ANS PHARMACOLOG

YIntroduction

Cholinergic system and drugs

Cholinoceptors

Drugs Cholinergic drugs

Anticholinergic drugs

Anticholinesterases

Adrenergic system and drugs

Adrenoceptors

Drugs Adrenergic drugs

Antiadrenergic drugs

INTRODUCTIONINTRODUCTION :

• Much of the action of the body in maintaining cardiovascular, gastrointestinal and thermal homeostasis occurs through ANS. The ANS is also our primary defense against challenges to that homoeostasis.

• It provides involuntary control and organization of maintenance and stress responses.

• Activation of sympathetic nervous system elicits fight or flight response.

• Parasympathetic system governs activities of the body more closely associated with maintenance of function.

• The intelligent administration of anesthetic care to patients require knowledge of ANS pharmacology to achieve desirable interactions of anesthetics with the involuntary control system and to avoid responses or interactions with deleterious effects.

CHOLINERGIC SYSTEM AND DRUGSCHOLINERGIC SYSTEM AND DRUGS :

Ach is major neurohumoral transmitter at autonomic

as well as somatic sites.

SYNTHESIS:-

ATP + Acetate + COEn - A

↓ Acetate activating reaction

Acetyl COEn - A

CHOLINE Choline acetylase

ACETYL CHOLINE + COEn A

DESTRUCTION:-

ACETYL CHOLINE

Cholinesterase

Acetate Choline

CHOLINOCEPTORSCHOLINOCEPTORS :

Muscarinic (G protein coupled receptor)

Nicotinic (Ligand gated cation channel)

M1 M2 M3

Location & function

Autonomic Ganglia :Autonomic Ganglia :

Depolarisation Depolarisation

Gastricgland: Hist relase Gastricgland: Hist relase acid secretionacid secretion

CNS: Not knownCNS: Not known

SA node - hyperpolarization

Av node:- ↓ conduction

Alrium & ventricle:- ↓ contraction

Nerveending: ↓ Ach release

Smooth muscle: ContractionGland: SecretionVascularendo: Vasodilatation

NM NN

Location & function

NeuromuscularJunction: Contraction

Autonomic Ganglia: DepolarisationAdrenal medulla: Catecholamine releaseCNS: Excitation or inhibition

CHOLINERGIC DRUGSCHOLINERGIC DRUGS :

(Cholinomimetic, parasympathomimetic)

These are drugs which produce actions similar to that

of Ach, either by directly interacting with cholinergic receptors

or by increasing availability of Ach at these sites.

Cholinergic Agonists

Choline Esters Alkaloids

Acetyl choline Muscarine

Metha choline Pilocarpine

Carbachol Arecoline

Bethanechol

ACTIONS (OF Ach as prototype)ACTIONS (OF Ach as prototype) :

A. MuscarinicHeart:- Bradycardia, even cardiac arrest.

Blood vessels:- Dilated → fall in BP & flushing.

Smooth muscles:- Contracted & sphincters relaxed.

Glands:- Increased secretion.

Eye:- Miosis, spasm of accomodation.

B. NicotinicAutonomic ganglia:- High doses cause tachycardia & rise in BP

Skeletal Muscles:- Contraction

C. CNS:- Produce complex pattern of stimulation followed by depression.

• Ach has no theropeutic application because of its diffuse sites of action and its rapid hydrolysis.

• Diseases exacerbated:- Asthma coronary artery disease and peptic ulcer disease.

UsesUses:

Choline esters are rarely if ever used.

Ach - Not used

Methacholine - rarely used to terminate parosysmal supraventricular tachycardia.

Bethanecol - Used in post operative / post partum nonobstructive urinary relention, neurogenic

bladder atony, congenital Megacolon.

• Dose:- 5mg SC repeated after 15 to 30 min if necessary

Carbachol - Used as topical drug in chronic therapy of

narrow angle glaucoma.

Pilocarpine

• Used only in the eye as 0.5 - 4% drops in open angle glaucoma.

• Other uses - to counteract Mydriatics to prevent or break adhesion of iris with lens.

Muscarine & Arccoline:- has no therapeutic use.

TOXICOLOGYTOXICOLOGY :

Mushroom poisoning

• Muscarine type:- due to inocybe. Symptoms characteristic of muscarinic action; Rx Atropine.

• Anticholinergic / hallucinogenic type:- due to Isoxazole have anticholinergic & hullucinogenic properties.

Atropine is contraindicated.

• Phallodin type:- due to peptide toxin. Inhibit RNA & protein synthesis.

ANTICHOLINERGIC DRUGSANTICHOLINERGIC DRUGS :

(Muscarinic receptor Antagonists, Atropinic,Parasympatholytic)

• Anticholinergic drugs are those which block actions of Ach on autonomic effectors and in CNS exerted through muscarinic receptors.

• All Anticholinergics are competitive antagonists.

CLASSIFICATIONCLASSIFICATION :

• Natural Alkaloids: Atropine, Hyoscine (Scopolamine)

• Semi synthetic derivatives: Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide.

• Synthetic compounds:

1. Mydriatics: Cyclopentolate, Tropicamide.

2. Antisecretory & antispasmodics.

Quaternary comp: Glycopyrrolate, propanthaline, Isopropamide,

Tertiary amine: Dicyclomine, pirenzepine, Oxybutynin.

3. Antiparkinsonian: Trihexyphenidyl (Benzhexol), Benztropine, Procyclidine.

MECHANISM OF ACTIONMECHANISM OF ACTION :

• Anticholinergic drugs combine reversibly with muscarinic cholinergic receptors and thus prevent access of neurotransmitter, Ach to these sites.

• Anticholinergic drugs do not prevent the liberation of Ach nor do they react with Ach.

• The effect of anticholinergic drugs can be overcome by increasing the concentration of Ach in the area of muscarinic receptors.

PHARMACOLOGICAL ACTIONS (Atropine as prototype)PHARMACOLOGICAL ACTIONS (Atropine as prototype) :

Atropine blocks all subtypes of muscarinic receptors.

1. CNS:- Atropine has over all CNS stimulant action.

• Cortical excitation, restlessness, disorientation, hallucination, delirium followed by respiratory depression & coma.

• It suppresses tremor & rigidity of parkinsonism, depresses vestibular excitation & has antimotion sickness property.

2. CVS:- Tachycardia

• PR interval is shortened.

• Small doses of Atropine, Scopolamine & glycopyrrolate produces Heart rate slowing

3. Eye:-

• Mydriasis

• Cycloplegia

• Abolition of light reflex.

4. Smooth muscle:- Relaxed

Constipation, urinary retention, bronchodilatation.

5. Glands:-

• Secretions are reduced.

• Skin & eye become dry, talking & swallowing may be difficult.

• Decreases acid & pepsin secretion.

6. Body temperature:-

• Rise in body temperature due to inhibition of sweating as well as stimulation of temperature regulating centre in hypothalamus.

• Children highly susceptible.

7. Local anaesthetic:-

Atropine has mild anaesthetic action on cornea.

PHARMACOKINETICSPHARMACOKINETICS :

Atropine GlycopyrrolateGlycopyrrolate

Onset of action (min) 1 2 - 3

Duration of action (min) 30 to 60 30 to 60

Elimination t½ (hr) 2.3 1.25

Excretion unchanged in urine 18 80

Lipid solubility + -

COMPARATIVE EFFECTSCOMPARATIVE EFFECTS :

Atropine Scopolamine GLYCO

SedationSedation + + + + 0

AntisialagogueAntisialagogue + + + + + +

Increase HRIncrease HR + + + + + +

Relax smooth muscleRelax smooth muscle + + + + +

Mydriasis, cycloplegiaMydriasis, cycloplegia + + + + 0

Prevent motion Prevent motion induced nauseainduced nausea

+ + + + 0

CLINICAL USESCLINICAL USES :

1. Preoperative Medication:

• Therapeutic goals are to produce sedation, prevent excessive salivary & tracheo bronchial secretions, prevent laryngospasm & protect heart from vagal reflexes.

2. Antisialagogue effect:

• Doses:- Atropine 10 to 20µg/kg im

Glycopyrrolate 5 to 8µg/kg im

Scopolamine 5µg/kg im

3. Treatment of reflex mediated Bradycardia.

Atropine 15 to 70µg/kg iv

4. Combination with anticholinesterase drugs:

• To prevent parasympathomimctics effects.

• Doses:- Atropine 20 µg/kg

Glyco 10 µg/kg

5. Bronchodilators:

• Anticholinergics cause relaxation of bronchial smooth muscles particularly in patients with bronchial asthma or chronic bronchitis.

• More effective when used as aerosol.

• Atropine 1 to 2 mg diluted in 3 to 5 ml of NS. Can be administered via nebulizer.

• Ipratropium:- 40 to 80 µg delivered by Metered dose inhater or

0.25 to 0.5 mg by nebulisation

6. Antispasmodic:

• Dicydomine 20mg oral.

7. Mydriasis & Cycloplegia:

8. Antagonism of Gastric hydrogen ion secretion pirengepine is selective M1 blocker 100 to 150 mg/day oral.

9. Prevention of Motion induced Nausea. Transdermal patch of scopolamine delivers drug at 5µg/hr for 72 hr blocks transmission to medulla of impulses arising from overstimulation of vestibular apparaths.

10. Constituents of Non prescription cold remedies.

CENTRAL ANTICHOLINERGIC SYNDROMECENTRAL ANTICHOLINERGIC SYNDROME :

• Scopolamine & Atropine can enter CNS & produce symptoms.

• Restlessness, hallucnation, somnolence & unconsiousness.

• Due to blockade of muscarinic cholinergic receptor & competitive inhibition of Ach in CNS.

• Physostigmine is specific treatment 15 to 60µg/kg iv.

DRUGS ACTING ON AUTONOMIC GANGLIADRUGS ACTING ON AUTONOMIC GANGLIA :

Ganglionic StimulantsGanglionic Stimulants

• Selective nicotinic agonists

Nicotine (small dose), Lobeline, DMPP, PTMA

• Non-Selective / Muscarinic agonists

• Acetylcholine

• Carbachol

• Pilocarpine

• Anti Cholinesterases.

NICOTINENICOTINE : (From Nicotiana tobacum)

• There is no clinical application of ganglionic stimulant.

• Nicotine transdermal has become available for treatment of nicotine dependance & as an aid to smoking cessation.

• 10, 20 & 30 cm2 patches are available.

GANGLION BLOCKING AGENTSGANGLION BLOCKING AGENTS :

A. Competitive blockers.

Quaternary comp:- Hexamethonium, pentolium

Amines :- Mecamylamine, pempidine

Monosulfonium comp:- Trimethaphan

B. Persistent depolarising blockers

Nicotine (large doses), Anticholinesterases (large dose)

TRIMETHAPHANTRIMETHAPHAN :

• Peripheral vasodilator & ganglionic blocker.

• Lowers systemic blood pressure

• Increases HR

• Hydrolysis by plasma cholinesterase

• CNS effects are unlikely

• Use continous infusion 10 to 200µg/kg/min to produce controlled hypotension.

• S/E

• Mydriasis

• Ileus

• Urinary retention

• Duration of action of drugs like Sch, Mivacurium may be prolonged.

ANTICHOLINESTERASESANTICHOLINESTERASES :• Some of the drugs of this class are often administered by anaesthesiologists

to facilitate the speed of recovery from the skeletal muscle effects produced by non-depolarizing neuromuscular blocking drugs.

• Anticholinesterases are agents which inhibit cholinesterase, protect Ach from hydrolysis.

CLASSIFICATIONCLASSIFICATION :

ReversibleReversible

Carbamates Acridine

• Phyrostigmine - Tacrine

• Neostigmine

• Pyridostigmine

• Endrophonium

IrreversibleIrreversible

Organophorphates Carbamates

• Echothiophate, Malathion - Carbaryl (Sevin)

• Parathion, Diazinon (Tik -20) - Propoxur (Buygon)

MECHANISM OF ACTIONMECHANISM OF ACTION :

a) Enzyme inhibition:-

Inhibit enzyme Acetyl cholinesterase (true).

Inhibition of hydrolysis of acetylcholine results in greater

availability of Ach at its sites of action.

b) Presynaptic effects:- (acetylcholine release)

c) Direct effects at Neuromuscular junction:-

Some form of Neuromuscular blockade at higher

doses (Desensitization).

Acetylcholinesterase consist of Anionic and an

esteratic site.

Anionic site Esteratic site

PHARMACOKINETICSPHARMACOKINETICS

EndrophoniumEndrophonium NeostigmineNeostigmine PyridostigminePyridostigmine

Onset of action Onset of action (min)(min)

1 - 21 - 2 7 - 117 - 11 1616

Duration (min)Duration (min) 6060 5454 7676

Principal site of Principal site of actionaction

Pre synapticPre synaptic Post synaptic Post synaptic Post synapticPost synaptic

Hepatic Hepatic MetabolismMetabolism

30 %30 % 50 %50 % 25 %25 %

Renal clearance Renal clearance contributioncontribution

70 %70 % 50 %50 % 75 %75 %

Lipid solubilityLipid solubility PoorPoor PoorPoor PoorPoor

Principal, Principal, metabolitemetabolite

Conjugation to Conjugation to endrophonum endrophonum glucotonideglucotonide

3 - OH Phenyl 3 - OH Phenyl trimethylammonitrimethylammoni

umum

3 - OH N - methyl 3 - OH N - methyl pyridiniumpyridinium

Vol. of distribution - 0.7 to 1.4 lit/kg.

COMPARATIVE FEATURESCOMPARATIVE FEATURES :

PhysostigminePhysostigmine NeostigmineNeostigmine

SourceSource Natural alkaloidNatural alkaloid SyntheticSynthetic

ChemistryChemistry Tertiary amine compoundTertiary amine compound Quaternary ammonium Quaternary ammonium compoundcompound

Oral absorptionOral absorption GoodGood PoorPoor

CNS action CNS action PresentPresent AbsentAbsent

Applied to eye Applied to eye Penetrates corneaPenetrates cornea Poor penetrationPoor penetration

Direct action on Direct action on cholinoceptorscholinoceptors

AbsentAbsent PresentPresent

Prominent effect Prominent effect Autonomic effectors Autonomic effectors Skeletal MusclesSkeletal Muscles

UseUse Miotic (glaucoma)Miotic (glaucoma) Myasthenia GravisMyasthenia Gravis

DoseDose 0.5 - 1mg oral / parentral 0.5 - 1mg oral / parentral 0.5 to 2.5 mg im/sc0.5 to 2.5 mg im/sc

0.1 - 1% eye drop0.1 - 1% eye drop 15 to 30 mg oral15 to 30 mg oral

Duration of actionDuration of action Systemic 4.6 hrs Systemic 4.6 hrs

in eye 6 to 24 hrin eye 6 to 24 hr3 - 4 hrs3 - 4 hrs

PHARMACOLOGIC EFFECTSPHARMACOLOGIC EFFECTS :

Lipid soluble agents - more marked muscarinic & CNS effects

Lipid insoluble agents - more marked effects on skeletal muscle

no central effects.

CVS:- Bradycardia & bradydysrhythnias, asystole.

Decrease in systemic blood pressure.

GI & GU Tract:- Increase gastric fluid secretion

Increase motility of entire git.

Salivary gland:- Augment production of secretion.

Bronchoconstriction.

Eye:- Miosis, Inability to focus for near vision, IOP declines.

Myasthenia Gravis:- Cholinergic crisis

Prolonged NM blockade.

Myotonia:- Twitching & fasciculations.

CLINICAL USESCLINICAL USES :

a) Antagonist - assisted reversal of neuromuscular blockade produced by non - depolarizing Nm blocking drugs.

Physostigmine is not used as the dose required to

achieve effect is excessive.

Endrophonium - 0.5 mg/kg iv

Neostigmine - 0.043 mg/kg iv (Max 70 µg/kg iv)

Pyridostigmine - 0.21 mg/kg iv.

They are to be administered along with anticholinergic drug.

b) Treatment of central Nervous System effects of certain Drugs.

Physostigmine (tertiay amine) crosses BBB

• Dose:- 15 to 60 µg/kg iv

Physostigmine is effective in antagonizing.

Restlessness & confusion due to atropine or scopolamine.

c) Treatment of Myasthenia Gravis.

d) Treatment of Glaucoma.

e) Diagnosis & Management of cardiac Dysrhythmias.

Edrophoniuna 5 to 10mg iv (25 to 30mg over 30 min) esp PSVT

including those due to WPW Syndrome.

f) Postoperative Analgesia:-

Intrathecal injection of Neostigmine 10 to 30 µg produces post op analgesia without ventilatory depression.

g) Post op shivering

Physostigmine 40 µg/kg iv at the conclusion of

anaesthesia decreases post op shivering.

OVERDOSE OF ANTICHOLINESTERASE DRUGSOVERDOSE OF ANTICHOLINESTERASE DRUGS :

• Acute overdose (intoxication) manifests as Muscarinic,

Nicotinic Symptoms on peripheral & CNS sites.

• Diagnosis is made by history of exposure & characteristic

signs & symptoms.

Treatment:-

• Termination of further exposure

• Supportive Measures

• Specific Antidotes.

Atropine 35 to 70µg/kg iv administered every 3 to 10 min until muscarinic

symptoms disappear.

Pralidoxime 15mg/kg iv over 2 minutes repeated after 20 min if skeletal muscle

weakness is not reversed.

It is an cholinesterase reactivator. It attaches to anionic site. It is contraindicated

in carbamale poisoning.

It is ineffective unless administered within minutes of exposure.

ADRENERGIC SYSTEM AND DRUGSADRENERGIC SYSTEM AND DRUGS :

Nor epinephrine is the neurotransmitter responsible

for most of the adrenergic activity of sympathetic Nervous

System.

Nor adrenaline, adrenaline & Dopamine are closely

related catecholamines.

Synthesis:- Phenylalanine Tyrosine DOPA hydroxylase hydrolcylase decarboxylase

Phenylalanine Tyrosine DOPA Dopaminea(Storage vesicle) Dopamine

β - hydroxylase

Epinephrine Nor - epinephrine (Adrenal Medulla)

Release:- Nerve impulse coupled

Uptake:- Uptake - 1 (amine mechanism)

Uptake - 2 (non - neuronal tissue)

Metabolism:- Nor-epinephrine Epinephrine

Nerve endings MAO

3, 4 dihydroxymandelic acid

↓ COMT

VMA

Normetanephrin MAO Metanephrin

↑ COMT ↑ COMT

Nor-epinephrine Epinephrine

In liver

RECEPTORSRECEPTORS :

α1 α2

Location Post junctional on Post junctional on effector organeffector organ

Prejunctional on nerve ending, Prejunctional on nerve ending, also post junctional in brain, also post junctional in brain, pancreatic pancreatic ββ cell, platelets cell, platelets

Functions Smooth muscle - Smooth muscle - contraction contraction vasoconstriction vasoconstriction Gland - secretionGland - secretion

Gut - relaxation Gut - relaxation

Heart - arrhythmiaHeart - arrhythmia

Inhibition of transmitter release Inhibition of transmitter release

vasoconstriction vasoconstriction

↓↓ central sympathetic flowcentral sympathetic flow

↓↓ insulin release insulin release

platelet aggregation.platelet aggregation.

β1 β2 β3

Location Heart, JG cells in kidney

Bronchi, blood vessels, uterus, git, urinary tract, eye

Adipose tissue

Functions ↑↑ in HR, ↑↑ contractility

↑ renin secretion

Bronchodilatation Vasodilatation

ADRENERGIC DRUGSADRENERGIC DRUGS :

(SYMPATHOMIMETICS)

Intro:-

Sympathomimetics include naturally occurring

(endogenous catecholamines), synthetic catecholamines &

synthetic Non - catecholamines. These drugs produce

physiologic responses similar to those produced by

endogenous activity of sympathetic nervous system.

MECHANISM OF ACTIONMECHANISM OF ACTION :

Sympathomimetics exert their pharmacological effects

by activating either directly or indirectly α, β or dopamine receptors.

Binding of endogenous or exogenous sympathomimetic to cell surface.

↓

Induce conformational change

↓

Activation of G protein

↓

Activation or inhibition of effector enzyme or opening or closing of ionchannel

↓

Activation of second messenger.

INDIRECT ACTING :

• These are synthetic non-catecholamines that activate adrenergic receptors by evoking the release of endogenous transmitter from post ganglionic sympathetic nerve endings.

• Denervation or depletion of neurotransmitter blunts the pharmacological response.

eg:- Ephedrine, Mephentermine.

DIRECT ACTING :

• These drugs activate adrenergic receptor directly. Denervation or depletion of transmitter do not prevent the activity of these drugs.

eg:- Phenylephrine, Methoxamine.

METABOLISMMETABOLISM :

• All drugs containing 3, 4, - dihydroxybenze structure are rapidly inactivated by enzymes MAO or COMT resulting methabolites ae conjugated with glucoronic acid & excreted in urine.

• Synthetic non-catecholamines lacking 3-hydroxyl group are not affected by COMT & thus depend on MAO for their metabolism.

ENDOGENOUS CATECHOLAMINESENDOGENOUS CATECHOLAMINES:

EPINEPHRINE (ADRENALINE):-EPINEPHRINE (ADRENALINE):-

Prototype drugs

Most potent activator of α & β receptors.

Effects:-

CVS:- Small doses (1 to 2 µg/min iv) stimulate β2

4 µg/min iv → β1

10 to 20 µg/min iv → both α & β

Stimulates β1 receptor → increase in systolic BP

↑ in Heart rate

↑ in Cardiac output.

β2 receptor → ↓ in diastolic BP.

Net effect is increase in pulse pressure & minimal change in MAP

α1 receptor → vasoconstriction in skin, mucosa & hepatorenal vasculatur.

RS:- Bronchodilatation (β2)

Metabolic:- β1 stimulation → ↑ liver glycogenolysis

adipose tissue lipolysis

α1 stimulation → inhibits release of insulin.

Overall effect is increase in plasma concentration of cholestrol,

phospholipids & LDL proteins.

• Hyperglycemia

• Increased plasma concentration of lactate.

Electrolytes:- Hypokalemia (β2)

Ocular:- Mydriasis (α1)

Git & GU:- Relaxation of gastrointestinal smooth muscle. Sphincters usually contract.

Relaxes detruror muscle (β) & contracts trigone & sphincter

muscle (α) → hesitancy

Coagulation:- Hypercoagulable state

ABSORPTION, FATE & EXCRECTION:

• Epinephrine is not effective after oral administration.

• Can be administered SC, IM, IV, inhalation or topical.

• Epinephrine is unstable in alkaline solution it turns pink on exposure to air or light.

• Available in 1:100; 1:1000; 1:10000; 1:100,000.

• Usual adult dose - SC 0.3 to 0.5 mg.

Adverse effect:-

Restlessness, throbbing headache, tremor, palpitation

cerebral hemorrhage, ventricular arrythmias.

CI - in patient on non-selective β blockers.

Uses:- Anaphylaxis

To prolong action of local anaesthetics

Topical hemostatic agent

Cardiac arrest

NOR - EPINEPHRINENOR - EPINEPHRINE:

• It is potent α & β1 agonist and has little agonist effect at β2 receptors.

• IV administration results in intense vasocontriction in vasculature of skeletal muscles, liver, kidney and skin.

• Systolic, diastolic and mean arterial pressure increases.

• Cardiac output is unchanged or decreases.

• Metabolic effects are similar to those produced by epinephrine.

• Ineffective when given orally, absorbed poorly from subcutaneous injection.

• Extravasation during infusion can produce severe local vasoconstriction & necrosis.

• Dose:- 0.4µg/kg/min.

• Used in treatment of low blood pressure in tilrated doses.

DOPAMINEDOPAMINE:

• Dopamine is an important neurotransmitter in CNS & peripheral nervous system.

• Rapid metabolism of dopamine mandates its use as a continuous infusion.

• It should be dissolved in 5% dextrose.

• Not effective orally & does not cross blood brain barrier.

• Dopamine stimulates different receptors depending on dose.

- 0.5 to 3µg/kg/min iv → D1 receptor causes vasodilation of renal, mesentric, coronary & cerebral vessels. → ↑in GFR, renal blood flow & Na+ excretion.

- 3 to 10µg/kg/min iv → β1 receptor causes positive inotropic effect, ↑ cardiac output, also causes release of nor epinephrine.

-10µg/kg/min iv → α1 receptor more general vasoconstriction.

• Extravasation of dopamine causes local vasoconstriction, sloughing & necrosis.

• Before dopamine is administered to patient in shock, hypovolemia should be corrected.

• Adverse effects are Nausea, vomiting, tachycardia, anginal pain, arrythmias, hypertension, peripheral vasoconstriction.

• Uses:- In treatment of severe congestive cardiac failure, cardiogenic shock, septic shock.

RELATED DRUGS INCLUDE RELATED DRUGS INCLUDE :

DOPEXAMINE:- (DOPACARD)DOPEXAMINE:- (DOPACARD)

• It is a synthetic catecholamine that activates Dopaminergic & β2 receptor.

• No α - adrenergic effects & negligible β1 effects.

• It produces systemic vasodilation and indirect inotropic activity and is used in CHF.

FENOLDOPAMFENOLDOPAM:-

• It is selective DA1 agonist and potent vasodilator.

NON CATECHOLAMINE SYMPATHOMIMETIC AMINES NON CATECHOLAMINE SYMPATHOMIMETIC AMINES :

EphedrineEphedrine:-

• It is both α and β agonist.

• The pharmacological effects are due to endogenous release of nor-epinephrine and also due to direct stimulant effect on adrenergic receptors.

• It is effective after oral administration.

• It increases blood pressure, promotes bronchodilation & is a CNS stimulant.

• Doses:- 2.5 to 25 mg iv

25 to 50 mg im

• Uses:- Used to increase systemic blood pressrue in presence of sympathetic blockade produced by regional anaesthesia.

• Can be used as chronic oral medication to treat bronchial asthma.

• Decongestant effect produces symptomatic relief from acute coryza.

• S/E:- Hypertension, Insomnia, Tachyphlaxis.

MEPHENTERMINE MEPHENTERMINE :

• It stimulates both α and β receptors.

• It acts both directly and indirectly.

• After im injection, onset of action is within 5 to 15 min.

• It increases CO, systolic and diastolic pressure.

• Use:- It is used to prevent hypotension which frequently accompanies spinal anaesthesia.

• S/E:- CNS stimucation, hypertension, arrhythmias.

ββ - ADRENERGIC AGONISTS - ADRENERGIC AGONISTS :

NON - SELECTIVE β - AGONISTS:-

Isoproterenol (Isoprenaline):-Isoproterenol (Isoprenaline):-

• It is potent activator at β1 & β2 receptor.

• Devoid of α agonist effect.

• Effects:- increases heart rate, myocardial contractility.

• Lowers peripheral vascular resistance

∀ ↑ cardiac output

∀ ↓ diastolic pressure.

• It relaxes all varieties of smooth muscle.

• Dose:-Infusion of 0.5 to 5 µg/min for adults.

• Uses:- iv or aerosol to produce bronchodilation.

Continous infusion to increase heart rate in presence of heart block.

Continous infusion to decrease pulmonary vascular resistance in patient with PHT.

• S/E:- Palpitation, tachycardia, headache, flushed skin, arrhythmias.

DOBUTAMINE DOBUTAMINE :

• Dobutamine resembles dopamine structurally.

• The pharmacological effects are due to direct interaction with α & β receptors predominantly with β1 receptors.

• It is administered as continous infusion at 2 to 10 µg/kg/min.

• It should be dissolved in D5.

• It is particularly useful in patients with CHF & MI complicated by low output state.

• It produces dose dependent increase in cardiac output & decreases in atrial filling pressures without associated significant increase in BP & HR.

• Coronary artery vasodilator.

• S/E:- Ventricular ectopics, Tolerance

ββ 22 SELECTIVE AGONISTS SELECTIVE AGONISTS :

They specifically relax bronchiole and uterine smooth

muscle.

• Resistant to methylation by COMT thus contributing to sustained duration of action.

• Route of administration - oral, inhalation, SC or iv.

• S/E:- Tremor, Tachycardia, hyperglycemia, hypokalemia, hypomagnesemia

• Use:- Preferred treatment for acute episodes of asthma and prevention of exercise induced asthma.

Ritodrine:-

β2 agonist most often used to stop uterine contractions of premature labour.

β2 Selectivity

Peak Duration

Conc/Puff

Method of administration

Intermediate (3 - 6hr)

Albuterol (Salbutamol)

+ + + ++ + + + 30 - 6030 - 60 44 9090 MDI, oralMDI, oral

Metaproterenol (orciprenaline)

+ + ++ + + 30 - 6030 - 60 3 - 43 - 4 200200 Oral, SCOral, SC

Terbutaline + + + ++ + + + 6060 44 200200 MDI, oral, SCMDI, oral, SC

Isoetharine + ++ + 15 - 6015 - 60 2 - 32 - 3 340340 MDIMDI

Bitolterol + + + ++ + + + 30 - 6030 - 60 55 370370 MDIMDI

Long acting (>12 hr)

Salmeterol + + + ++ + + + > 12> 12 2121 MDIMDI

αα 11 SELECTIVE AGONISTS SELECTIVE AGONISTS :

PhenylephrinePhenylephrine:-

• Synthetic non-catecholamine principally stimulating α1 receptor.

• It activates β receptor at higher concentration.

• Increases systemic blood pressure.

• Dose:- 50 to 200µg iv.

• It is a nasal decongestant.

• Produces mydriasis without cycloplegia.

• It is effective in prolonging spinal anaesthesia when added to Local anaesthetic solution.

• It mimics the effects of norepinephrine but is less potent & longer lasting.

Methoxamine:-

• It is a synthetic Non catecholamine acts directly & selectively on α receptor.

• It increases systolic & diastolic blood pressure.

• Baroreceptor mediated reflex bradycurdia.

• Dose 5 to 10 mg iv.

• Used in treatment of hypotensive state.

Midodrine:-

• It is a produrg

• It causes contraction of arterial & venous smooth muscle

• Use:- In treatment of autonomic insufficiency and postural hypotension.

αα 22 SELECTIVE AGONISTS SELECTIVE AGONISTS :

Clonidine:-

• Centrally acting selective partial α2 agonist.

• Its antihypertensive effects are caused by central and peripheral attenuation of sympathetic outflow and central activation of non-adrenergic imidazoline preferring receptors.

• It is lipid soluble & crosses BBB.

• It decreases release of norepinephrine from peripheral nerve endings.

• Well absorbed after oral administration peak effect - 1 to 3 hr elimination half life - 6 to 24 hr.

• Doses:- Oral 4 - 5 µg/kg;

IM 2 µg/kg

IV 4 - 8 µg/kg

Epidural 6 - 8 µg/kg

Or 1 - 2 µg/kg/hr.

• Adverse effects:- Sedation

Bradycardia

Hypotension

• Uses:- In treatment of hypertension

Used as an anesthetic adjuvant

Epidural clonidine in control of pain

Treatment of shivering (75 µg iv)

Used in differential diagnosis of patient with hypertension and suspected pheochromocytoma.

In treating and preparing addicted subjects for withdrawl from narcotics alcohol & tobacco.

Improve diabetic diarrhea.

Dexmedetomidine:-

α2 agonist

iv 1µg/kg over 10min or 0.4 to 0.7 µg/kg/hr iv

decreases anaesthetic requirement.

Methyl dopa:-

• It is centrally acting antihypertensive

• It activate α2 receptors and lower blood pressure in a manner similar to clonidine.

MISCELLANEOUS ADRENERGIC AGONISTS MISCELLANEOUS ADRENERGIC AGONISTS :

Amphetamine:-

It has CNS stimulant effect in addition to α and β

adrenergic receptor stimulation.

• Increases systolic and diastolic BP.

• Appetite suppressant action.

• Drug dependence and tachyphylaxis occurs.

Methylphenidate:-

• Structurally related to Amphetamine.

• Abuse potential

• Effective in treatment of Narcolephsy & Attention - deficit hyperactivity disorder.

ANTI-ADRENERGIC DRUGS ANTI-ADRENERGIC DRUGS :

These are drugs which antagonize the receptor action of

adrenaline & related drugs. They are competitive antagonists at α or β receptors.

αα - Adrenergic blocking Agents- Adrenergic blocking Agents:-

These drugs inhibit adrenergic responses mediated through α receptor.

Classification:-

I. Non - equilibrium type

i) Phenoxybenzamine.

II. Equilibrium type (competitive)

A. Non selective

i) ergot alkaloid - Ergotamine, Ergotoxine

ii) hydrogenated ergol alkaloid - dihydroergotamine.

iii) Imidazolines - phentolamine, Tolazoline

iv) Miscellaneous - chlorpromazine

B. α1 selective - prazosin, Terazosin, Doxazosin, Tamsulosin.

C. α2 selective - Yohimbine.

GENERAL EFFECTS OF GENERAL EFFECTS OF αα BLOCKERS BLOCKERS :

1. Blockade of α1 (also α2) receptor reduces peripheral resistance & causes pooling of blood → decreased venous return & cardiac output → fall in BP.

Postural reflex is interfered → marked hypotension on standing.

• Blockade of α2 receptor in brain → increases vasomotor tone.

• They block pressor action of Adr which produces fall in BP (β2 → vasodilatation).

2. Reflex tachycardia.

3. Nasal stuffiness

4. Miosis

5. Intestinal motility is increased

6. Na retention & increase in blood volume.

7. Tone of smooth muscle in bladder trigone, sphincter & prostate is reduced.

8. Inhibit ejaculation.

Phenoxybenzamine :

• It is haloalkylamine that acts on α1 and α2 receptors irreversibly.

• Oral absorption is incomplete

Onset of action - 60 min

Elimination half life - 24 hr

• Orthostatic hypotension is prominent.

• Uses:- 0.5 to 1 mg/kg orally administered preoperatively to control BP in patient with pheochromocytoma.

Phentolamine:-

• It is substituted imidazoline derivative.

• Used in treatment of acute hypertensive emergencies (30 to 70 µg/kg iv)

• Local infiltration of phentolamine is used when sympathominetics is

accidentaly administered extravascularly.

Prazosin:-

• Highly selective α1 blocker.

∀ α1 : α2 selectivity ratio 1000:1

• Produces fall in BP

• Does not increase HR

• First dose effect (postural hypotension occurs in beginning)

• Effective orally, metabolized in liver and excreted primarily in bile;

t½ - 2 to 3hr.

• Used as antihypertensive & in treatment of benign prostatic hyperplasia.

Terazosin:-

• Structurally similar to prazosin.

• Higher bioavailability & longer plasma t½

Tamsulosin:-

• Recently introduced uroselective α1A blocker

• Does not cause significant changes in HR & BP

Yohimbine:-

• Selective α2 antagonist

• Useful in treatment of patient with idiopathic orthostatic hypotension; impotence.

• Crosses BBB

• S/E tachycardia, hypertension, rhinorrhea, dissociative state.

ββ - ADRENERGIC BLOCKING AGENTS - ADRENERGIC BLOCKING AGENTS :

∀ β blockers bind selectively to β receptors.

• All β - blockers are compelitive inhibitors.

Classification:-

Non-selective (β1 & β2)

• Without intrinsic sympathomimetic activity: propranolol, sotalol, timolol.

• With intrinsic sympathomimetic activity: pindolol

• With additional α blocking property: Labetalol, carvedilol

Cardio selective (β1)

Metoprolol, Atenolo, Esmolol, Betaxolol, Acebutolol, Bisoprolol,

Celiprolol.

Selective (β2)

Butoxamine

PHARMACOLOGICAL ACTIONS PHARMACOLOGICAL ACTIONS :

The pharmacology of propranolol is described as prototype.

1. CVS:

Heart:- Decreases Heart rate, force of contraction and cardiac output.

CHF may be precipitated or aggravated. Cardiac work & O2 consumption are reduced.

At high doses membrane stabilizing action is exerted.

Blood vessels:- Has no direct effect on blood vessels on prolonged

administration BP gradually falls in hypertensive patient.

2. RS:- increases bronchial resistance

3. CNS:- Suppresses anxiety in short term stressful situations.

4. Local anaesthetic:- not used because of its irritant property.

5. Metabolic:- TG level & LDL/HDL ratio is increased also inhibits glycogenolysis

6. Skeletal muscle:- inhibits adrenergically provoked tremors.

7. Eye:- reduces secretion of aqueous humor, i.o.t. is lowered.

COMPARATIVE CHARACTERISTICS OF COMPARATIVE CHARACTERISTICS OF ββ - BLOCKER - BLOCKER :

Cardio select

Intric act

Memb sta

Protein bin

Clear-ance

Active Metab

Eli t½ hr

Dose (mg)

PropranololPropranolol No 0 + + 90 - 95 Hepatic Yes 2 - 3 40-800

NadololNadolol No 0 0 30 Renal No 20-24 40-320

PindololPindolol No + ± 40 - 60 Hepatic renal

No 3 - 4 5 - 20

TimololTimolol No ± 0 10 Hepatic No 3 - 4 10 - 30

SotalolSotalol No 0 0 0 Renal No 8 80-640

MetoprololMetoprolol Yes 0 ± 10 Hepatic No 3 - 4 50-400

AtenololAtenolol Yes 0 0 5 Renal No 6 - 7 50-200

BetaxololBetaxolol Yes ± 0 Hepatic, renal

- 11-22 10-20

EsmololEsmolol Yes Plasma hgdrolys

is

No 0.15 10-80 iv

ADVERSE EFFECTS AND CONTRAINDICATIONS ADVERSE EFFECTS AND CONTRAINDICATIONS :

1. Accentuates myocardial insufficiency; can precipitate CHF

2. Bradycardia

3. Worsens chronic obstructive lung disease

4. Exacerbates variant (primzmetal) angina

5. Carbohydrate tolerance may be impaired

6. Plasma lipid profile is altered

7. Withdrawl of propranolol after chronic use should be gradual, otherwise rebound hypertension, worsening of angina can occur. (due to supersensitivity of β receptor)

8. Propranol is CI in partial & complete heart block

9. Tiredness & reduced exercise capacity

10. Cold hands & feet worsening of PVD

11. Gi upset, nightmares, forgelfullness.

CLINICAL USES CLINICAL USES :

1. Treatment of essential hypertension.

2. Management of angina pectoris.

3. Treatment of post - myocardial infarction patient.

4. Prophylaxis in patient undergoing non-cardiac surgery.

5. Pre-op preparation of hyperthyroid patient.

6. Suppression of cardiac dysrhythmias.

7. Prevention of excessive sympathetic activity.

8. Glaucoma, Anxiety, essential tremor.

αα + + ββ BLOCKER BLOCKER :

Labetalol:-

• Selective α1 and non selective β1 & β2 antagonist

• It is a unique parenteral & oral antihypertensive drug

• It lowers systemic BP by decreasing systemic vascular resistance.

• Dose 0.1 to 0.5 mg/kg iv

• Elimination half time is 5 to 8 hr

• Metabolised by conjugation of glucuronic acid

• Used in treatment of hypertensive emergencies

• S/E:- orthostatic hypotension, Bronchospasm, fluid retention.

Carvedilol:-

∀ α1 + β1 + β2 blocker

• Produces vasodilatation

• Has antioxidant property

• Used in hypertensive emergencies and is the β blocker especially employed as cardioprotective in CHF