleus in color) Mixed onium chlorofumarate

77. Steps in excitation-contraction coupling

78. Classification of Neuromuscular Blockers The neuromuscular blockers can be classified according to mechanism of action and time course of action When classified by mechanism of action, these drugs fall into two categories: Non-depolarizing NMJB agents and Depolarizing NMJB agents When classified by time course, these drugs fall into three categories: long acting, intermediate acting, and short acting

79. Depolarizing NMJ blockers Non depolarizing NMJ blockers Short acting Short acting Succinylcholine Mivacurium Gantacurium Intermediate acting Atracurium Cisatracurium Rocuronium Vecuronium Long acting Tubocurarine Pancuronium Pipecuronium Doxacurium

80. Tubocurarine and all other neuromuscular blocking agents contain a quaternary nitrogen atom As a result, these drugs always carry a positive charge, and Therefore cannot readily cross membranes The inability to cross membranes has three clinical consequences First, neuromuscular blockers cannot be administered orally Second, these drugs cannot cross the BBB, and hence have no effect on CNS Third, neuromuscular blockers cannot readily cross the placenta, and hence effects on the fetus are minimal

81. Non depolarizing NMJ blockers In general, they are bulky, rigid molecules Given by IV injections The choice of a particular drug is often determined by the side-effects produced These include: histamine release, vagal blockade and ganglion blockade At low dose , compete with ACh at the receptor without stimulating it muscle responds to direct electrical stimulation At high dose can block the ion channels of the motor end plate Reduced ability of cholinesterase inhibitors to reverse Muscle does not respond to direct electrical stimulation

82. Tubocurarine (long acting) Partial blockade probably is produced both at autonomic ganglia and at the adrenal medulla, Produce histamine release which results in a fall in blood pressure and tachycardia Long acting agents including tubocurarine is removed from market Pancuronium Shows less ganglionic blockade at common clinical doses Atracurium, vecuronium, doxacurium, pipecuronium, mivacurium, and rocuronium are even more selective, showing less ganglionic blockade Has a vagolytic action, presumably from blockade of muscarinic receptors, which leads to tachycardia

83. Succinylcholine, mivacurium, and atracurium cause histamine release, but to a lesser extent unless administered rapidly Pancuronium, vecuronium, pipecuronium, and rocuronium, have even less tendency to release histamine after intradermal or systemic injection Vecuronium It is an analog of Pancuronium The drug does not produce ganglionic or vagal block and does not release histamine Consequently, cardiovascular effects are lessened Vecuronium is excreted primarily in the bile

84. Atracurium It is only stable when kept cold and at low PH At body PH and temperature it decomposes spontaneously in plasma and therefore does not depend on renal or hepatic function for its elimination It is the drug of choice in patients with sever renal or hepatic diseases Atracurium may cause histamine release with flushing and hypotension

85. Adverse Effects of non depolarizing NMJ blockers Prolonged apnea Hypotension Drug Interactions General Anesthetics All inhalational anesthetics produce some degree of skeletal muscle relaxation can thereby enhance the actions of neuromuscular blockers Reduce dose of NMJ blockers Antibiotics Aminoglycosides (e.g., gentamicin), tetracyclines Intensify responses to neuromuscular blockers

86. Cholinesterase Inhibitors Can decrease the effects of competitive neuromuscular blockers Increase responses to succinylcholine, a depolarizing neuromuscular blocker Electrolyte disturbance Low potassium levels can enhance paralysis, whereas High potassium levels can reduce paralysis

87. Depolarizing NMJ blocking drugs Suxamethonium (succinylcholine) Is used because of its rapid onset and very short duration of action The drug is normally hydrolysed rapidly by plasma pseudocholinesterase But a few people inherit an atypical form of the enzyme and in such individuals Nm block may last for hours Suxamethonium depolarizes the endplate and, because the drug does not dissociate rapidly from the receptors, a prolonged receptor activation is produced

88. The resulting endplate depolarization initially causes a brief train of muscle action potentials and muscle-fibre twitches Neuromuscular block occurs as a result of: Inactivation of the voltage sensitive Na + channels in the surrounding muscle-fibre membrane, so that action potentials are no longer generated Transformation of the activated receptors to a ‘desensitized’ state, unresponsive to ACh

89. Succinylcholine initially produces short-lasting muscle fasciculations, followed by paralysis The main disadvantage of suxamethonium is that the initial asynchronous muscle-fibre twitches cause damage, which often results in muscle pains the next day The damage also causes potassium release

90. Succinylcholine adverse effects Prolonged apnea in patients with low pseudocholinesterase activity Hyperkalemia promotes release of potassium from tissues May lead to cardiac arrest Malignant hyperthermia in susceptible patients (ryanodine receptor1 gene abnormality is common) Caused by volatile anesthetic agents, succinylcholine Muscle pain (due to the fasciculation) Cholinesterase inhibitors and aminoglycosides Intensify succinylcholine effect

91. Sequence of paralysis : First muscle to be blocked by both depolarizing and non depolarizing muscle relaxants are the central muscles then peripheral muscles blocked So the sequence of blockade is: Eye muscles, Jaw, Larynx, limbs and trunk, intercostal muscles and the diaphragm The muscles recover in the reverse manner Antidote: Neostigmine, Edrophonium , pyridostigmine to increase ACh ----for competitive NMJ blockers Atropine to block ACh muscarinic stimulation---for depolarizing NMJ blocker

92. Others agents which cause muscle relaxation Diazepam---Central muscle relaxants---used to control spastic muscle tone Dantrolene It is postsynaptic muscle relaxant Inhibits the release of calcium from the sarcoplasmic reticulum By antagonizing ryanodine receptor Used as prophylaxis & treatment for malignant hyperthermia

93. Clinical uses of NMJ blockers Surgery adjuvant to anesthetic agents Low dose anesthetics required Less side effect from anesthetics Endotracheal intubation Gag reflexes can fight tube insertion By suppressing these reflexes, NMJ blockers can make intubation easier Succinylcholine is the preferred agent for this use Mechanical ventilation NM blockers reduces spontaneous respiratory movements (the patient can hear); facilitate ventilation

94. 4 . Adjunct to Electroconvulsive Therapy Electroconvulsive therapy is an effective treatment for severe depression Benefits derive strictly from the effects of electroshock on the brain; the convulsive movements that can accompany electroshock don't help relieve depression Neuromuscular blockers are now used to prevent convulsive movements Succinylcholine is used primarily for muscle relaxation during endotracheal intubation, electroconvulsive therapy, endoscopy, and other short procedures Succinylcholine is less desirable than the nondepolarizing blockers for use in prolonged procedures (i.e., surgery and mechanical ventilation )

95. Quiz Hunters in Amazon (south America) shoot animals using arrows immersed in curare extract (arrow poison). The animals got paralysed. But, when the people eat the meat contaminated with curare, they are not affected. Why???

96. Adrenergic Agonists On the basis of chemical structure, adrenergic agonists can be placed into two major groups: Catecholamine Non-catecholamine Because of their chemistry, all catecholamines have 3 properties in common: Cannot be used orally Have a brief duration of action Cannot cross the blood-brain barrier

97. The non- catecholamines have ethylamine in their structure But do not contain the catechol moiety The non-catecholamines differ from the catecholamines in three important respects: They lack a catechol group, non- catecholamines are not substrates for COMT and are metabolized slowly by MAO Non-catecholamines can be given orally They are considerably less polar than catecholamines, and hence are more able to cross the blood-brain barrier

98. SAR of Sympathomimetic Amines β-Phenylethylamine can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring and an ethylamine side chain The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms , and the terminal amino group to yield a variety of compounds with sympathomimetic activity

99. SAR of Sympathomimetic Amines… Separation of Aromatic Ring and Amino Group Generally, by far the greatest sympathomimetic activity occurs when two carbon atoms separate the ring from the amino group Substitution on the Amino Group Increase in the size of the alkyl substituent increases β receptor activity (e.g., isoproterenol) NE has, in general, rather feeble β2 activity; this activity is greatly increased in EPI by the addition of a methyl group In general, the smaller the substitution on the amino group, the greater the selectivity for α activity, although N-methylation increases the potency of primary amines. Thus, α activity is maximal in EPI, less in NE, and almost absent in isoproterenol

100. SAR of Sympathomimetic Amines… Substitution on the Aromatic Nucleus Maximal α and β activity depends on the presence of hydroxyl groups on positions 3 and 4 When one or both of these groups are absent, with no other aromatic substitution, the overall potency is reduced Phenylephrine is thus less potent than EPI at both α and β receptors, with β2 activity almost completely absent Hydroxyl groups in positions 3 and 5 confer β2 receptor selectivity on compounds with large amino substituents Thus, terbutaline and similar compounds relax the bronchial musculature in patients with asthma but cause less-direct cardiac stimulation than do the nonselective drugs

101. SAR of Sympathomimetic Amines… Terbutaline structure Groups other than hydroxyls have been substituted on the aromatic ring In general, potency at α receptors is reduced, and β receptor activity is minimal Fig. Methoxamine

102. SAR of Sympathomimetic Amines… The response to noncatecholamines is partly determined by their capacity to release NE from storage sites These agents thus cause effects that are mostly mediated by α and β1 receptors because NE is a weak β2 agonist Phenylethylamines that lack hydroxyl groups on the ring and the β-hydroxyl group on the side chain act almost exclusively by causing the release of NE from sympathetic nerve terminals

103. SAR of Sympathomimetic Amines… Substitution on the α-Carbon Atom The substitution on the α-carbon atom blocks oxidation by MAO, greatly prolonging the duration of action of noncatecholamines The duration of action of drugs such as amphetamine is thus measured in hours rather than in minutes Substitution on the β-Carbon Atom Substitution of a hydroxyl group on the β-carbon generally decreases actions within the CNS, largely because it lowers lipid solubility However, such substitution greatly enhances agonist activity at both α and β adrenergic receptors Although ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing blood pressure and heart rate Fig. Methamphetamine

104. Synthesis of adrenaline

105. There is a tendency for NE to leak from the vesicles into the cytosol, where it is destroyed by a mitochondrial enzyme, monoamine oxidase (MAO) However, most of the NE that leaks out of the vesicle is rapidly up taken in to storage vesicles by an active transport system Vesicular Storage of NE

106. Release of NE An Action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron The increase in calcium causes synaptic vesicles to fuse with the cell membrane to undergo exocytosis and expel their contents into the synapse

107. NE binding to receptors Postsynaptic receptors on the effector organ triggers a cascade of events within the cell Presynaptic receptors ( α 2) on the nerve ending Inhibits further release NPY and adenosine derived from ATP act on Y 2 and P 1 receptors respectively to inhibit NE release Other receptors also have effects to Increase NE release:  2 -AR, angiotensin II, nicotinic receptors Inhibit NE release : muscarinic (M 2 & M 4 ) receptors

108. Removal of NE from the synapse Termination of its transmitter role Three processes contribute to this process Transport back into the noradrenergic neuron (reuptake 1, uptake 1 or NET) Dilution by diffusion out of the junctional cleft and uptake into extraneuronal sites (extraneuronal uptake or ENT, uptake 2 ) Metabolic transformation By MAO and COMT (catechol-O-methyl transferase)

109. COMT Little or not found in sympathetic neurons Not significant in presynaptic terminals in the brain, but found in some postsynaptic neurons & glial cells It is largely cytosolic , except in the chromaffin cells of the adrenal medulla, where COMT is membrane bound Plays a major role in the metabolism of endogenous circulating and administered catecholamines MAO (MAO-A degrade NE, 5-HT, DA; MAO-B degrade mainly DA) Associated with the outer surface of mitochondria Metabolizes transmitter within the nerve terminal

110. Receptor specificity of adrenergic agonists Catecholamine Non- catecholamines Drug Receptor stimulated Drug Receptor stimulated Adrenaline α 1 , α 2 , β 1, β 2 Ephedrine α 1 , α 2 , β 1, β 2 Noradrenaline α 1 , α 2 , β 1 Phenylephrine α 1 Isoproterenol β 1, β 2 Terbutaline β 2 Dopamine α 1 , β 1 , dopamine R Dobutamine β 1

111. Adrenoceptors Can broadly be divided into two: -AR: which constitutes  1 &  2 subtypes  1A ,  1B , and  1D  2A ,  2B , and  2C -AR: which constitutes  1 ,  2 &  3 subtypes

112. -AR Regulate heart rate and contractility, smooth muscle relaxation, and multiple metabolic events Couple to G s and activate adenylyl cyclase (  cAMP  activation PK A  activation of target proteins ) G s can enhance directly the activation of voltage-sensitive Ca 2+ channels in skeletal and cardiac muscle Catecholamines promote  receptor feedback regulation, i.e., desensitization & down-regulation (  2 most susceptible )

113.  1 -AR 1A is predominant receptor that causes vasoconstriction in many vascular beds  1B is the most abundant subtype in the heart  1D predominant receptor that causes vasoconstriction in the aorta Primarily activate phospholipase C (PLc) Most smooth muscle:  ed Conc. of intracellular Ca 2+ , activates Ca 2+ -sensitive protein kinases such as the calmodulin-dependent myosin light-chain kinase which results in contraction GI smooth muscle  ed Conc. of intracellular Ca 2+ causes hyperpolarization and relaxation by activation of Ca 2+ -dependent K + channels

114.  2 -AR Mainly inhibit adenylate cyclase activity Activate G protein-gated K + channels leads to membrane hyperpolarization Inhibit voltage gated Ca 2+ channels  2A inhibition of NE release from nerve endings and suppresses sympathetic outflow from the brain  2B mediates vasoconstriction  2C inhibits the release of catecholamines from adrenal medulla and modulates dopamine neurotransmission in brain Suppression of insulin secretion and inhibition of lipolysis The α2 receptors also mediate contraction of some arteries and veins

115. Therapeutic Applications of Alpha1 Activation Activation of alpha1 receptors elicits two responses that can be of therapeutic use: Vasoconstriction (in blood vessels of the skin, viscera, and mucous membranes) Mydriasis Hemostasis: arrest of bleeding Adrenaline is applied topically to produce hemostasis Nasal congestion: Drugs can relieve this congestion by causing alpha 1 mediated vasoconstriction

116. C. Adjunct to local anaesthetics : Frequently combined with local anaesthetic to delay anaesthetic absorption It prolongs anaesthesia It allows reduction in anaesthetic dosage It reduces the systemic effects that a local anaesthetic might produce D. Elevation of blood pressure Can elevate blood pressure in hypotensive patients E. Mydriasis: Activation of alpha1 receptors on the radial muscle of the iris causes mydriasis (dilation of the pupil)

117. Adverse Effects of Alpha1 Activation Hypertension (due to wide spread vasoconstriction) Necrosis: The cause is lack of blood flow to the affected area secondary to intense local vasoconstriction Bradycardia: Alpha1-mediated vasoconstriction elevates blood pressure, which triggers the baroreceptor reflex, causing heart rate to decline

118. Clinical Consequences of Alpha2 Activation Alpha2 receptors are located at sympathetic presynaptic nerve endings, and their activation inhibits NE release Activation of alpha2 receptors in the periphery has little clinical significance In contrast to alpha2 receptors in the periphery, alpha2 receptors in the CNS are of great clinical significance By activating central alpha2 receptors, we can produce two useful effects: Reduction of sympathetic outflow to the heart and blood vessels Relief of severe pain

119. Therapeutic applications of Beta1 stimulation Treatment of cardiac arrest Treatment of heart failure: A positive inotropic effect Treatment of shock Treatment of atrioventricular Heart Block Drugs are only a temporary form of treatment For long-term management, a pacemaker is implanted Adverse effects of Beta1 Stimulation Tachycardia or even arrhythmia Angina Pectoris

120. Therapeutic application of Beta2 Stimulation Asthma: Since stimulation of beta2 receptors in the lung causes bronchodilation Delay of premature labour Adverse effects of beta2 stimulation Hyperglycaemia only in patients with diabetes activation of beta2 receptors in the liver and skeletal muscles, which promotes breakdown of glycogen into glucose in patients with normal pancreatic function, insulin release will maintain blood glucose at an appropriate level Tremor: occurs because activation of beta2 receptors in skeletal muscle enhances contraction

121. Mechanism of action of adrenergic agonists Ephedrine pseudoephedrine Epinephrine, norepinephrine, isoproterenol, and phenylephrine Amphetamine Cocaine

122. Indirect acting drug Action Mixed acting drug Action Imipramine B locks neuronal transporter (NET) Has atropine like action Ephedrine NA release, β , α agonist, weak CNS stimulant Cocaine Local anaesthetic; blocks NET CNS stimulant Amphetamine Displace stored NA lead NA release, CNS stimulant Tyramine Enter the nerve terminal and displace stored NA lead NA release

123. Important individual adrenergic agonists Epinephrine actions: Increase HR, force of contraction of myocardium, renin release via 1R Constricts arterioles in the skin, mucous membranes, and viscera (α effects), Dilates vessels going to the liver and skeletal muscle (β2 effects) Cause hyperglycemia (via 2R increase glucagon release, 2R inhibit insulin release)

124. Therapeutic Uses Because of its ability to cause alpha-mediated vasoconstriction, adrenaline is used to: Delay absorption of local anaesthetics Control of superficial bleeding Produce nasal decongestion and Elevate blood pressure Stimulation of Alpha1 receptors on the iris is employed to produce mydriasis during ophthalmologic procedures

125. Adrenaline is used to restore cardiac arrest Promotes bronchodilation in patients with asthma Adrenaline is the drug of choice for treating anaphylactic shock Pharmacokinetics Absorption: Adrenaline is administered topically, by injection and by inhalation, the drug is not administered by mouth Inactivation Adrenaline has a short plasma half-life because of two processes: a. Enzymatic inactivation (MAO and COMT) b. Uptake into adrenergic nerves

126. Adverse effects Hypertensive crisis Arrhythmias Angina Necrosis Hyperglycemia

127. Dopamine Dopamine has dose-dependent receptor specificity At low therapeutic doses , dopamine acts on dopamine receptors only At moderate therapeutic doses , dopamine activates beta1 receptors in addition to dopamine receptors And at very high doses , dopamine activates alpha1 receptors along with beta1 and dopamine receptors Degraded by MAO-B &COMT

128. Therapeutic Uses Shock: Benefits derive from effects on the heart and renal blood vessels By activating beta1 receptors in the heart, dopamine can increase cardiac output, improving tissue perfusion By activating dopamine receptors in the kidney, dopamine can dilate renal blood vessels, improving renal perfusion At very high doses that activate alpha1 receptors, vasoconstriction may decrease renal perfusion, overriding the effects of dopamine activation

129. Heart Failure: Dopamine can help alleviate symptoms by activating beta1 receptors on the heart, which increases myocardial contractility and thereby increases cardiac output The most common adverse effects Tachycardia Dysrhythmias Anginal pain Necrosis

130. Dobutamine A synthetic, catecholamine that is a β1 receptor agonist Has relatively more prominent inotropic than chronotropic effects on the heart Increases cardiac output and stroke volume, usually without a marked increase in heart rate It is less arrhythmogenic than epinephrine

131. Therapeutic Uses For the short-term treatment of cardiac decompensation that may occur after cardiac surgery or In patients with congestive heart failure or Acute myocardial infarction Adverse Effects Tolerance may develop with prolonged use Tachycardia

132. Xylometazoline, naphazoline, and oxymetazoline Are relatively selective α2 agonist They have a longer duration of action than ephedrine They are used as nasal decongestants, as well as ophthalmic drops For the relief of redness of the eyes associated with swimming, colds, and contact lenses They constrict blood vessels supplying the nasal mucosa and conjunctiva, thereby producing vasoconstriction and decreasing congestion

133. Adverse Effects Nervousness, headaches, and trouble sleeping, local irritation and sneezing Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur

134. Phenylephrine Synthetic adrenergic drug that binds primarily to α1 receptors. It has no effect on the heart itself but, rather, induces reflex bradycardia when given parenterally Therapeutic uses To treat hypotension (especially those with a rapid heart rate) As a nasal decongestant when applied topically or taken orally Also used in ophthalmic solutions for mydriasis Adverse effect At large doses it causes hypertensive headache and cardiac irregularities

135. Midodrine A prodrug , is metabolized to the pharmacologically active desglymidodrine A selective α1 agonist, which acts in the periphery to increase arterial and venous tone Indicated for the treatment of orthostatic hypotension To avoid supine hypertension, doses within 4 hours of bedtime are not recommended Adverse effect At large doses it causes hypertensive headache and cardiac irregularities

136. Clonidine Act centrally on presynaptic α2 receptors Produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery- used in resistant HTN Minimize the symptoms that accompany withdrawal from opiates, tobacco smoking, and benzodiazepines The most common side effects are lethargy, sedation, constipation, and xerostomia Abrupt discontinuation must be avoided to prevent rebound hypertension

137. -methyldopa Methyldopa, an analog of DOPA, is decarboxylated to -methyldopamine which is then actively transported to vesicles where it is -hydroxylated to the  2 -AR agonist,-methyl norepinephrine α-Methyldopa gives rise to false transmitter (α methylnoradrenaline), which is a potent α2 agonist, thus causing powerful presynaptic inhibitory feedback (also central action) Use: treatment of hypertension (it is the preferred agent during pregnancy) Adverse effects: sedation, dry mouth, bradycardia, hepatotoxicity, hemolytic anemia

138. Albuterol and terbutaline Are short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler Used for the management of acute asthma symptoms Terbutaline is also used off-label as a uterine relaxant to suppress premature labor Adverse effects Tremor, anxiety, restlessness Upon oral administration can cause tachycardia ( 1 effect)

139. Salmeterol and formoterol Are long acting β agonists that are 2 selective Are highly efficacious when combined with a corticosteroid Are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications

140. Ephedrine (mixed acting adrenergic agonists) Is not a catechol and is a poor substrates for COMT and MAO An agonist at both α and β receptors It enhances release of NE from sympathetic neurons Ephedrine produces a mild stimulation of the CNS This increases alertness, decreases fatigue, and prevents sleep Cause life threatening cardiovascular reaction (due to this, its clinical use is declining) It is eliminated largely unchanged in urine Used orally to treat nasal and sinus congestion

141. Adrenergic Receptor Antagonists Drugs that inhibit the interaction of NE, epinephrine, and other sympathomimetic drugs with α and β receptors Most of these agents are competitive reversible antagonists; an important exception is phenoxybenzamine, an irreversible antagonist that binds covalently to α receptors Important structural differences amongst the various types of adrenergic receptors, have permitted development of compounds with substantially different affinities for the various receptors

142. The selectivity is relative, not absolute Nonetheless, selective antagonists of β1 receptors block most actions of epinephrine and NE on the heart, while having less effect on β2 receptors in bronchial smooth muscle and no effect on responses mediated by α1 or α2 receptors

143. Adrenoceptor blockers Alpha blockers Non selective Alpha 1 selective Alpha 2 selective Beta blockers Non selective Beta 1 selective Beta 2 selective

144. Non selective alpha receptor blockers Normal sympathetic control of the vasculature occurs in large part through agonist actions on α-adrenergic receptors Blockade of these receptors in vasculature reduces the sympathetic tone of the blood vessels Resulting in decreased peripheral vascular resistance This induces a reflex tachycardia resulting from the lowered blood pressure

145. An increase in cardiac output that is due in part to reflex sympathetic nerve stimulation The cardiac stimulation is accentuated by enhanced release of NE from cardiac sympathetic nerve due to antagonism of presynaptic α2 receptors Postural hypotension is a prominent feature with these drugs This, accompanied by reflex tachycardia that can precipitate cardiac arrhythmias, Severely limits the use of these drugs to treat essential hypertension

146. Phenoxybenzamine It acts irreversibly Not recommended for treatment of HTN as it blocks presynaptic alpha 2 receptors Therapeutic uses Pheochromocytoma, tumor of the adrenal medulla and sympathetic neurons Prior to surgical removal of the tumor , patients are treated preclude the hypertensive crisis that can result from manipulation of the tissue Chronic management of these tumors, particularly when the catecholamine-secreting cells are diffuse and, therefore, inoperable

147. Phentolamine Its action is reversible Produces reversible alpha-adrenergic blockade Useful to treat hypertensive crisis due to Abrupt withdrawal of clonidine Ingesting tyramine -containing foods in patients taking monoamine oxidase inhibitors Used for the short-term management of pheochromocytoma

148. Adverse Effects Orthostatic Hypotension The major adverse effect of phenoxybenzamine and phentolamine Reflex cardiac stimulation May cause alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction Reversible inhibition of ejaculation May occur due to impaired smooth muscle contraction in the vas deferens and ejaculatory ducts

149. α1 selective adrenergic receptor antagonists Blockade of α1 adrenergic receptors inhibits vasoconstriction Induced by endogenous catecholamines; vasodilation may occur in both arteriolar resistance vessels and veins The result is a fall in blood pressure due to decreased peripheral resistance For most α receptor antagonists, the fall in blood pressure is opposed by baroreceptor reflexes That cause increases in heart rate and cardiac output, as well as fluid retention Prazosin, doxazosin, tamsulosin, terazosin …

150. Therapeutic Uses Hypertension Vasodilation Improve lipid profiles and glucose-insulin metabolism in patients with hypertension who are at risk for atherosclerotic disease Congestive Heart Failure Short term effects of α receptor blockade are due to dilation of both arteries and veins, resulting in a reduction of preload and after load, which increases cardiac output and reduces pulmonary congestion Not drug of choice Benign Prostatic Hyperplasia: relaxation of smooth muscle in the bladder neck, prostate capsule, and prostatic urethra (Tamsulosin, alfuzosin, and silodosin) These drugs rapidly improve urinary flow

151. Therapeutic Uses… Peripheral Vascular Disease Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels Occasionally, individuals with Raynaud phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients

152. Adverse effects A major potential adverse effect of prazosin and its congeners is the first dose effect; Marked postural hypotension and syncope The risk of the first-dose phenomenon is minimized by Limiting the initial dose (e.g., 1 mg at bedtime) Increasing the dosage slowly Introducing additional antihypertensive drugs cautiously Reflex tachycardia, Nasal congestion Inhibition of ejaculation Fluid retention and increased blood volume

153. α2 selective antagonists Blockade of α2 receptors with selective antagonists Can increase sympathetic outflow Potentiate the release of NE from nerve endings, leading to activation of α1 and β1 receptors in the heart and peripheral vasculature with a consequent rise in blood pressure The effects of α2 receptor antagonists on the cardiovascular system are dominated by actions in the CNS and on sympathetic nerve endings

154. Yohimbine A selective competitive α2-blocker that works at the level of the CNS to increase sympathetic outflow to the periphery It is sometimes used in the treatment of orthostatic hypotension A naturally occurring alkaloid; various synthetic analogues have been made, such as idazoxan Generally not used clinically

155. β- Adrenergic Blocking Agents The myriad β antagonists can be distinguished by the following properties: Relative affinity for β1 and β2 receptors Intrinsic sympathomimetic activity Blockade of α receptors Differences in lipid solubility (CNS penetration) Capacity to induce vasodilation Pharmacokinetic parameters Although all β-blockers lower BP, they do not induce postural hypotension, Because the α-adrenoceptors remain functional Normal sympathetic control of the vasculature is maintained

156. Nonselective β antagonist Nadolol, propranolol, timolol, pindolol Propranolol Therapeutic uses Hypertension By decreasing CO By inhibition of renin release Angina pectoris Useful in the chronic management of stable angina by decreasing oxygen demand of myocardium

157. Myocardial infarction The mechanism for these effects may be a reduction in the actions of catecholamines that increase the oxygen demand in an already ischemic heart muscle Used to prevent migraine Hyperthyroidism Used to avoid symptoms associated with sympathetic activation Pharmacokinetics Propranolol is almost completely absorbed It is subject to first-pass effect Extensively metabolized, and most metabolites are excreted in the urine Readily crosses BBB due to its high lipophilicity

158. Adverse effects Bronchoconstriction Arrhythmias If the drug is stopped abruptly On long term t/t by up regulation of receptors Metabolic disturbances (inhibit lipolysis, increase TG, decrease HDL) CNS effects: depression, dizziness, lethargy, fatigue, weakness, visual disturbances, hallucinations Sexual impairment in male (mechanism unknown) Not due to beta receptor blockade b/c β-blockers do not affect ejaculation (mediated by α receptors)

159. Drug interactions Cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects by inhibiting its metabolism Barbiturates, phenytoin, and rifampin, can decrease its effects by inducing its metabolism Timolol More potent than propranolol Timolol reduces the production of aqueous humor in the eye It is used topically in the treatment of chronic open-angle glaucoma

160. Selective β1 antagonists Acebutolol, atenolol, betaxolol , bisoprolol , esmolol, metoprolol , and nebivolol At high doses, they may antagonize β2 receptors Because have less effect on peripheral vascular β2 receptors, Coldness of extremities (Raynaud phenomenon), a common side effect of β-blockers, is less frequent Therapeutic uses Treatment of hypertensive patients with impaired pulmonary function Treatment of chronic stable angina Bisoprolol & XR metoprolol are indicated for The management of chronic heart failure

161. Esmolol Has a very short half-life due to metabolism of an ester linkage It is only available intravenously Used to control blood pressure or heart rhythm in critically ill patients and those undergoing surgery or diagnostic procedures Nebivolol In addition to its cardioselective β-blockade, nebivolol releases nitric oxide from endothelial cells and causes vasodilation

162. Antagonists with partial agonist activity Acebutolol & celiprolol ( β1- selective antagonist) Pindolol, penbutolol, labetalol, carteolol (nonselective β- blocker) These drugs can also weakly stimulate both β1 and β2 receptors These partial agonists stimulate the β receptor to which they are bound, yet they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine

163. Therapeutic use β-Blockers with ISA are effective in hypertensive patients with moderate bradycardia, because a further decrease in heart rate is less pronounced with these drugs β-blockers with ISA are not used for stable angina or arrhythmias due to their partial agonist effect

164. Antagonists of both α and β adrenoceptors Labetalol and carvedilol Are nonselective β-blockers with concurrent α1-blocking actions that produce peripheral vasodilation Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure Labetalol is used as alternative to methyldopa for t/t of pregnancy-induced hypertension Labetalol is also used to treat hypertensive emergencies Carvedilol as well as metoprolol and bisoprolol are beneficial in patients with stable chronic heart failure Carvedilol for t/t of HTN Adverse effects: Orthostatic hypotension and dizziness

165. Reserpine Blocks noradrenaline accumulation in vesicles by vesicular monoamine transporter (VMAT), thus depleting noradrenaline stores and blocking transmission Blocks the VMAT dependent transport of biogenic amines (NE, dopamine, and serotonin) From the cytoplasm into storage vesicles in the adrenergic nerve terminals in all body tissues This causes the ultimate depletion of biogenic amines Clinically obsolete Guanethidine Inhibits nerve impulse coupled release of NE –inhibit transmission Has little use

166. Generalized diagram of a noradrenergic nerve terminal, showing sites of drug action . EMT, extra neuronal monoamine transporter; MAO, monoamine oxidase; MeNA, methylnoradrenaline; NA, noradrenaline; NET, neuronal noradrenaline transporter

167. References Goodman& Gilman, The pharmacological basis of therapeutics. 13 th edition Bertram G. Katzung. Basic & Clinical Pharmacology. 14 th Edition Essentials of medical pharmacology 8 th edition Other sources

168. THANK YOU!