DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM

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DRUGSACTING ONAUTONOMIC NERVOUS SYSTEM

• DR.SUDHIR
• MUBARAK ALKABEER HSPITAL

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SYMPATHETIC NERVOUS SYSTEM
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PARASYMPATHETIC NERVOUS SYSTEM
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Neurotransmitters
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ADRENERGIC
MUSCURANIC
ß
M2
M4
M1
M3
M5
a2
a1
cell membrane
Gs
Gi
Gq
s
s
s
I
ADENYL CYCLASE
PLP C
PLP A2
PIP2
cAMP
K
Ca 2
ATP
IP3
PROTEIN KINASE
EFFECT
EFFECT
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Autonomic receptors Organs- Actions
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Cont.
Activation of Muscarinic receptors causes DUMBELS
syndrome Defecation, Urination,
Miosis,Bronchoconstriction, Emesis, Lacrimation,
Salivation
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SYNTHESIS
CATECHOLAMINE
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Norepinephrine fate adrenergic synapse
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CATECHOLAMINE METABOLISM
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CLASSIFICATION
DRUGS ACTING ON SYMPATHETIC NERVOUS SYSTEM
DRUGS ACTING ON PARASYMPATHETIC NERVOUS SYTEM
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DRUGS ACTING ON SYMPATHETIC NERVOUS SYSTEM
SYMPATHOMIMETICS
SYMPATHOLYTICS
CATECHOLAMINES
CENTRALLY ACTING

• ENDOGENOUS
• EPI ,NOREPI , DOPAMINE
• SYNTHETIC
• ISOPRENALINE,DOBUTAMINE,DOPEXAMINE

CLONIDINE METHYDOPA MOXONIDINE
NON-CATECHOLAMINES
PERIPHERALLY ACTING

• GANGLION BLOCKERS
• ADRENEGIC NEURON BLOCKERS
• ALPHA BLOCKERS
• BETA BLOCKERS

ADRENERGIC EPHEDRINE,PHENYEPHRINE,METHOXAMINE,META
RAMINOL NON ADRENERGIC PDES,DIGOXIN,GLUCAGON,CALC
IUM,LEVOSIMENDAN
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DRUGS ACTING ON PARASYMPATHETIC NERVOUS SYTEM
PARASYMPATHETIC AGONISTS
1.NATURAL ACETYLCHOLINE, MUSCURINE,PILOCARPINE,A
RECHOLINE 2.SYNTHETIC- METHACHOLINE,CARBACHOL,BET
HANECOL 3.ANTICHOLINESTERASES-
NEOSTIGMINE,PYRIDOSTIGMINE, PHYSOSTIGMINE,EDROP
HONIUM, OP- COMPOUNDS
PARASYMPATHETIC ANTAGONISTS
ANTIMUSCURANICS
ANTINICOTINIC S
ATROPIE HYOSCINE GYCOPYRROLATE
GANGLION BLOCKERS NMBS
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SYMPATHOMIMETICS

• DIRECT( mimic effects of epinephrine at
  adrenergic receptors)
• Catechols,phenyleprine,methoxamine
• INDIRECT(causes release of endogenous
  norepinephrine from post ganglionic symp. nerve
  terminals )
• Amphetamines,TCAs
• BOTH
• Ephedrine,metraminol,dopamine
• INOCONSTRCITORS
• Norepinephrine,epinephrine,ephedrine
• INODILATORS
• Dobutamine,dopexamine, isoproterenol, PDE inhibs

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EPINEPHRINE

• 80-90 of adrenal medullary catecholamines is
  epinephrine
• Powerful agonist at a and ß receptors
• More powerful than norepinephrine at a and
  isoproterenol at ß receptors
• DOC- acute anaphylaxis
• 0.5 -1 mg IM or 11000 0.5 1 ml
• Cardiac arrest(a effects)
• 1 mg repeated 3 times
• Bronchospasm
• Shock ( sepsis) dose 0.01 0.2 µg/kg/min)
• Low dose ß2 effects prominent ,vosodilatation,
  decresed SVR, decreased Diastolic B.P , mean
  pressure remains same
• High dose- a effects prominent- vosoconstriction
  at skin,kidneys decreased renal blood flow but
  coronary blood flow preserved
• Topical vosoconstrictor
• Used with L.A drugs

Side effect Tachyarrythmias
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NOREPINEPHRINE

• Potent arteriolar and venoconstrictor
• Acts exclusively at a receptors
• Increased systolic,diastolic,pulmonary, central
  venous pressure
• Heart rate normal or decreased baroreflex
  activity
• Septic shock- 0.01 0.1 µg/kg/min
• High dose renal blood flow decreased,GFR

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Dopamine

• Natural precursor of epi and norepinephrine
• Dose dependenet actions
• Low dose(lt 3 µg/kg/min)
• DA1 agonist action,? renal splanchnic blood
  flow, ?GFR ?sodium excretion( diuretic action)
• Medium dose( 5-10 µg/kg/min)
• DA1 agonist ß1 agonist action, ?cardiac output
  ?renal blood flow so DOC in cardiogenic
  ,traumatic and septic shock
• Advantages limited by tachycardia.
• High dose( gt 15 µg/kg/min)
• a1 agonist actions predominate, direct
  vasosconstricion and ?cardiac output ( like
  norepinephrine), ?renal splanchnic blood flow
• Central dopamine receptors Basal ganglia ,CTZ
  mediate pituitary prolaction secretion and nausea
  vomiting
• ?CNS dopamine parkinsons disease
• Dopamine antagonists phenothiazines ,
  butryphenones- antipsychotics and antiemetics-
  extrapyramidal side effects.

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Isoprenaline ( isoproterenol)

• ß1 agonist ß2 agonist ,virtually no action on
  a receptors
• ?Heart rate ? peripheral resistance ?cardiac
  output
• Relaxation of bronchial smooth muscle mast cell
  stabilisation
• Dose 0.5 to 10 µg/min
• Most important current indication
• Bradyarrthymias or AV block with low C.O ( post
  MI)
• Stokes adams attacks

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Dobutamine

• Primarily a ß1 agonist .( mod ß2 a agonist)
• NO activity at DA1 receptors.
• ?cardiac output(ß1 ) . Heart rate also
  increases(ß2)
• Dose 2.5 25 µg/kg/min.
• Myocardial O2 consumption less
• Low cardiac output states
• dobutamine dopamine or norepinephrine

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dopexamine

• Agonist at ß2 DA1 receptors.
• Weak DA2 agonist uptake 1 inhibitor.
• Produces vasodilatation in skeletal muscles.
• Mild ?in cardiac output(ß2 )
• Renal , mesentric,cerebral corornary
  vasodilatation(ß2 DA1 )
• Natriuresis (DA1 )
• Dose 0.5 6.0 µg/kg/min.
• Some anti-inflammatory effects.

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• Fenoldapam
• DA1 agonist peripheral vasodilatation ?renal
  blood flow sodium ,water excretion.
• Hypertensive emergencies.
• No rebound hypertension ( unlike SNP)
• Ibopamine
• oral dopamine(DA1 DA2)
• Prodrug converted to epinine after oral intake
• Cardiac failure

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Ephedrine

• Direct action agonist at a , ß1 ß2
• Indirect action- endogenous N.E release
• Also MAO inhibitor action
• Effects are similar to epinephrine but action is
  10 times longer ( half life 3-6 hrs)
• Blood flow ?coronary skeletal muscle
  ?renal splanchnic
• Also bronchodilator
• Tachyphylaxis can occur .
• Used for post spinal hypotension , post GA
  hypotension
• Especially useful in OBS patients as UTERINE
  BLOOD FLOW is maintained.
• Dose IV. 3- 12 mg or 15-30 mg IM

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• Phenylephrine
• Potent synthetic direct acting a1 agonist
• Effects similar to N.E
• IV boluses 20-50 µg or 20 -50 µg/min infusion
• Nasal decongestant mydriatic
• Methoxamine
• Direct acting a1 agonist with weak ß antagonist
  action
• Vasoconstriciton bradycardia ( baroreflex ß
  blocker)
• Used in Post spinal GA hypotension. 2-5 mg iv
  bolus
• Acs within 2 mins and lasts for 20 mins
• Metaraminol
• Both direct indirect acting
• a effects predominate vasoconstriciton,reflex
  bradycardia
• 1-5 mg iv bolus aacts within 3 mins and lasts
  for 25 mins

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Phosphodiesterase inhibitors

• ? cAMP
• ?Ca2 so positive inotropy lusitropy (cardiac)
• ? Ca2 - smooth muscle- vasodilatation
• Amrinone , Milrinone,(bipyridines)
  enoximone(imidazole)
• PDE III inhibitors-potent arteriolar coronary
  vasodilators
• ?preload,afterload,PVR,PCWP ?cardiac index
• Myocardial O2 consumption not increased
• Does not cause tachyphylaxis
• Most useful in CCF where downregulatio of ß
  receptors occurs.
• Side effects hypotension, tachyarrhythmia's
  ,thrombocytopenia
• Half life ? in CCF or renal failure ,so only one
  loading dose over 5 mins is enough( 20 hrs)
• Enoximone- active sulfoxide metabolite
• Loading dose 0.5 mg/kg infusion 5 µg/kg/min

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• GLUCAGON
• ?adenylate cyclase and hence ?c AMP in cardiac
  cells by a mechanism independent of ß receptors.
• Nausea, vomiting,hyperglycemia hyperkalemia
• Used as inotrope in ß-blocker poisoning.
• CALCIUM
• Ca2 is involved in excitation contraction
  coupling of smooth muscle an contraction in
  cardiac muscle
• ?extra cellular Ca2 increases intracellular Ca2
  consequently the force of contraction of cardiac
  myocytes
• Cardio Pulmonary Bypass 5 mg/kg.
• Also indicated in hypocalcemia, hyperkalemia,
  calcium channel blocker toxicity.

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Levosimendan

• increases myocardial sensitivity to Ca - enhances
  affinity of Troponin C for Ca2
• suppresses vascular endothelin-1 release
• some PDE III inhibiton
• activates ATP sensitive K channels
• Inodilator
• reduces SVR and PCR
• increase SV and CO
• non-cAMP dependent

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Selective ß2 agonists

• They relax bronchial ,uterine vascular smooth
  muscle with less effects on heart.
• Salbutamol,Trebutaline,Ritodrine,salmeterol(
  partial agonists)
• Mostly used as bronchodilators
• High dose ß2 mediated tremor, tachyarrhythmia's
  ,hypokalemia,hypergylcemia,hypomagnesemia may
  occur

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• Salbutamol most commonly used bronchodilator.
• MDI , 1-2 puffs ,each 100µg.duration 3-5 hrs
• Nebulizer ,2.5mg given as 2.5ml of 0.1 sol.
• I.V dose 250µg slowly or infusion 5µg./min( 3-20
  µg./min)
• Salmeterol Highly lipophilic.longer acting BD
  dose
• Ritodrine Tocolytic, can cause tachycardia(ß1
  ), pulmonary oedema( renin?)
• Selective ß1 agonists xamoterol (partial
  agonist)
• At high doses act as ß blocker
• It has 45 of the intrinsic activity of
  isoproterenol
• Useful in moderate heart failure, severe heart
  failure act as ß blocker

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Sypmpatholytic drugs

• Clonidine
• Central action
• Partial a2 agonist - brainstem NTS RVLM -
  ? sympathetic tone
• Also partial agonist at central imidazoline
  receptors.( I1)
• Peripheral a2 agonist I1 agonist (kidneys)
• Baroreceptor reflexes are preserved ,so effects
  of ephedrine or phenylephrine may be exaggerated
• a2 a1 gt 2001
• .

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• Used to avoid intubation response.
• Decrease MAC of inhalational agents( by 50)
• Itrathecally used to provide analgesia-
  activating descending spinal supraspinal
  inhibitory pathways
• They modify local release of nociceptive
  neurotransmitters substance P CGRP.
• Also use for perioperative shivering opiate
  withdrawal(Lofexidine).
• Side effects- dry mouth ,sedation,rebound
  hypertension( locus coerulus)
• Dexmedetomidine Azepexole more selective a2
  agonists

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• Methydopa
• Crosses BBB converted to a methylnorepinephrine
  which is a full agonist(a2 a1 101)
• Used for PIH
• Perpipheral oedema,hepatotoxicity,hemolytic
  anemia
• Moxonidine
• selective I1 receptor agonist (I1gt a2)
• Minimal a2 related side effects
• No effects on lipid carbohydrate metabolism
• ? sodium excretion urine flow.
• Benefecial in congestive cardiac failure
• Potentiaetes bradycardia
• Contraindicated in second or third degree heart
  block

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• Ganglion blockers
• Hexamethonium Trimpetaphan
• They inhibit the effects of Ach at autonomic
  ganglia and block both sym. parasymp.
  Transmission
• Trimetaphan used in hypotensive technique.
• Adrenergic nurone blocker
• Gaunethedine
• It has L.A properties
• Used in IVRA ( beirs block) to treat CRPS

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a adrenergic antagonists

• Used maily as vosodilators in second line
  treatment of hypertension
• Urinary tract smooth muscle relaxants
• BPH
• Pheochromocytoma
• Common side effects- postural hypotension
  reflex tachycardia

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• a1 selective antagonists
• Prazocin,doxazocin,phenoxybenzamine Urapidil
• Labetalol carvedilol
• Tamsulosin- a1A antagonist - BPH
• Urapidil - a1 selective antagonist agonist at
  central 5 HT1A receptor in RVLM.
• Arterio venodilator with little effect on heart
  rate(central 5 HT1A stimulation attenuates reflex
  tachycardia)
• Pre-eclampsia, hypertensive crisis,perioperative
  hypertension
• a2 selective antagonists yohimbine
• Non selective a antagonists
• Phentolamine, tolazoline pheochromocytoma
• More postural hypotension reflex tachycardia

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ß blockers

• ß blockers are competetive antagonists at ß
  receptors.
• Most are stereo isomers with L-forms more active.
• Calssification
• I ) Relative affinity to ß1 or ß2 receptors
• First generatrion ( non selevtive)
• propranolol, timolol
• Second generation( selective ß1blockers wihtout
  ancillary effects )
• Atenolol,metoprolol.bisoprolol
• Third generation (ß1selective effects on other
  receptors)
• Labetolol,carvedilol, bucindilol

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• II) Partial agonist activity ( ISA)
• Dichloroisoprotrenol is the first ß blocker
  isolated and has similar structure to
  isoproterenol
• It has 50 agonist activity of isoproterenol.
• Stimulant effect is evident if the patient has
  low sympathetic activity but antagonist at high
  sympathetic activity
• May be advantageous in patients of
• Low resting heart rate
• PVD
• Hyperlipidemias
• Pindolol, acebutolol,oxeprenalol,sotalol,timolol.

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• III) Membrane stabilizing effect
• Along with ß blocking they also block Na
  channels ( local anesthetic action)
• So reduce the phase 4 of action potential
• Hence decrease conduction in cardiac tissue
• It occurs only with high doses above therapeutic
  range.
• Propranolol,acebutalol,labetalol
• IV) Ancillary effects
• Vasodilators Bucindolol ,Nebivolol
• Ant oxidants carvedilol
• Ca2 channel blockers carvedilol

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Pharmacokinetics

• Highly lipid soluble
• Proronolol,labetalol, exepranolol,metoprolol
• Well absorbed
• Significant first pass metabolism
• So reduced bioavailability,
• short terminal half life, highly protein bound
• But all the hydroxy metabolites are active ,so
  duration is long enough
• Transfer via BBB and placenta( sedation
  ,sleep,fetal bradycardia)
• Water soluble
• Atenolol,celiprolol,nadolol,sotalol
• Less well absorbed but are not subject to first
  pass metabolism
• Eliminated unchnged by kidney ,long terminal half
  lifes
• Slightly protein bound
• Do not cross BBB or Placenta

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Indications

• Hypertension
• First line therapy
• ? heart rate, C.O, myocardial contractility
• ? central sympathetic activity
• ? renin secretion( non selective
  propranolol,timolol)
• ? peripheral vascular resistance( unopposed a
  stimulation)
• IHD
• Secondary prevention of M.I
• Obstructive cardiomyopathy
• Congestive cardiac failure

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• Arrhythmias
• SVT
• ? H.R in A.F Flutter
• Sotolol( class II II )
• Migraine prophylaxis
• Essential tremor
• Anxiety states
• Glaucoma( timolol,betoxolol,cartelol)
• Thyrotoxicosis

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Adverse reactions

• Can precipitate heart failure
• Can cause AV block
• Excessive ß blockade treatment
• ß agonists isoproterenol, dobutamine
• Calcium chloride
• Glucagon ( ?cAMP by mechanism independent of ß
  receptors
• Bronchospasm
• Non selective more , ß1 selective less
• Raynauds phenomenon PVD
• Hypoglycemia unawareness ( Diabetes)
• Muscle fatigue
• Impotence
• Depression
• Occulomucocutaneous syndrome( proctolol)

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Newer ß blockers

• Labetolol
• a1ß1ß2 antagonist
• Partial agonist at ß2 receptors
• 4 to 7 times more potent at ß than a
• Oral IV forms available 5- 10 mg
• Perioperative hypertension,controlled
  hypertension ot pheochromocytoma
• Carveidolol
• ß a is 101
• Antoxidant activity and Ca2 channel blocker(
  high doses)
• Stereisomer ,extensive first passmetabolism,
  active metabolites

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• Bucindolol
• Produces vasodilatation by cGMP dependent
  mecahnism
• Nebivolol
• Lipophilic ,recemic mixture with NO mediated
  vasodilator properties
• Celiprolol - ß1 selective blocker with
  weak ß2 agonist effects
• COPD PVD
• Esmolol
• Rapid onset , short acting , ( rapidly
  metabolised by red cell esterases elimination
  half life- 9 mins
• Perioperative HTN , SVT , AF 0.5 2.0 mg/kg iv
  bolus or 25 - 500 µg/kg/min
  infusion.

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