DRUGS

ACTING ON

AUTONOMIC NERVOUS SYSTEM

Neurotransmitters
SOMATIC NERVOUS SYSTEM ACh Striated muscle

AUTONOMIC NERVOUS SYSTEM Sympathetic ACh ACh ACh Parasympathetic Ad. M. ACh E, NE

NE ACh

Heart Sm. mus. Glands Sweat glands

ACh

Heart Sm. mus. Glands

ADRENERGIC
MUSCURANIC

Gs

M 2 M4
Gi

M1 M3 M5
Gq

ADENYL CYCLASE

PLP A2

PLP C

ATP

cAMP
PROTEIN KINASE

K+

Ca 2+

PIP2

IP3 EFFECT

EFFECT

Autonomic receptors Organs- Actions

Cont.

Activation of Muscarinic receptors causes DUMBELS syndrome: Defecation, Urination, Miosis,Bronchoconstriction, Emesis, Lacrimation, Salivation

Norepinephrine fate adrenergic synapse

CATECHOLAMINE METABOLISM

CLASSIFICATION
DRUGS ACTING ON SYMPATHETIC NERVOUS SYSTEM

DRUGS ACTING ON PARASYMPATHETIC NERVOUS SYTEM

DRUGS ACTING ON SYMPATHETIC NERVOUS SYSTEM

SYMPATHOMIMETICS

SYMPATHOLYTICS

CATECHOLAMINES
ENDOGENOUS
EPI ,NOREPI , DOPAMINE

CENTRALLY ACTING
CLONIDINE METHYDOPA MOXONIDINE

SYNTHETIC
ISOPRENALINE,DOBUTAMINE,DOPEXAMINE

NON-CATECHOLAMINES

PERIPHERALLY ACTING
GANGLION BLOCKERS ADRENEGIC NEURON BLOCKERS ALPHA BLOCKERS BETA BLOCKERS

ADRENERGIC
EPHEDRINE,PHENYEPHRINE,METHOXAMINE,METARAMINOL

NON ADRENERGIC
PDES,DIGOXIN,GLUCAGON,CALCIUM,LEVOSIMENDAN

DRUGS ACTING ON PARASYMPATHETIC NERVOUS SYTEM

PARASYMPATHETIC AGONISTS

1.NATURAL ACETYLCHOLINE, MUSCURINE,PILOCARPINE,ARECHOLINE 2.SYNTHETIC- METHACHOLINE,CARBACHOL,BETHANECOL 3.ANTICHOLINESTERASES- NEOSTIGMINE,PYRIDOSTIGMINE, PHYSOSTIGMINE,EDROPHONIUM, OP- COMPOUNDS

PARASYMPATHETIC ANTAGONISTS

ANTIMUSCURANICS ATROPIE HYOSCINE GYCOPYRROLATE

ANTINICOTINIC S

GANGLION BLOCKERS NMBS

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

 80-90% of adrenal medullary catecholamines is epinephrine Powerful agonist at and receptors More powerful than norepinephrine at and isoproterenol at receptors DOC- acute anaphylaxis
0.5 -1 mg IM or 1:1000 0.5 1 ml

EPINEPHRINE

Cardiac arrest( effects)

1 mg repeated 3 times

Side effect Tachyarrythmias

Bronchospasm Shock ( sepsis) dose: 0.01 0.2 g/kg/min)

Low dose 2 effects prominent ,vosodilatation, decresed SVR, decreased Diastolic B.P , mean pressure remains same High dose- effects prominent- vosoconstriction at skin,kidneys decreased renal blood flow but coronary blood flow preserved

Topical vosoconstrictor
Used with L.A drugs

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

 Natural precursor of epi and norepinephrine Dose dependenet actions Low dose(< 3 g/kg/min)
DA1 agonist action, renal & splanchnic blood flow, GFR & sodium excretion( diuretic action)

Dopamine

Medium dose( 5-10 g/kg/min)

DA1 agonist & 1 agonist action, cardiac output & renal blood flow so DOC in cardiogenic ,traumatic and septic shock Advantages limited by tachycardia.

High dose( > 15 g/kg/min)

1 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 , butryphenonesantipsychotics and antiemetics- extrapyramidal side effects.

Isoprenaline ( isoproterenol)
1 agonist & 2 agonist ,virtually no action on receptors Heart rate peripheral resistance & cardiac output Relaxation of bronchial smooth muscle & mast cell stabilisation Dose 0.5 to 10 g/min Most important current indication
Bradyarrthymias or AV block with low C.O ( post MI) Stokes adams attacks

Dobutamine
Primarily a 1 agonist .( mod 2 & agonist) NO activity at DA1 receptors. cardiac output(1 ) . Heart rate also increases(2) Dose : 2.5 25 g/kg/min. Myocardial O2 consumption less Low cardiac output states :
dobutamine + dopamine or norepinephrine

dopexamine
Agonist at 2 & DA1 receptors. Weak DA2 agonist & uptake 1 inhibitor. Produces vasodilatation in skeletal muscles. Mild in cardiac output(2 ) Renal , mesentric,cerebral & corornary vasodilatation(2 & DA1 ) Natriuresis (DA1 ) Dose : 0.5 6.0 g/kg/min. Some anti-inflammatory effects.

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

Ephedrine

Direct action agonist at , 1 2 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

Phenylephrine Potent synthetic direct acting 1 agonist Effects similar to N.E IV boluses 20-50 g or 20 -50 g/min infusion Nasal decongestant & mydriatic Methoxamine Direct acting 1 agonist with weak antagonist action Vasoconstriciton & bradycardia ( baroreflex & 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 effects predominate vasoconstriciton,reflex bradycardia 1-5 mg iv bolus aacts within 3 mins and lasts for 25 mins

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 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 g/kg/min

 GLUCAGON adenylate cyclase and hence c AMP in cardiac cells by a mechanism independent of receptors. Nausea, vomiting,hyperglycemia & hyperkalemia Used as inotrope in -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.

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

Selective 2 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 2 mediated tremor, tachyarrhythmia's ,hypokalemia,hypergylcemia,hypomagnesemia may occur

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

Sypmpatholytic drugs
Clonidine: Central action: Partial 2 agonist - brainstem NTS & RVLM sympathetic tone Also partial agonist at central imidazoline receptors.( I1) Peripheral 2 agonist & I1 agonist (kidneys) Baroreceptor reflexes are preserved ,so effects of ephedrine or phenylephrine may be exaggerated 2 :1 > 200:1 .

 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 2 agonists

 Methydopa Crosses BBB converted to methylnorepinephrine which is a full agonist(2 :1 10:1) Used for PIH Perpipheral oedema,hepatotoxicity,hemolytic anemia Moxonidine selective I1 receptor agonist (I1> 2) Minimal 2 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

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

 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

1 selective antagonists Prazocin,doxazocin,phenoxybenzamine & Urapidil Labetalol & carvedilol Tamsulosin- 1A antagonist - BPH Urapidil - 1 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 2 selective antagonists yohimbine Non selective antagonists Phentolamine, tolazoline pheochromocytoma More postural hypotension & reflex tachycardia

blockers are competetive antagonists at receptors. Most are stereo isomers with L-forms more active. Calssification I ) Relative affinity to 1 or 2 receptors First generatrion ( non selevtive)
propranolol, timolol

blockers

Second generation( selective 1blockers wihtout ancillary effects )

Atenolol,metoprolol.bisoprolol

Third generation (1selective & effects on other receptors)

Labetolol,carvedilol, bucindilol

 II) Partial agonist activity ( ISA) :

Dichloroisoprotrenol is the first 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.

 III) Membrane stabilizing effect :

Along with 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

 Highly lipid soluble

Pharmacokinetics
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

Indications
Hypertension :
First line therapy heart rate, C.O, myocardial contractility central sympathetic activity renin secretion( non selective propranolol,timolol) peripheral vascular resistance( unopposed stimulation)

IHD Secondary prevention of M.I Obstructive cardiomyopathy Congestive cardiac failure

 Arrhythmias:
SVT H.R in A.F & Flutter Sotolol( class II & II )

Migraine prophylaxis Essential tremor Anxiety states Glaucoma( timolol,betoxolol,cartelol) Thyrotoxicosis

Adverse reactions
Can precipitate heart failure Can cause AV block Excessive blockade treatment
agonists isoproterenol, dobutamine Calcium chloride Glucagon ( cAMP by mechanism independent of receptors

Bronchospasm :
Non selective more , 1 selective less Raynauds phenomenon & PVD

Hypoglycemia unawareness ( Diabetes) Muscle fatigue Impotence Depression Occulomucocutaneous syndrome( proctolol)

Newer blockers
Labetolol
112 antagonist Partial agonist at 2 receptors 4 to 7 times more potent at than Oral & IV forms available 5- 10 mg Perioperative hypertension,controlled hypertension ot pheochromocytoma

Carveidolol
: is 10:1 Antoxidant activity and Ca2+ channel blocker( high doses) Stereisomer ,extensive first passmetabolism, active metabolites

 Bucindolol :
Produces vasodilatation by cGMP dependent mecahnism

Nebivolol
Lipophilic ,recemic mixture with NO mediated vasodilator properties

Celiprolol - 1 selective blocker with weak 2 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 g/kg/min infusion.