health doc about autonomic nerve system of pharmacology power point which is very useful for health students in university hggggggggggggggggggggggggggggg

1. ANS pharmacology

2. NTs in ANS
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3. Receptors in the ANS
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4. CholinergicAgonistandAntagonists
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5. I. Cholinergic Agonists
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6. A. Direct-acting cholinomimetic drugs
• Mimic the effects of ACh by binding directly to
cholinoceptors (muscarinic or nicotinic).
• These agents may be broadly classified into two
groups:
1) Choline esters, which include
 endogenous ACh and
 synthetic esters of choline, such as methacholine
carbachol , and bethanechol, and
2) Naturally occurring alkaloids, such as nicotine ,
lobeline, muscarine, and pilocarpine
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7. 1. Choline esters
• They are hydrophilic.
• Poorly absorbed and
• poorly distributed into
the central nervous
system
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8. 2.Natural cholinomimetic alkaloids
• Pilocarpine, nicotine, and lobeline are well
absorbed from most sites of administration.
• Muscarine, a quaternary amine, is less
completely absorbed from the gastrointestinal
tract than the tertiary amines
• These amines are excreted chiefly by the
kidneys.
• Acidification of the urine accelerates clearance
of the tertiary amines
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9. B. Indirect-Acting Cholinergic Agonists
• Inhibit acetylcholinesterase (ACHE)
• some also have direct actions at nicotinic at receptors
at NMJ (Physostigmine).
• AChE inhibitors are divided into two main types,
1) Reversible:
 Non covalent/short-acting inhibtors ; edrophonium,
tacrine, and donepezil and
 Covalent /Intermediate-acting / carbamate inhibitors;
physostigmine, neostigmine, and pyridostigmine
2) Irreversible: organophosphorus or organophosphate
[ sarin, soman, and tabun, parathion and malathion;
echothiophate and isoflurophate. ]
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10. 1.Reversible ACHE inhibitors
• Edrophonium, neostigmine, and pyridostigmine
 are synthetic quaternary ammonium
 Poorly absorbed from the conjunctiva, skin, gut, and lungs
 Distribution into the central nervous system is negligible.
• Physostigmine (eserine) is a naturally occurring tertiary
amine
 It is highly lipid soluble
 is well absorbed from all sites and can be used topically in
the eye
 It is distributed into the central nervous system and is
more toxic
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11. 2. Irreversible inhibitors
• Many of the organophosphates (echothiophate is
an exception) are highly lipid-soluble liquids.
• Echothiophate, a thiocholine derivative, is of
clinical value
 because is more stable in aqueous solution.
• Sarin is an extremely potent “nerve gas.”
• Parathion and malathion are thiophosphate
prodrugs
 they are converted to the phosphate derivatives in
animals and plants and are used as insecticides
paraoxon and malaoxon, respectively..
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12. Effects of Cholinergic Agonists
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13. Cont’d
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14. Therapeutic uses of cholinergic
agonists
• ACH lacks therapeutic importance because of its
 multiplicity of actions (leading to diffuse effects) and
 its rapid inactivation by the cholinesterases.
• Other cholinergic drugs used for several
indications
A. Glucoma :
 Pilocarpine, physostigmine,
carbachoal,Echothiophate,Isoflurophate
B. Postoperative ileus, congenital megacolon,
urinary retention (non-obstructive), constipation
 Bethanechol, Neostigmine
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15. Cont’d
C. Reversal of neuromuscular blockade
 Neostigmine, edrophonium, Pyridostigmine
D. Diagnosis of myasthenia gravis and
cholinergic crisis
 Edrophonium
E. Treatment of myasthenia gravis
Pyridostigmine, neostigmine
F. Sjögren syndrome/dry eyes and mouth/
 Pilocarpine, Cevimeline
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16. Cont’d
G. Anticholinergic poisoning
 Physostigmine
H. Treat patients with Alzheimer’s disease
 tacrine, donepezil , galantamine, and rivastigmine
I. Preventive therapy for organophosphate
poising
 pyridostigmine,
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17. Adverse effects of cholinergic drugs
• The side effects of muscarinic receptor agonists
are an extension of their parasympathomimetic
actions and include :
 miosis, blurred vision, lacrimation, excessive
salivation and bronchial secretions, sweating,
bronchoconstriction, bradycardia, abdominal
cramping, increased gastric acid secretion, diarrhea,
decreased blood pressure (with reflex tachycardia)
and polyuria.
• Muscarinic receptor agonists that can penetrate
into the brain also cause
 tremor, hypothermia, and convulsions.
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18. Cont’d
• The toxic effects of a large dose of nicotine are
 central stimulant actions, which cause convulsions and
may progress to coma and respiratory arrest;
 skeletal muscle end plate depolarization, which may lead
to depolarization blockade and respiratory paralysis; and
 hypertension and cardiac arrhythmias.
• Muscarinic receptor agonists are contraindicated in
patients with
 chronic obstructive pulmonary disease (COPD) and
asthma
 peptic ulcer disease
 GI or urinary tract obstructions
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19. II. Cholinergic Antagonists
• They are commonly known as anticholinergic
agents or parasympatholytics
• Bind to cholinoceptors (muscarinic or nicotinic)
and prevent the effects of acetylcholine (ACh)
and other cholinergic agonists.
• The most clinically useful of these agents are
selective blockers of muscarinic receptors.
• Nicotinic receptor blockers
 Ganglionic blockers( both sympatholytic and
parasympatholytic)
Neuromuscular blocker
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20. A. Antimuscarinic Agents
• Atropine
• Ipratropium
• Scopolamine
• Tolterodine ,
• pirenzepine, and
• darifenacin
• Antihistamines, tricyclic antidepressants, and
antipsychotics
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21. Clinical uses
• Examination of the retina and measurement of
refraction; inflammatory uveitis
• Excessive motility of GI and urinary tract; urinary
incontinence;
• irritable bowel syndrome
• Chronic obstructive pulmonary disease, asthma
• Motion sickness
• Gastric acid secretion /PUD
• Antidotes to cholinesterase inhibitors and mushrooms
containing muscarine
• Parkinson’s disease
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22. Cont’d
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23. Cont’d
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24. Adverse Effects
• Antimuscarinic agents cause
 mydriasis, cycloplegia, blurred vision, dry mouth,
tachycardia, urinary retention, cutaneous
vasodilation, and decreased motility of the stomach
and intestines with constipation.
• Muscarinic antagonists that enter the brain cause
 sedation and interfere with memory.
 excitation, hallucinations, delirium, stupor, toxic
psychosis, and convulsions, which may lead to
respiratory depression and death.
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25. Adrenergic agonists and antagonists

26. 1. Adrenergic agonists
• Also called as sympathomimetics or
adrenomimetics with the exception of α2
agonists,
• Sympathomimetics can be grouped in to
three
 Direct agonists
 Indirect agonists
 Both direct and indirect (mixed action)
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27. A. Direct agonists
 Directly interact with and activate
adrenoceptors.
 Based on receptor affinity direct agonists
grouped in to:
• Non-selective
– Cathecolmines
• Selective
– α1 receptor agonists: phenylephrine and methoxamine,
– β1 receptor agonist: Dobutamine
– β2 receptors agonists : albuterol, bitolterol, formoterol,
metaproterenol, pirbuterol, salmeterol, and terbutaline
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28. I. Cathecolamines
• These include:
• Endogenous cathecolamines
 epinephrine, norepinephrine, dopamine,
• Synthetic cathecolamines
 isoproterenol
• For α receptors, the rank order of potency and
affinity is
 epinephrine ≥ norepinephrine >> isoproterenol.
• For β receptors, the rank order of potency is
 isoproterenol > epinephrine > norepinephrine
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29. A.Epinephrine
• Epi is the prototype direct-acting sympathomimetic
• Epi is synthesized from NE
• It activates all known adrenergic receptors.
• Has only a brief period of action when given
parenterally,
• Ineffective when administered orally.
• Do not readily penetrate into the CNS.
• It is rapidly metabolized by MAO and COMT
• The metabolites metanephrine and vanillylmandelic
acid are excreted in urine.
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30. Major effects mediated by α- and β-
adrenoceptors activation by
Epinephrine.
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31. Therapeutic uses
• Anaphylactic shock
• Cardiac arrest/ asystole/pulseless arrest,
• ventricular fibrillation, or pulseless ventricular
tachycardia.
• As a component of local anesthesia
• intraocular surgery
• Bradycardia unresponsive to atropine
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32. Adverse effects of Epi and precautions
• anxiety, fear, tension, headache, and tremor.
• Tachycardia.
• Cardiac arrhythmias
• Pulmonary edema
• Hyperglycemia
• Dose must be reduced in hyperthyroidism patients
• Concomitant use in combination with digoxin and non-
selective β-blockers should be avoided
• In diabetic patients, dosages of insulin may have to be
increased.
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33. B. Norepinephrine
• Clinically relevant doses stimulate only α1 , α2 , and β1
receptors.
• NE has relatively low potency at β2 receptors
• In contrast to EPI, NE
 produces only vasoconstriction
 Increase total peripheral resistance and
 Both systolic and diastolic blood pressures increase
 Induces reflex bradycardia
 first-choice vasopressor for the treatment of septic shock.
 it is not useful for the treatment of anaphylactic shock
 has low metabolic adverse effects
 Has similar pK and adverse effect profile with Epi
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34. C. Isoproterenol (isoprenaline)
• Is a very potent β-receptor agonist and has little effect on α
receptors
• stimulates both β1 - and β2 - adrenergic receptors.
• Has positive chronotropic and inotropic actions.
• It is a potent vasodilator
• Reduces total peripheral resistance,
• resulting in a reduction in diastolic blood pressure and
increase systolic blood pressure .
• Like Epi, ISO relaxes bronchial smooth muscle and induces
metabolic effects.
• it is rarely used therapeutically due to side effects
• ISO may be used to relieve bronchoconstriction
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35. D. Dopamine
• Is the immediate metabolic precursor of norepinephrine
• DA produces complex dose-dependent peripheral actions.
• Low doses of DA (0.5–2 mg/kg/min) relax smooth muscle in
various vascular beds, including renal, mesenteric, and
coronary.
 caused by D1 receptor activation and decreased NE release
caused by presynaptic D2 receptor activation.
• Moderate doses of DA (2–10 mg/kg/min) activate β1
receptors in addition to DA receptors
 elicit positive chronotropic and inotropic effects.
 DA has actions similar to dobutamine at these doses..
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36. Cont’d
• High doses of DA (>10 mg/kg/min) activate α1
receptors in addition to β1 and cognate DA
receptors.
• Thus the receptor activation profile of DA is
similar to NE when administered at high doses,
and it may be used therapeutically like NE
• Dopamine can be used for cardiogenic and septic
shock and is given by continuous infusion.
• Dopamine is also used to treat hypotension,
severe heart failure, and bradycardia
unresponsive to other treatments.
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37. Selective α -adrenergic receptor
agonists
• Phenylephrine and methoxamine
• Are less potent but longer acting than NE
• primarily act on vascular smooth muscle
• Increases total peripheral resistance
• Produce a reflex bradycardia greater than for NE
• Phenylephrine and methoxamine used to treat
hypotension and shock.
• Phenylephrine is also used in topical preparations
as a mydriatic, as a nasal decongestant and for
the treatment of hemorrhoids.
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38. β1-selective agonist
• Dobutamine
• a relatively β1-selective agonist
• Clinical formulations of dobutamine are a racemic mixture
of (–) and (+) isomers,
• Each with contrasting activity at α1 and α2 receptors.
 The (+) isomer is a potent β1 agonist
 The (+) enantiomer also activates β2 receptors and inhibits α1
receptors
 The (–) isomer is a potent α1 agonist
• Dobutamine has relatively greater inotropic than
chronotropic effect compared with isoproterenol.
• Peripheral resistance does not decrease significantly
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39. cont’d
• Dobutamine is used clinically for the short-term
management of
 cardiac decompensation in patients with refractory
heart failure (American Heart Association Stage D),
 cardiogenic shock, and septic shock who have been
adequately fluid resuscitated but have low cardiac
output.
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40. Selective β2 -Adrenergic Receptor
Agonist
• Albuterol,
• bitolterol,
• formoterol,
• metaproterenol,
• pirbuterol,
• salmeterol, and
• terbutaline
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41. Cont’d
• These drugs differ from ISO because they are
effective orally and have a longer duration of
action.
• Selective β2 -receptor agonists relax vascular
smooth muscle in skeletal muscle and in
bronchi and the uterus.
• used for the treatment of asthma and chronic
obstructive pulmonary disease (COPD)
• Used to prevent premature labor.
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42. β3 agonist
• Mirabegron is a β3 agonist that relaxes the
detrusor smooth muscle and increases bladder
capacity.
• It is used for patients with overactive bladder.
• Mirabegron may increase blood pressure and
should not be used in patients with uncontrolled
hypertension.
• It increases levels of digoxin and inhibits the
CYP2D6 isozyme, which may enhance the effects
of other medications metabolized by this
pathway (for example, metoprolol).
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43. Selective α2 -Adrenergic Receptor
Agonists
• Clonidine,
• guanfacine, and
• methyldopa
• evoking a sympatholytic response
• decreased total peripheral resistance, heart rate, and
cardiac output.
• are used to lower blood pressure in patients with moderate
to severe hypertension.
• α-methyldopa is a first-line antihypertensive for gestational
hypertension.
• Clonidine is also used to ameliorate signs and symptoms
that accompany withdrawal from long-term opioid use.
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44. Oxymetazoline
• Is a direct-acting synthetic adrenergic agonist that
stimulates both α1 - and α2 -adrenergic receptors.
• Oxymetazoline directly stimulates α receptors on blood
vessels supplying the nasal mucosa and conjunctiva
• Oxymetazoline is found in many over-the-counter nasal
spray decongestants, as well as in ophthalmic drops
• It is absorbed in the systemic circulation regardless of the
route of administration and may produce nervousness,
headaches, and trouble sleeping.
• Local irritation and sneezing may occur with intranasal
administration.
• Use for greater than 3 days is not recommended, as
rebound congestion and dependence may occur.
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45. Indirect agonists
• Their actions are dependent on their ability to enhance the
actions of endogenous catecholamines by
(1) inducing the release of catecholamines (eg, tyramine,
amphetamine),
(2) inhibiting their neuronal reuptake (eg, cocaine and tricyclic
antidepressants), or
(3) preventing the enzymatic metabolism of norepinephrine
(monoamine oxidase and catechol-O-methyltransferase
inhibitors).
• The pharmacologic effects of indirect sympathomimetics
are greater under conditions of
 increased sympathetic activity and norepinephrine storage and
release.
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46. Reading assignment
• Read on MAO and COMT inhibitors
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47. Mixed action agonists
• Promote the cytoplasmic release of NE and directly
activating adrenergic receptors
Eg. ephedrine and pseudoephedrine
• Similar to those of epinephrine, although less potent
and and slower acting.
• These drugs have a long duration of action
• Ephedrine and pseudoephedrine have excellent
absorption after oral administration and penetrate the
CNS,
• Oral pseudoephedrine is primarily used to treat nasal
and sinus congestion.
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48. Cont’d
• Ephedrine is eliminated largely unchanged in urine,
and pseudoephedrine undergoes incomplete hepatic
metabolism before elimination in urine.
• Ephedrine raises systolic and diastolic blood pressures
by vasoconstriction and cardiac stimulation and it is
indicated in anesthesia-induced hypotension.
• Ephedrine produces bronchodilation, but it is less
potent and slower acting than epinephrine or
isoproterenol.
• Ephedrine produces a mild stimulation of the CNS.
• This increases alertness, decreases fatigue, and
prevents sleep.
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49. Summary of the adrenergic agonists
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50. Cont’d
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51. 2. Adrenergic Antagonists
• also called adrenergic blockers or sympatholytic
• Numerous adrenergic antagonists have important
roles in clinical medicine,
 primarily to treat diseases associated with the
cardiovascular system
• Adrenergic antagonists are classified according to
their relative affinities as
 α-Adrenergic receptor antagonists
 β-Adrenergic receptor antagonists
 Mixed-action α1/β-adrenergic receptor antagonists
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52. 1. α-Adrenergic Blocking Agents
• Nonselective blocker of α1 - and α2 -adrenergic receptors.
 Phenoxybenzamine, non competitive and irreversible
antagonist
 Phentolamine , competitive antagonist
• Selective α1 -Adrenergic Receptor Antagonists
 Prazosin, terazosin, doxazosin, tamsulosin ,alfuzosin , and
silodosin
 are selective competitive blockers of the α1 receptor.
• Selective competitive α2 –blocker
 Yohimbine
 works at the level of the CNS to increase sympathetic outflow to
the periphery.
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53. Therapeutic uses of α-Adrenergic
Receptor Antagonists
• Benign prostatic hyperplasia and urinary
retension
 tamsulosin ,alfuzosin , and silodosin
• Pheochromocytoma
 phenoxybenzamine and phentolamine
• Hypertension
 Prazosin, terazosin, doxazosin
 not used as monotherapy for the treatment of
hypertension
• Treatment of erectile dysfunction
 Yohimbine
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54. Adverse effects
• Postural hypotension
• Reflex tachycardia.
• Dizziness and headache
• Sexual dysfunction
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55. 2. β-Adrenergic Blocking Agents
• All of the clinically available β-blockers are competitive
antagonists.
• Most β-blocking drugs in clinical use are pure
antagonists
• Some are partial agonists
• some β blockers (eg, betaxolol, metoprolol) are inverse
agonist
• The β-receptor–blocking drugs also differ in their
 relative affinities for β1 and β2 receptors
 pharmacokinetic characteristics and
 local anesthetic membrane-stabilizing effects.
 CNS effect
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56. Pharmacokinetic Properties of the
Beta-Receptor Antagonists
• Most of the drugs in this class are well absorbed after oral
administration
• Propranolol undergoes extensive hepatic (first-pass)
metabolism
• The β antagonists are rapidly distributed and have large
volumes of distribution.
• Propranolol and metoprolol are extensively metabolized in
the liver, with little unchanged drug appearing in the urine.
• The CYP2D6 genotype is a major determinant of
interindividual differences in metoprolol plasma clearance
• Atenolol, celiprolol, and pindolol are less completely
metabolized.
• Nadolol is excreted unchanged in the urine
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57. Therapeutic uses of beta blockers
• β-Blockers are effective in treating
 systemic as well as portal hypertension,
 angina ,
 cardiac arrhythmias ( supraventricular cardiac
arrhythmias)
 myocardial infarction,
 heart failure,
 hyperthyroidism, and
 Open angle glaucoma (timolol, carteolol, evobunolol,
metipranolol,and betaxolol ).
• They are also used for the prophylaxis of migraine
headache (propranolol)
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58. Non-Selective β -Adrenergic Receptor
Antagonists
• propranolol
• Penbutolol
• Pindolol
• Sotalol
• Timolol
• Nadolol
• Labeilol
• Carteolol
• Carvedeilol
• Levubunolol
• Metiprolol
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59. Actions of a nonselective β antagonist
• Blocks both β1 and β2 receptors with equal affinity
• have both negative inotropic and chronotropic effects
• Have the ability to block the actions of isoproterenol
• The actions of norepinephrine on the cardiovascular system mostly
remains unaffected
• Triggers a reflex peripheral vasoconstriction
• Causes contraction of the bronchiolar smooth muscle
• Decrease glycogenolysis and decreased glucagon secretion.
• Pronounced hypoglycemia may occur after insulin injection.
• β-Blockers also attenuate the normal physiologic response to
hypoglycemia, except diaphoresis
• Increased triglycerides and reduced high-density lipoprotein
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60. Selective β1 -Adrenergic Receptor
Antagonists
• Acebutolol,
• atenolol,
• betaxolol,
• bisoprolol,
• esmolol,
• metoprolol, and
• nebivolol
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61. Actions and therapeutic uses of
selective β1 antagonists
• Preferentially block the β1 receptors
• This cardioselectivity is most pronounced at low doses
• Have fewer effects on pulmonary function, peripheral
resistance, and carbohydrate metabolism.
• Nebivolol releases nitric oxide from endothelial cells and
causes vasodilation.
• Are useful in hypertensive patients with impaired
pulmonary function.
• These agents are also first-line therapy for chronic stable
angina
• Bisoprolol and the extended-release formulation of
metoprolol are indicated for the management of chronic
heart failure.
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62. Beta antagonists with partial agonist
activity
• Acebutolol
• pindolol
• Penbutolol
• Celiprolol
• Carteolol
• Can weakly stimulate both β1 and β2 receptors and are said to have
ISA
• Have a diminished effect on reduction of cardiac rate and cardiac
output compared to that of β-blockers without ISA.
• minimize the disturbances of lipid and carbohydrate metabolism
• are effective in hypertensive patients with moderate bradycardia,
and/or respiratory risk
• are not used for stable angina or arrhythmias
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63. β blockers with local anesthetic action
• Aceubutolol
• Labetolol
• Metoprolol
• pindolol
• Propranolol
• This action is the result of typical local anesthetic
blockade of sodium channels
• The membrane stabilizing β blockers are not used
topically on the eye
 because local anesthesia of the cornea, eliminating its
protective reflexes,
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64. Mixed-action α1/β-adrenergic
receptor antagonists
• Labetalol and carvedilol
• are nonselective β-blockers with concurrent α1 -
blocking actions
• Decrease peripheral vascular resistance
• Carvedilol also decreases lipid peroxidation and
vascular wall thickening, effects that have benefit in
heart failure.
• Labetalol is used as an alternative to methyldopa in the
treatment of pregnancy-induced hypertension.
• Intravenous labetalol is also used to treat hypertensive
emergencies
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65. Properties of several beta-receptor–
blocking drugs
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66. Indirect adrenergic antagonists
• Reserpine
• Block the VMAT, and inhibit storage
• Causes the ultimate depletion of biogenic
amines
• used for the management of hypertension
• It is also indicated in agitated psychotic states
such as schizophrenia to relieve symptoms.
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