1. ANS
PHARMACOLOG
YIntroduction
Cholinergic system and drugs
Cholinoceptors
Drugs Cholinergic drugs
Anticholinergic drugs
Anticholinesterases
Adrenergic system and drugs
Adrenoceptors
Drugs Adrenergic drugs
Antiadrenergic drugs
2. 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.
3. 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
4. CHOLINOCEPTORSCHOLINOCEPTORS :
Muscarinic (G protein coupled receptor)
Nicotinic (Ligand gated cation channel)
M1 M2 M3
Location
& function
Autonomic Ganglia :Autonomic Ganglia :
DepolarisationDepolarisation
Gastricgland: Hist relaseGastricgland: Hist relase
acid secretionacid secretion
CNS: Not knownCNS: Not known
SA node -
hyperpolarization
Av node:- ↓ conduction
Alrium & ventricle:- ↓
contraction
Nerveending: ↓ Ach
release
Smooth muscle:
Contraction
Gland: Secretion
Vascularendo:
Vasodilatation
NM NN
Location &
function
Neuromuscular
Junction: Contraction
Autonomic Ganglia: Depolarisation
Adrenal medulla: Catecholamine release
CNS: Excitation or inhibition
5. 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
6. ACTIONS (OF Ach as prototype)ACTIONS (OF Ach as prototype) :
A. Muscarinic
Heart:- 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. Nicotinic
Autonomic 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
14. 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
15. 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.
16. 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.
17. 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.
19. 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.
20. 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)
21. 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
22. PHARMACOKINETICSPHARMACOKINETICS
EndrophoniumEndrophonium NeostigmineNeostigmine PyridostigminePyridostigmine
Onset of actionOnset of action
(min)(min)
1 - 21 - 2 7 - 117 - 11 1616
Duration (min)Duration (min) 6060 5454 7676
Principal site ofPrincipal site of
actionaction
Pre synapticPre synaptic Post synapticPost synaptic Post synapticPost synaptic
HepaticHepatic
MetabolismMetabolism
30 %30 % 50 %50 % 25 %25 %
Renal clearanceRenal clearance
contributioncontribution
70 %70 % 50 %50 % 75 %75 %
Lipid solubilityLipid solubility PoorPoor PoorPoor PoorPoor
Principal,Principal,
metabolitemetabolite
Conjugation toConjugation to
endrophonumendrophonum
glucotonideglucotonide
3 - OH Phenyl3 - OH Phenyl
trimethylammonitrimethylammoni
umum
3 - OH N - methyl3 - OH N - methyl
pyridiniumpyridinium
Vol. of distribution - 0.7 to 1.4 lit/kg.
23. COMPARATIVE FEATURESCOMPARATIVE FEATURES :
PhysostigminePhysostigmine NeostigmineNeostigmine
SourceSource Natural alkaloidNatural alkaloid SyntheticSynthetic
ChemistryChemistry Tertiary amine compoundTertiary amine compound Quaternary ammoniumQuaternary ammonium
compoundcompound
Oral absorptionOral absorption GoodGood PoorPoor
CNS actionCNS action PresentPresent AbsentAbsent
Applied to eyeApplied to eye Penetrates corneaPenetrates cornea Poor penetrationPoor penetration
Direct action onDirect action on
cholinoceptorscholinoceptors
AbsentAbsent PresentPresent
Prominent effectProminent effect Autonomic effectorsAutonomic effectors Skeletal MusclesSkeletal Muscles
UseUse Miotic (glaucoma)Miotic (glaucoma) Myasthenia GravisMyasthenia Gravis
DoseDose 0.5 - 1mg oral / parentral0.5 - 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 hrsSystemic 4.6 hrs
in eye 6 to 24 hrin eye 6 to 24 hr
3 - 4 hrs3 - 4 hrs
24. 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.
25. 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.
26. 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.
27. 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.
28. 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)
30. RECEPTORSRECEPTORS :
α1 α2
Location Post junctional onPost junctional on
effector organeffector organ
Prejunctional on nerve ending,Prejunctional on nerve ending,
also post junctional in brain,also post junctional in brain,
pancreaticpancreatic ββ cell, plateletscell, platelets
Functions Smooth muscle -Smooth muscle -
contractioncontraction
vasoconstrictionvasoconstriction
Gland - secretionGland - secretion
Gut - relaxationGut - relaxation
Heart - arrhythmiaHeart - arrhythmia
Inhibition of transmitter releaseInhibition of transmitter release
vasoconstrictionvasoconstriction
↓↓ central sympathetic flowcentral sympathetic flow
↓↓ insulin releaseinsulin 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
31. 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.
32. 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.
33. 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.
34. 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 &
35. 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
36. 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
37. 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.
38. 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.
39. - 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.
40. RELATED DRUGS INCLUDERELATED 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.
41. NON CATECHOLAMINE SYMPATHOMIMETIC AMINESNON 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.
42. MEPHENTERMINEMEPHENTERMINE :
• 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.
43. 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.
44. DOBUTAMINEDOBUTAMINE :
• 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
45. ββ22 SELECTIVE AGONISTSSELECTIVE 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.
47. αα11 SELECTIVE AGONISTSSELECTIVE 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.
48. 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.
49. αα22 SELECTIVE AGONISTSSELECTIVE 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.
50. • 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.
51. 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.
52. MISCELLANEOUS ADRENERGIC AGONISTSMISCELLANEOUS 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.
53. ANTI-ADRENERGIC DRUGSANTI-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.
54. GENERAL EFFECTS OFGENERAL EFFECTS OF αα BLOCKERSBLOCKERS :
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.
55. 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.
56. 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
57. 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.
59. PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL 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.
60. COMPARATIVE CHARACTERISTICS OFCOMPARATIVE 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
61. ADVERSE EFFECTS AND CONTRAINDICATIONSADVERSE 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.
62. CLINICAL USESCLINICAL 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.
63. αα ++ ββ BLOCKERBLOCKER :
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
