Pharmacology DNB Q & A.pdf

Notes in Anesthesiology
Pharmacology
Edited by:
Dr. Azam
Consultant Anesthesiologist
& Critical Care Specialist
www.drazam.com
Updated up to December 2013, 3rd Edition
Postgraduates appearing
for MD, DNB & DA Exams
Dr. Azam’s....

3
Dr Azam’s Notes in Anesthesiology 2013
Dedication
To Mohammed Shafiulla, my father, my oxygen, companion, and best friend; for
being my major pillar of support and making this vision a reality. Thank you for your
continual sacrifices with boundless love and limitless gratitude, for the sake of your
children. I owe you a debt I can never repay.
I also would like to thank my mom (Naaz Shafi), my wife (Roohi Azam), my two lovely
kids (Falaq Zohaa & Mohammed Izaan), for their support, ideas, patience, and
encouragement during the many hours of writing this book.
Finally, I would like to thank my teachers (Dr.Manjunath Jajoor & team) & Dr T. A. Patil . The
dream begins with a teacher who believes in you, who tugs and pushes and leads you to the next
plateau, sometimes poking you with a sharp stick called "truth."

Dr. Azam
4
A NOTE TO THE READER
Anesthesiology
is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience
broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the
most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the
method and duration of administration, and contraindications.
However, in view of the possibility of human error or changes in medical sciences, neither the author nor the publisher nor any other party
who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect
accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information
contained in this work. Readers are encouraged to confirm the information contained herein with other sources. It is the responsibility of the
licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual
patient. Neither the publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this
publication.

5
Contents
1. Pharmacology of Intravenous induction agents - 5
2. Anti Hypertensive drugs & pharmacology - 30
3. Preoperative usage Antihypertensives - 35
4. Anti Hypertensive Classification according to the site of action -
36
5. Anti Anginal Drugs and its pharmacology - 37
6. Porphyrias - 40 & 98
7. Cardiac Glycosides - 41
8. Anti-Arrhythmic Drugs & its pharmacology - 43
9. Calcium Channel blockers - 51
10.Muscle Relaxant - 53
11. Muscle relaxants in ICU - 67
12. Differences between depolarizing and non depolarizing muscle
relaxants - 68
13.Atropine (Anticholinergic) - 69
14.Glycopyrrolate - 70
15.Levosimendan - 71 & 242
16.Describe the pharmacokinetics & pharmacodynamics of
Etomidate - 72, 228 & 243
17.Role of lipid emulsion in local anesthetic toxicity - 74,77, 90 &
245
18.Nitrous Oxide - Current Status in Anesthesia practice - 75
19.Nitric Oxide - 79
20.Dexmedetomidine - 81 & 247
21.Classify inotropes on the basis of their mechanism of action.
compare dopamine & dobutamine - 82
22.What are the factors affecting neuro-muscular blockage?
Discuss various methods to monitor neuromuscular blockage -
86
23.Renal effect of the inhalation agents - 87
24.CVS effects of inhalation anesthetics - 89
25.Role of Magnesium in Anesthesia & Critical Care - 91
26.Drug Interactions - 92
27.Enzyme Induction - Its role in anesthesia with examples - 95
28. Plasma proteins & Anesthesia - 96
29. Intrathecal Opioids - 100
30. Anticoagulants - 102
31. Heparin - 104
32. Warfarin - 106
33. Amrinone. Phosphodiesterase inhibitor (PDE Inhibitor) - 107
34. Milrinone - 108
35. Sodium Bicarbonate. (Alkalization agent) - 109
36. Other Alkalization agent - 110
37. Diuretics - 111
38. Anti-Epileptic Drugs - 115
39. Anti-Parkinsonian Drugs - 119
40. CNS Stimulants - 120
41. Neurolytic Agents - 121
42. Steroids in Anesthesia Practice - 122 & 225
43. Nitroglycerine - 125
44. Beta Blocker - 126
45. Intraoperative Management of patients on beta blocker - 131
46. Adrenergic neuron blockers - 133
47. Inotropes - 134
48. Co-Analgesia 138
49. Antacids & prokinetics - 139
50. Serotonin - 5 HT3 antagonist - 143
51. Neostigmine - 144
52. Inhalation Agents - 146
53. Inhalation Grid - 162
54. Opioids & Opioid Receptors - 166
55. Newer Opioids - 173
56. Difference between Sufentanil, Alfentanil & Remifentanyl - 175
57. Opioids - Mixed agonist antagonist - 177
58. Opioid Antagonist - 178
59. Intrathecal Opioids / Neuraxial Opioids - 180
60. Local Anesthetics - 184

6
Contents
61. Hypotensive Anesthesia - 202
62. Drug Metabolism - 207
63. Binding of Drugs to Plasma Proteins - 209
64. Hoffmannʼs Elimination - 211
65. Digitalis and related drugs - 212
66. Drug Interactions - 214
67. Anaphylactic reactions under Anesthesia - 217 & 248
68. Rationale for premedication - 223
69. Remifentanil - 230
70. Naloxone - 231
71. Adenosine - 232
72.Aminocaproic Acid. Hamostat - 233
73. Aprotinin - 234
74. ARGININE VASOPRESSIN (ADH) - 236
75. Lorazepam - 238
76. Flumazenil - 239
77. Sugammadex. Org 25969 - 240
78. Context Sensitive half life/half time - 243

7
1.Pharmacology of Intravenous induction agents.
Definition:
• A drug or combination of drugs, which will induce anaesthesia,
safely and reversibly, when injected in sufficient doses and which
could also be given intermittently or by infusion for maintenance.
Classification:
Induction agents can be classified as:
• Inhalation Agents "" " "
• I.V. Induction Agents
I.V. Induction Agent:
• It can also be classified into:
Barbiturates ! !
• Thiopentone, Methohexital
Non-Barbiturates
• Dissociative Anaesthesia – Ketamine
• Benzodiazepines – Diazepam, Midazolam "
• Phenol Derivatives – Propofol "
• Neurolept analgesia " and "
• Neurolept anaesthesia Droperidol+Fentanyl
• Imidazole Derivatives –Etomidate
• Eugenols – Propanidid
It can also be classified into:
• Rapid acting
• Slower action
Rapid acting:
• Barbiturate: Thiopental, Methohexital,
• Phenols: Propofol
• Imidazole: Etomidate
• Steroid: Althesin, Pregnonolone
• Eugenols:Propanidid
Slower acting:
Phencyclidine: Ketamine,
Benzodiazepines: Midazolam, Diazepam
Neuroleptic: (Innovar Droperidol + Fentanyl)
GABA Receptor:
• This is typical GABA receptor / Oligomeic
complex, enclosing central chloride channel.
• Contains 5 protein subunits, as they have
different action, at different site of various drugs

8
Pharmacology of Intravenous induction agents.Continuation:
BARBITURATES
Structural activity of barbiturates:
• Substitution of the hydrogen at the carbon atom position 5 with
alkyl or aryl group is essential for hypnotic and sedative activity.
• A phenyl group on C5 on one of the N2 of the barbitutric acid ring
is essential for anti convulsants activity.
• Increase in the length of one or both of the alkyl side chain at C5
increases hypnotic potency, but if the side chains are increased
more than 5 or 6 carbon hypnotic activity is reduced and
anticonvulsant property results.
• Co-administration of these with muscle relaxant can lead to
formation of 15,000 to 20,000 17 to 39 micro particles / ml. which
occlude I.V
Thiopental Sodium:
History:
• Thiopental Sodium was first used in 1934 by Lundy and Waters
Basic pharmacology:
• Thiopental is sulphur analogue of pentobarbital
• Its Chemical Structure is 5-Ethyl -5-1 Methylbuty-2- thiobarbituric
acid
• It is Ultra Short acting barbiturate.
• It is Yellowish-white hygroscopic power, with a bitter taste and faint
smell of garlic.
• It is highly alkaline drug, PH of 10-11 and Pka of 7.6. It is diluted to
2.5% solution.
• Elimination half-life is 9Hrs.
• Thiopentone Vial contains N2 gas, which prevents thiopental powder
coming in contact with CO2.
• The buffering action of the sodium carbonate in the presence of
atmospheric carbon-di-oxide maintains the moderate alkalinity.
• A decreasing in the alkalinity of barbiturates solutions can result in
their precipitation as free acid.
• Hence therefore, they should not be reconstituted with Ringerʼs
lactate solution, and also should not be mixed with acidic solution.
Mechanism of action:
The Gama - aminobutryic acid [GABA] receptor complex is the most
likely site of thiopentone actions.
• Activation of GABA receptor increases chloride conductivity through
the ion channel causing hyperpolarisation and thereby reducing the
excitability of the postsynaptic neuron. GABA receptors are also
called as Ligand – gated chloride channels.

9
Dose:
• Adults - 3 to 5 mg/kg
• Children - 5 to 6 mg/kg
• Infants - 7 to 8 mg/kg
• Injection of thiopentone given over a period of 15 seconds, the
injection is continued until the desired level of narcosis is reached.
• Respirations must be assisted if unduly depressed.
• Hence slow injection rates are associated with reduced incidents of
apnea and decrease in arterial pressure.
End point for induction of anaesthesia:
• Loss of eyelash reflex (excellent sign of adequate induction).
• Loss of palpebral reflex.
• Los of verbal contact.
• Dysarthria.
• Loss of gagging or coughing in response to LMA insertion.
• Loss of response to surgical stimuli.
PHARMACOLOGICAL ACTIONS OF THIOPENTONE SODIUM
Central Nervous System:
• When given I.V effect is seen within 30 seconds.
• It rapidly crosses blood brain barrier.
• Has hypnotic action.
• Causes retrograde Amnesia
• Thiopentone-induced cerebral vasoconstriction occurs only in the
normal area, these agents tend to redistribute blood flow from
normal to Ischemic area in the brain; this is reverse steal or Robin
Hood effect.
• The cerebral vasculature, in Ischemic area remains maximally
dilated and is unaffected, because of vasomotor paralysis.
• The cerebral cortex and the ascending reticular – activating system
are depressed before the medullary centre.
• It decreases cerebral blood flow, decreases intra cranial pressure.
• It decreases cerebral metabolism and oxygen consumptions
(CMRO2) and hence cerebral protective.
Mechanism of Neuroprotection:
• This mechanism is brought about by suppression of excitatory
transmission by interfering with nitric oxide cyclic guanosine
monophosphate system. It may inhibit the action of nitric oxide or
inactivate nitric oxide in vascular smooth muscle.
• The other mechanism is attenuation of N-methyl-D-aspartate
(NMDA) and AMP- mediated glutamate excitatoxicity.
Respiratory System:
• Causes central respiratory depression.
• This can be treated with gentle IPPV.
• It does not affect larynx directly, but increases sensitivity to stimuli
(Saliva, blood mucus, for which laryngeal spasm may occur).
Cardiovascular System:
• Fall in cardiac output and peripheral vasodilatation causing
pooling of blood in the extremities and a reduction of the venous
return to the heart.
• It has direct depressant action on the Myocardium and hence
decreases the Myocardial Contractility.
• Mechanism:
• Mechanism for depressed myocardial contractility involves
interference with calcium transport across myocardial cells and
altering the nitric oxide mechanism.
• Hypotension is seen due to vasodilatation in skin and muscle.
• Thiopentone results in increased myocardial oxygen
consumption, coronary blood flow decreases.
• Arrhythmias are rare as long as hypercarbia and hypoxia are
avoided.

10
Alimentary tract:
• It produces some amount of depression of the intestinal motility.
Liver and Kidneys:
• It is a powerful stimulator ADH [Antidiuretic hormone] Urine
output is decreased because renal blood flows and renal artery
construction.
Reproductive System:
• It rapidly crosses the placental barrier, and enters the fetal
circulation.
• Neonatal respiration can be depressed by thiopentone and the
degree of depression depends upon the dose of the drug gives
to the mother and the duration of time that elapses between
induction of anaesthesia and delivery of the baby.
Metabolic effects:
• Heat loss results because of vasodilatation of cutaneous and
skeletal muscle vessels, which may contribute to post-Op
shivering.
Lower induction dose of thiopentone will be required:
• In the pre medicated patients.
• In-patient with severe anaemia or burns.
• In malnourished patients.
• In-patient with uremia and liver failure.
• In the Hypovolemic individuals.
Acute Tolerance:
• It was first described by Brodie and subsequently by Dundee.
• The plasma thiopental concentration at awaking is proportional
to the dose used that is the depth of anaesthesia is
independent of the plasma thiopental concentration.
• This suggests that the higher the induction dose of thiopental,
the less sensitive a patient will be to a subsequent dose.
Fate of Thiopental in body
• Fate in the body – Redistribution Metabolism and excretion.
Graph:
• Following I.V administration of thiopental, it mixes rapidly in a central
blood pool and is redistributed by blood flow and molecular diffusion to
tissue according to rate of perfusion.
• Much of the drug is taken up by vessel rich group-central nervous
system (rate of drug transfer is known to be very fast, because of the
drugʼs Lipophilic property)
• Subsequently redistributes to muscle and fat depots.
• As a result the drug leaves the Central Nervous System for the
periphery and recovery of consciousness ensures.
• Most of the drug-injected dose is still present in the body.
• Sequestration occurs to fat depot where the drug remains for many
days. If the second dose of thiopental is given, the recovery from its
effect will take longer.
• Thiopental is entirely metabolized in liver. Less than 0.5% is excreted
unchanged in urine. Metabolism renders the molecule less lipid and
more water soluble, by decreasing their biological action.
The pathways involved in the liver are three namely:
• Side chain oxidation at C3.
• Oxidative replacement of sulphur at C2 to form small quantity of the
drugs oxy-equitant.
• Ring-cleavage to form urea and three-carbon fragment.

11
Drug
Interaction
that
affects
the
Dynamic
of
Thiopental.
Drug Effect
1 Adrenergic drug Increased risk of arrhythmias.
2 Probenicid and
Slulphafurazole
Potentiates the effect of thiopentone.
3 Propofol Synergistic anaesthetic effect.
4. Volatile agent Halothane reduces the apparent volume of
distribution of thiopental, synergistic effect of
anaesthesia.
Clinical Uses:
• Induction agent in anaesthesia –(Drug of choice in Neurosurgical
Operations )
• Anticonvulsant agent.
• To produce simple sedation.
• Infusion of 2 to 3 mg/kg/hr has been used to treat refractory
aminophylline seizures.
• To control the hyperdynamic state after coronary by-pass surgery.
• As Nero protective
• Thiopental is the DOC in hyperthyroidism because of its thiourea
structure leads antithyroid activity of the drug
• ECT
• Hyperthyrodism
Contraindication
Absolute Contraindications:
• Porphyria:
• Barbiturates can precipitate acute or even fatal attacks of
porphyria owing to the induction of Delta ALA –synthetase which
catalyses the rate limiting step in biosynthesis of porphyrins.
• Cardiovascular collapses or shock.
Relative Contraindications:
• Cardiovascular disease: Ischemic heart disease,
Hypertension, Valvular Heat diseases
• Respiratory obstruction or inadequate airway before induction
or where maintenance of airway is difficult.
• Status Asthmatics a situation where laryngeal spasm and
respiratory depression are especially dangerous
• Hypothyroid
• Hypovolemia, Hemorrhage, Burns, fluid depletion and
dehydration.
• Uremia
• Acute Adrenocortical insufficiency
• Sever septicemia
Complication/Side effects/adverse effects:
Local Complications:
• Pain, Redness, Swelling haematoma due to high alkalinity of
the solution. It might lead to median nerve injury, if injected
into antecubital fossa. Hence the antecubital fossa is
considered the Graveyard of thiopentone.
Accidental intra-arterial injection of thiopental may lead to:
• Pain during injection.
• A white hand with cyanosed fingers due to arterial spasm,
which may be accomplished by arterial thrombosis.
• Patches of skin discoloration in the limb.

12
Pathogenesis:
• The change in PH of thiopental which occurs when it is mixed
with blood in an artery results in precipitation or Rombid
crystals, as these crystals remain in the small vessels (they cut
the intima) their irritation property causes a local release of nor-
adrenaline with subsequent vascular spasm and causes arterial
thrombosis and endothelial damage may occur.
Treatment:
• Leave cannula in the artery.
• Dilution of injected thiopentone with heparin and saline.
• Heparin, 1000 units is give through the cannula.
• Papaverine 40-80 mg in 10-20 ml of saline is injected.
• Prostacycline infusion 1 micro g/ml.
• Dexamethasone 8 mg. injection to reduce edema.
• Tolazoline 5ml of 1% solution is given (it is nor-adrenaline
antagonist)
• Perform Stellate ganglion block to remove vasoconstriction and
pain.
• Vascular surgery if required.
Late Signs:
• Ulcer or blisters.
• Edema of forearm and hand.
• Gangrene following the intra-arterial injection (but rare with
2.5%) solution.
• Thrombophlebitis.
• Auto erythrocyte sensitization syndrome.

13
THE PROPOFOL
History:
• It is the most recent intravenous anaesthetic agent. It was
introduced in 1977 by kay and Rolly.
Basic Pharmacology:
• It is one of a group of alkyl phenols.
• It is hindered phenol.
• The chemical structure is 2-6-di-iso propylphenol.
• Propofol is insoluble in water and therefore was initially prepared
with cremophor EL.
• PH of 7, Pka of propofol in water is 11.
• It is available as 1% solution in 20ml clear glass ampoules (or)
vials, 50 and 100 ml vials, and in 50ml pre filled syringes.
• It is highly lipid soluble.
Propofol: 1%
• 10% Soya bean oil
• 2.25% Glycerol
• 1.2% Purified egg phosphatides
CNS:
• Neuroprotection: By attenuation of changes in adenosine
triphosphate, calcium, sodium and potassium caused by hypoxic
injury.
Mechanism of Action:
• Propofol exert its sedative-hypnotic effects through an interaction
with gamma-amino butyric acid (GABA) principal inhibitory
neurotransmitter in the Central Nervous System.
• When GABA receptor is activated transmembrane chloride
conductance increases, resulting in hyperpolarisation of the
postsynaptic cell membrane and functional inhibition of the
postsynaptic neurons.
• It decreases the rate of dissociation of GABA from its receptor,
thereby increasing the duration of the GABA-activated opening
of the chloride channel with resulting hyperpolarisation of cell
membrane.
Effect on organ system:
Central Nervous system:
• Propofol decreases cerebral metabolic rate for oxygen (CMRO2).
• Decreasing cerebral blood flow.
• Decreasing intracranial pressure.
• Decreasing in early component of somato sensory and motor evoked
potentials.
CARDIOVASCULAR SYSTEM:
• Propofol decreases in systematic blood pressure.
• Hence adequately hydration before I.V administration of Propofol is
recommended to minimize the blood pressure effect.
• The relaxation of vascular smooth muscle produced by Propofol is
primarily due to inhibition of sympathetic vasoconstrictor nerve
activity.
• A negative inotropic effect of propofol may result from a decrease in
intracellular calcium availability secondary to inhibition of trans-
sarcolemmal calcium influx. Decrease in Cardiac output, cardiac
Index, Systemic Vascular Resistance, and Stroke Volume, Left
Ventricular Stroke work index also decreased.
• Decrease in systemic pressure following induction is due to both
vasodilatation and myocardial depression. Heart rate do not change
due to either it resets or inhibits the baroreflex, thereby reducing
tachycardiac response to hypotension.
• An infusion of propofol resulting is a significant reduction in both
myocardial blood flow and myocardial oxygen consumption. Finding
suggests that the global myocardial oxygen supply ratio is preserved.
• Bradycardia and asystole have been seen after the induction of
anaesthesia with propofol. Hence itʼs recommended that
anticholinergic drug be administered when vagal stimulation is like to
occur with administration of propofol.

14
Mechanism for CVS effects of propofol:
• It is due to decrease in sympathetic nervous activity to a greater
extent than parasympathetic nervous system activity, resulting in
a predominance of parasympathetic activity.
Respiration system:
• Propofol produces does-dependent depression of ventilation with
apnea occurring is 25% to 35% patients after induction.
• Maintenance infusion of propofol decreases tidal volume and
frequency of breathing.
• It produces bronchodilation and decreases the incidence of intra-
operative wheezing in patients with asthma.
• Propofol: Produces decrease in amplitudes of the early
components of somatosensory evoked potential.
Hepatic and Renal Function:
• It does not affect hepatic and renal function.
• Prolonged infusion of propofol may result in excretion of green
colored urine, which reflects, the presence of phenols in the
urine.
Eye: Decreases the intraocular pressure occur immediately after
induction.
Dose of propofol:
Induction of general Anaesthesia:"1 to 2/5 mg/kg I.V
Maintenance of general anaesthesia:50 to 150 micro g/kg/min I.V
Sedation:25 to 75 micro g/kg/min I.V.
Metabolism:
• Propofol is rapidly metabolized is the liver, conjugation to
glucuronide and sulphate to produce water-soluble compounds,
which are excreted by the kidneys.
• Metabolites of propofol are inactive.
• Propofol itself results in a concentration dependent inhibition of
Cytochrome P-450 and then may alter the metabolism of drug
dependent enzyme system.
Clinical use:
• Propofol has become the induction drug of choice for many forms of
anaesthesia, especially when rapid and complete awakening is
considered essential. Commonly used for producing I.V conscious
sedation or as a part of balanced (or) total I.V anaesthetic.
• Induction of anaesthesia: (1 to 2.5 mg/kg/ iv)
• Intravenous sedation: (25 to 75 micro g/kg/iv)
• Maintenance of Anaesthetic: (50 to 150 micro g/kg/iv)
• Day care surgery
• Antiemetic effect: (10 to 15 mg i.v)
• Sub hypnotic doses of propofol (10 to 15mg/IV) may be used in
the post anaesthesia care unit to treat nausea and vomiting.
Very effective against Chemotherapy-induced nausea and
vomiting.
• More effective than ondansetron in preventing postoperative
nausea and vomiting.
Mechanism:
• Propofol has a profile of Central Nervous System depression that
differs from other anaesthetic drugs.
• Propofol uniformly depress Central Nervous System structures,
including sub cortical centres.
• Most drugs of know antiemetic efficacy exerts this effect via sub
cortical structure; hence propofol inhibits sub cortical pathways to
inhibit nausea and vomiting or produces direct depressant effect on
the vomiting centre. It is also believed that antiemetic effect of
propofol based on inhibition the dopaminergic system.
Antipruritic Effect:
• Propofol 10mg I.V is effective is the treatment of pruritis associated
with Neuraxial opioid or cholestasis.
Mechanism:
• Mechanism of the Antipruritic effect may be due to the drugs ability to
depress spinal cord activity.

15
Anti convulsants Activity:
• It possesses anti-epileptic properties presumably reflecting
GABA mediated pre-synaptic and post-synaptic inhibition
A dose of more than 1mg/kg I.V decreases seizure duration.
Side effect:
Allergic Reactions:
• Allergic components of propofol are phenyl nucleus and
diisopropyl side chain.
Pain on Injection:
• It is the most common side effect associated with Propofol.
• Using large veins and avoiding veins in the dorsum of the hand
and adding Lidocaine to the propofol solution reduce this.
Abuse potential:
• Intense dreaming activity amorous behavior and hallucinations
has been seen during recovery from the effects of propofol.
Addiction is reported.
Bacterial Growth:
• Propofol strongly supports growth of Escherichia coli and
pseudomonas Aeruginosa.
Hypotension:
• The most significant side effect on induction is the decrease in
systemic blood pressure.
Pro-convulsants Activity:
• Prolonged myoclonus associated with meningismus has been
associated with propofol administration.
Miscellaneous effects:
• Temporally abolition of tremors in patients with Parkinsonʼs disease
may occur after the administrating of propofol. For this reason
propofol may not be ideally suited for patients undergoing
stereotactic neurosurgery such as pallidotory.
Propofol Infusion Syndrome:
• Propofol infusion syndrome is a rare syndrome which affects patients
undergoing long-term treatment with high doses of the anaesthetic
and sedative drug propofol.
• It can lead to cardiac failure, rhabdomyolysis, metabolic acidosis and
renal failure and is often fatal.[1][2][3] Hyperkalemia,
hypertriglyceridemia, and hepatomegaly are also key features.
• It is associated with high doses and long-term use of propofol
(>4 mg/kg/hr for more than 24 hours).
• It occurs more commonly in children, and critically ill patients
receiving catecholamines and glucocorticoids are at high risk.
• Treatment is Supportive. Early recognition of the syndrome and
discontinuation of the propofol infusion reduces morbidity and
mortality.

16
Thiopentone Propofol
History 1934 by Lundy and waters 1977 by kay and Roller
Family Barbiturate ultra short acting Alkyl phenols short acting
Appearance Yellowish sulphur powder form Slightly milky white substance (most recent)
PH Highly alkaline, PH 10-11 PH -7
Chemical , Structure 5-Ethyl-5-1-Methlylbutyl-2 thiobarbituric acid 2-6, Di-Iso-propofol
Dose Induction:3 to5 mg/kg iv 1 to 2.5 mg/kg i.v
Maintenance: 50 to 150 micro g/kg/min
Sedation: 25-75 mg/kg/lit
Anaphylactic Reaction Rare Common
Contents Vial contains, Nitrogen gas, Thiopentone
Sodium
1% of propofol contains: 10% Soybean oil
2.25% Glycerol 1.25% Purified egg
phosphate.
Bacterial Growth No E-Coil, Pseudomonas,
Mechanism of Action Through GABA receptors Through GABA receptors
Central nervous System Decreases CMRO 2 Decreases CMRO2
Antiemetic Effect No Yes
Anti Pruritic Effect No Yes
Acute Tolerance Common Not seen
Cardiovascular System Decreases CO, decreases Blood pressure
(20%)
Decreases BP (25 to 49%)
Contraindications Porphyria Can be used

17
KETAMINE (PHENCYCLIDINE)
History:
• Phencyclidine was the first drug of it class to be used for
Anaesthesia.
• It was synthesized by Maddox and introduced into clinical use in
1958 by Greifenstein and in 1959 by Johnstone.
• Ketamine was synthesized in 1962 by Stevens and was first
used in humans in 1965 by Corrsen and Domino.
Basic Pharmacology:
• 2-0-chlorophenyl-2methylaminocyclohexanone hydrochloride.
• Ketamine belongs to Phencyclidines group.
• Molecular weight 238 KD.
• White partially water-soluble and forms a white crystalline
powder supplied as a colourless solution in concentration of 10%
50% and 100%.
• It contains Benzethonium as a preservative.
• PH varies between 3.5 to 5.5
• PKA is 7.5
• It has significant analgesic effect.
• Ketamine molecule contains, a choral centre and therefore
occurs as to resoluble optical isomers is enantiomers.
• The commercial preparations being mixture of both isomers S
and R in equal amounts.
• The positive S isomer producers:
• More intense analgesia
• More rapid metabolism and thus recovery.
• Lower incidence of the Emergence of reactions than the
negative (R) isomer.
Mechanism of Actions:
• Ketamine interacts with N-methyl-D- aspartate (NMDA) receptors,
opioid receptors monoaminergic receptors, muscarinic receptors and
voltage sensitive calcium channels
• receptor activity à analgesic effect.
• NMDA = general anaesthetic effect and some analogies
• Morphine
• K – Ketocyclazocine
N-Methyl-D- Aspartate Receptors Antagonism:
The NMDA receptors, a member of the glutamate receptor family.
• Ketamine is a non-competitive antagonist of the NMDA receptor
calcium pore.
• Ketamine interacts with the Phencyclidine – Binding receptor site,
leading to inhibition of NMDA receptor activity.
Opioid Receptors:
• Ketamine interacts with mu, delta Kappa receptors ketamine may be
an antagonist at mu receptors and an agonist at kappa receptors.
Monoaminergic Receptors:
• The antinociceptive actins of ketamine may involve descending
inhibiting monoaminergic pain pathways.
Muscarinic Receptors:
• Ketamine anaesthesia is partially antagonized by anticholinesterase
drugs. The fact that ketamine produces anticholinergic symptoms
(Emergence delirium, bronchodilation sympathomimetic action),
suggests that an antagonist effect of ketamine at muscarinic
receptors is more likely than an agonist effect.

18
Pharmacology:
Effect on the organ system:
• It produces anesthetized state, which has been termed as
“Dissociative Anaesthesia” which is characterized by evidence of
as the EEG of dissociation between the thalamo-cortical and
limbic systems.
• Dissociative anaesthesia resembles a cataleptic state in which
the eyes remain open with a slow nystagmic gaze, have
profound analgesia, and maintain corneal, cough and swallow
reflexes, may all be present but not be assumed to be protective.
Emergence reacting:
Can be decreased by using BZD,
" Like Midazolam
" " Diazepam
" " Lorazepam
" " Thiopentone
The primary site of Central Nervous System actions of Ketamine:
• Thalamoneocortical projection systems.
• Depresses neural functions in part of, cortex (especially
association area) and,
• Thalamus while simultaneously stimulating parts of the Limbic
system, including the hippocampus.
• The spinal cord analgesic effect of Ketamine is postulated to be
due to inhibitions of dorsal horn.
Ketamine increases cerebral metabolism, cerebral blood flow and
intracranial pressure. It also increases CMRO2.
• When patient is coming out of Ketamine anaesthesia he
experience what is termed as “Emergence Reactions”. The
common manifestations of these reactions, which vary in
severity, dreaming, extra corporeal experiences (Sense of
floating out of body), illusions (misinterpretation of a real external
sensory experience).
• These incidents of dreaming and illusion are often associated
with excitement, confusion, euphoria and fear.
Respiratory System:
• Transient apnoea is followed and decreased in respiratory rate and
tidal volume.
• The pharyngeal and laryngeal reflexes remain active.
• Protection is not absolute and that silent aspiration can still occur
(especially in children).
• It causes a marked increase pharyngeal secretion and hence
anticholinergic agent should be administered prior to Ketamine.
• It is a bronchial. Smooth muscle relaxant and hence can be used in
patients with reactive airway disease, bronchospasm pulmonary
compliance is improved.
• It is safe to use in status Asthmatics.
Eye sign of Ketamine:
• Pupils dilated
• Lacrimation
• Raised IOP
• Nystagmus
• Eyes open
• Diplopia
• Loss of light reflex.
Increase in Arterial Blood Pressure of around 15-25%.
Increase in Heart rate, cardiac output and pulmonary artery pressure.
Mechanism:
The mechanisms are as follows:
• Increase in circulating norepinephrine (noradrenaline) after ketamine.
• These changes are caused by Central Nervous System stimulation
with an increase in sympathetic flow.
• It blocks the re-uptake mechanism.
• Releases noradrenaline from the sympathetic ganglia.
• It increases myocardial oxygen consumption, hence contraindicated
in patients within Ischemic heart disease.

19
DOSES OF KETAMINE:
Induction of general Anaesthesia:""
• 0.5 to 2 mg/kg I.V
• 4 to 6 mg/kg I.M"
Maintenance of General Anaesthesia:
• 0.5 to 1 mg/kg I.V with N20 50% in 02
• 15-45 mg/kg/min I.V with N2O 20-70% in O2
• 30-90 mg/kg/min I.V without N2O.
Sedations and Analgesia:
• 0.2 to 0.8 mg/kg/I.V"
• 2-4 mg/kg/.min I.M
Metabolism:
• Ketamine is metabolized extensively by hepatic microsomal
enzymes.
• By demethylation of Ketamine
%&'('$&)$*(+,-./(0$
./8?7,1+/#+@#3-/-"&2#$/&-),0-)1&A# # ;>B#,+#<#'3CD3#.>E#
# # # # # # F#,+G#'3CD3#.>H# #
!"#$%&$"$'&()*(+&$&,"-(.$"&/%0&/#"1(
• ;>B#,+#:#'3CD3#.>E#=1,0#*<;#B;I#1/#;<#
• :B5FB#'3CD3C'1/#.>E#=1,0#*<J#<;5K;I#1/#J<#
• L;5M;#'3CD3C'1/#.>E#=1,0+?,#*<J>#
2&3"%#)$/("$3(.$"-4&/#"1(
• ;><#,+#;>N#'3CD3C.>E# #
• '3CD3C>'1/#.>H##
!&%"5)-#/61(
• O-,&'1/-#1)#'-,&P+21%-8#-Q,-/)1R-24#P4#0-S&,17#'17"+)+'&2#-/%4'-)>#
• T4#8-'-,042&,1+/#+@#O-,&'1/-#
U48"+Q4D-,&'1/-#..5BV#G#W!-048"+5/+"D-,&'1/-#
# # # # # ## # #U48"+Q4#/+"D-,&'1/-#..#
# O-,&'1/-## # ##
*+"D-,&'1/-##### ##U48"+Q4#/+"D-,&'1/-#.#
# # # # # # # ##U48"+Q4#/+"D-,&'1/-#...#
# # # # #
#
#U48"+Q4#O-,&'1/-#.#
#
• *+"# O-,&'1/-# 1)# ,0-# &7,1R-# '-,&P+21,-# '&4# 7+/,"1P?,-# ,+# S"+2+/3-8# -@@-7,)# +@#
O-,&'1/->#
• *+"#O-,&'1/-#1)#-R-/,?&224#048+Q42&,-8#&/8#,0-/#7+/X?3&,-8#,+#@+"'#'+"-#=&,-"#
)+2?P2-#&/8#1/&7,1R-#32?7?"+/18-#'-,&P+21,-)#,0&,#&"-#-Q7"-,-8#P4#,0-#O18/-4)>#
7%0&,(&**&'%/1(
• Y&1)-)#1/,"&+7?2&"#S"-))?"-#&/8#'&4#7&?)-#S+),+S-"&,1R-#/&?)-&#&/8#R+'1,1/3>#
• ./7"-&)-)#'?)72-#,+/-#&/8#7&?)-)#)?88-/#X-"D4#'+R-'-/,)V#=0170#'&4#1/,-"@-"-#
=1,0# )?"3-"4# &/8# "-Z?1"-# )-8&,1+/# =1,0# !1&%-S&'# ["-8?7-)# ,0-# 1/718-/7-# +@#
1/R+2?/,&"4#'?)72-#'+R-'-/,)>#
#
+R-"#<5L#'1/#
• Nor Ketamine is the active metabolite may contribute to prolonged
effects of Ketamine.
• Nor Ketamine is eventually hydoxylated and then conjugated to
form more water soluble and inactive glucuronide metabolites that
are excreted by the Kidneys.
Other effects:
• Raises intraocular pressure and may cause postoperative nausea
and vomiting.
• Increases muscle tone and causes sudden jerky movements, which
may interfere with surgery and require sedation with Diazepam
(reduces the incidence of involuntary muscle movements.)
Clinical uses:
• As sole anaesthetic agent for minor surgery.
• As induction agent.
• State of shock (Hypovolemic patients).
• Dressing burns patient, Debridementʼs and skin grafting.
• Mass Casualties.
• To produce analgesia.
Mechanism:
Effect is primarily due to its activity in thalamic and limbic systems,
which are responsible for the interpretations of painful signals.
• Analgesia can also be produced during labour without associated
depression Neonate.
• Neuraxial analgesia.
• For induction of anaesthesia in small children
• Where airway control is difficult.
• Certain neurological, radio diagnostic and therapeutic procedures.
• For intubation as an alternative to topical awake intubation in
presence of full stomach.
• For patients with acute intermittent porphyria.
• For prevention and management of priapism.
• In muscular dystrophy and myopathic disorder (to avoid thiopentone
use).
• Epidural use for postoperative pains.
• Ketamine ampules (without preservative) can be used for spinal
anaesthesia.

20
Side Effects:
• It increases cerebral blood flow and CMRO2.
• It increases intracranial pressure.
• It increases myocardial Oxygen requirement.
• Transient apnoea can be seen.
• It increases systemic and pulmonary arterial blood pressure,
heart rate, and cardiac output.
• Ketamine when administered in presence of halothane may
result in hypotension.
Emergence Delirium:
• Emergence from Ketamine anaesthesia in the Postoperative
period may be associated with visual auditory proprioceptive and
confusional illusions, which may progress to delirium. Cortical
blindness may be transiently present.
• Dreams and hallucinations can occur up to 24 hrs after
administration to Ketamine. The dreams frequently have a
morbid content and are often experienced in vivid colour. Dreams
and Hallucination usually disappear within few hours.
Mechanism:
• It occurs secondary to Ketamine induced depression of the
inferior colliculus and medial geniculate nucleus leading to
misinterpretation of auditing and visual stimuli.
• Loss of skin and musculoskeletal sensation resulting in
decreased ability to perceive gravity, there by producing a
sensation of bodily detachment (or) floating in space.
Contraindications:
• Psychiatric disturbances (Schizophrenia).
• Patients on thyroid medication.
• In hypertensive patients.
• IHD patients (severe myocardial disease, coronary insufficiency).
• Patients with increased intra cranial pressure and with
intracranial mass lesion.
• In open eye injury (or) other ophthalmologic disorders
Nystagmus).
• In patients with vascular aneurysms (sudden change in arterial
pressure).
BENZODIAZEPINES - MIDAZOLAM AND DIAZEPAM
Midazolam
History:
• Midazolam was synthesized in 1976 by Fryer and Walkerʼs.
Basic Pharmacology:
• Midazolam was the first Benzodiazepine that was produced primarily
for use in Anaesthesia.
• It is water-soluble Benzodiazepines with Imidazole ring in its
structure (that accounts for stability in aqueous solutions and rapid
metabolism).
• It is available for injection either in 2 ml ampules at a concentration of
15mg/ml (or) 5ml ampules containing 2 mg/ml. it is also available in 5
ml or 10 ml vials at a concentration of 1mg/ml.
• Pka is 6.15
• PH of 3.5k (this is important because Midazolam is characterized by
a PH-dependant ring-opening phenomenon in which the ring remains
open at ph values of less than 4, thus maintaining water solubility of
the drug. The ring closes at ph value of more than 4).
• Midazolam solution or 5mg/ml with 0.8% of sodium chloride, 0.001%
disodiumedetate with 1% benzyl alcohol as a preservative.
• An important inhibiting neurotransmitter in the brain is GABA, while
glycine the major inhibiting neurotransmitter in the spinal cord and
brain stem.
• Inhibition at Gamma-amino butyric acid (GABA) receptors, by binding
to specific site on GABA-A receptor.
• It augments (or) facilitates GABA- ergic neurotransmission producing
sedation and anti convulsants activity.

21
Continuation of Mechanism of action of Midazolam:
• Increases affinity of the GABA receptors for the inhibiting
neurotransmitter, there by enhanced chloride conductance
producing hyperpolarisation of the postsynaptic cell membrane
and rendering post synaptic neurons more resistance to
excitation.
• This resistance to excitation is presumed to be the mechanism
by which Midazolam produces anxiolysis, anti convulsants and
skeletal muscle relaxant effect.
Effect on Organ System:
• It decreases cerebral metabolic oxygen requirements (CMRO2)
and cerebral blood flow.
• It possesses anxiolytic, hypnotic, anti convulsants, muscle
relaxant and anterograde amnestic properties.
• Midazolam is a safe anaesthetic agent for neurosurgical patients.
• It blocks EEG arousal from stimulating of the brain stem and
reticular system.
• It is myocardial depression.
• It causes moderate reduction in systolic and diastolic blood
pressure, decreases cardiac output.
• Systemic vascular resistance is decreased and causes
venodilation.
• It does not abolish the hemodynamic response to tracheal
intubation.
• The resultant hypotension caused, activates the baroreceptor
reflex arc, catecholamine stimulation occurs and then increases
in heart rate and myocardial contractility.
Respiratory System:
• It causes Central Respiratory Depression.
• Transient apnoea may occur after rapid injections of large doses
of Midazolam (More than 0.15mg/kg I.V)

22
Dose of Midazolam:
• Induction:" " 0.05 to 0.15 mg/kg I.V
• Maintenance:" 0.05 mg/kg to 0.1 mg/kg/IV or 1 mg/kg IM
• Sedation:
" 0.5 to 1 mg repeater. 0.07 mg/kg I.M
• Increment doses given until desired degree of sedation is
obtained.
• It is used orally, intra muscular, intravenous, epidural.
Metabolism:
• It undergoes extensive hydroxylation by hepatic microsomal
Oxidative mechanisms (Cytochrome –P-450 3A) to form 1-
hydoxy Midazolam and 4-hydoxy Midazolam.
• These water-soluble metabolites are excreted in urine as
glucuronide conjugates.
• Drugs that inhibit their clearance are antibiotics (Erythromycin),
calcium channel blockers.
Clinical Uses:
" Midazolam is the most commonly used Benzodiazepines for
preoperative medication in paediatric patients I.V sedation
(conscious) and induction of anaesthesia.
• Preoperative medication: 0.5 mg/kg orally 30 mins before
induction.
• Intravenous Sedation: 0.5mg to 1 mg
• Induction of Anaesthesia: 0.05 mg/kg to 0.15 mg/kg I.V
• Maintenance of Anaesthesia: 0.05 mg/kg
• It is used to produce sedation during relatively unpleasant
procedures such as upper intestinal, endoscopy, bronchoscopy,
dental work carried out under local anaesthesia.
• Co-induction of anaesthesia: A combination of two (or) more
synergistic (or) addictive induction agents to produce
anaesthesia using smaller doses of each drug.
Drugs
Used: Midazolam, Propofol, Fentanyl, and Thiopentone.
Advantage: If drug act on same receptor group there is potentiation of
anaesthesia effect with reduced side effects.
Disadvantage: Interactions, Interference, binding metabolism, action,
distribution (or) excretion. Differing onset times and durations of
different drugs.
Dose of flumazenil:
• Reversal of BNZ: 0.1 to 0.2 mg repeat up to 3 mg.
• Diagnosis the cause: 0.5 mg repeats up to 1 mg.
Precautions:
• Conjugates of its main metabolites, alpha-Hydroxy Midazolam has
been shown to accumulate in renal failure.
• Deaths have occurred from a combination of respiratory depression
and obstruction.

23
DIAZEPAM:
History:
• Diazepam was synthesized by Stern Bach in 1959.
Basic Pharmacology:
• Each milliliter of diazepam solution (5 mg) contains propylene
glycol 0.4 ml, benzyl alcohol 0.015 ml and sodium benzoate/
benzoic acid in water for injections
• The solution is viscid and dilution with water (or) saline causing
cloudiness.
• PH of 6.6 to 6.9, it is a weak base, with a Pka of 3.3
• Diazepam is also available in unique soya bean oil, which has
been emulsified in water by means of egg yolk, phosphatides
and acetylated monoglycerides.
• Elimination half-life of30-60 hr.(90 Hrs)
•
Doses of Diazepam:!
1. Induction: 0.3 to 0.5 mg/kg I.V
2. Maintenance: 0.1 mg/kg
3. Sedation: 2mg
Effects on Organ System:
• Potent tranquilizer effect and anti-convulsants effects are due to,
Mechanism:
• It depresses the limbic system, electrical discharge from
amygdaloidal nuclei and amygdalohippocampal transmission are
inhibited at low doses that do not depress other areas of the
brain.
• Anterograde amnesia is seen.
• It has a good cardiovascular stability when compared to thiopentone.
Hence a good induction agent for patients with IHD effect.
• Minimal cardiovascular depressant effect is seen.
• Small transient increases in heart rate.
• It dilates coronary blood vessels and increases coronary blood flow.
• Coronary vasodilatation may produce redistribution of myocardial
flow to normal area and hence increases regional ischemia (coronary
steal syndrome)
Respiratory System:
• Large doses cause respiratory depression and apnoea.
• The breathing frequency falls and there is decrease in the slope of
the CO2 ventilation curve.
• 0.14 mg/kg I.V depresses the sensitivity of the respiratory centre.
Skeletal Muscle:
Skeletal muscle relaxant effect is due to action of Diazepam on spinal
internuncal neurons and not at the NMJ.
Diminishes the tonic facilitatory influence on spinal gamma neurons
and thus skeletal muscle tone is decreased.
Metabolism:
• Diazepam is principally metabolized by hepatic microsomal enzyme
using an oxidative pathway of N-demethylation.
• Two principal metabolites of diazepam are desmethyldiazepam and
Oxazepam.

24
Pathway for Biotransformation of Diazepam:
! !"#"$%&'($)*+,
!)(-".(#, !"/#"$%&'0)(-".(#,
1&02*3&('($)*+, 1&02*3&'($)*+,
!"#"$%&'($)*+,
4,5,#"$%&'*3(-".(#, 63(-".(#,
Clinical uses:
1. It is given as pre medicant drug (because of its ability to allay
anxiety and apprehension in 0.1 to 0.2 mg/kg orally 1 to 2 mg/kg
orally 1 to 2 hrs before surgery).
2. Induction Agent: For the aged, the poor risk patients with
cardiac disease and the severely traumatized patients.
3. Use of Diazepam anaesthesia and surgery include
cardioversion, endoscopic procedures, and dentistry and minor
surgical procedures.
4. As anti convulsants to ecliptic patient 0.25 mg/kg/I.V to 0.1 mg/
kg I.V (best against Lidocaine-induced convulsion)
5. Used orally in treatment of patient with psychosomatic illness
and tetanus.
Precautions and side effects:
• The elimination half-life is increased in patients with liver disease and
elderly.
• Cimetidine reduces the clearance and prolongs the elimination half-
life of both diazepam and its active metabolite, desmethyldiazepam.
• Large veins to be used for I.V as it cause pain and phlebitis at the
injection site.
• It causes Central Nervous System depression, drowsiness, muscle
weakness ataxia, Dysarthria and respiratory depression.
• Diazepam of 0.1 mg/kg I.V effective in abolishing seizure activity
caused by Lidocaine, delirium tremens and status epilepticus
Mechanism:
• It reflects its ability to facilitate the actions of the inhibitory
neurotransmitter GABA. It selectively inhibits activity in the limbic
system, particularly the hippocampus. The duration of anti
convulsants activity exceeds the elimination half time of diazepam,
suggesting the role for the pharmacological active metabolite
desmethyldiazepam.

25
Comparis
on:
Diazepam
Midazola
m
History
1959,Stern
Bach
1976,
Fryer
and
Walkerʼs
Duration
Long
acting
Short
acting
Solubility
Highly
lipid
soluble
Water
soluble
P
H
Pka
PH:
6.6
to
6.9
Pka:
3.3
PH:
3.5,
Pka:
6.15
Elimination
half-life
30
to
60
hr
1.7
to
2.6
Dose
(mg/kg)
Induction:
0.3
to
0.5
0.05
to
0.15
Maintenance
:
0.1
0.05
Sedation:
2
mg
0.5
Contents
0.4ml
propylene
glycol
0.1
ml
alcohol,
0.015
ml
benzyl
alcohol
and
Sodium
bicarbonate.
0.8%
sodium
chloride
0.001%
di-sodium-ed
ate
1%
benzyl
alcohol.
CNS
Effects:
Potent
tranquilizer,
Anti-convuls
ants
Anxiolytic,
Hypnotic
CVS
Effects:
Coronary
vasodilatatio
n
Myocardial
Depressant,
Cardiac
output
decreased
RS
Effects:
Respiratory
depressant
Respiratory
depressant
Skeletal
Muscle:
Skeletal
muscle
relaxant
-------
Metabolites:
Des-methyl
diazepam
Oxazepam
1-hydroxymi
dazolam
4-hydroxymi
dazolam
Uses:
Premedican
t
Drug
Induction
Agent
During
Cardioversio
n,
endoscopic
procedure
dentistry
Anti-convuls
ants
Premedican
t
Drug
Induction
Agent
During
Cardioversio
n,
endoscopic
procedure
dental
work.
Side-effects:
CNS
depression
Pain
on
injection
Respiratory
depression
Alpha-Hydro
xy
midazolam
gets
accumulated
in
renal
failure.
Death
has
been
occurred
in
combination
with
respiratory
depression.

26
IMIDAZOLE:
ETOMIDATE:
History:
• Etomidate was synthesized in 1964. It was introduced into
clinical practice in 1972.
Basic Pharmacology:
• It is a carboxylated imidazole derivative
• It si pentylethyl IH-imidazole -5-carboxylate sulfate.
• It is presently formulated in 0.2% solution with 35% propylene
glycol.
• PH of 6.9 and Pka of 4.2
Doses of Etomidate:
• Induction of GA:" 0.2 to 0.6 mg/kg I.V
• Maintenance of GA: 10 micro gm/kg/min with N2O
• Sedation and Analgesia:" 5 to 8 micro gm/kg/min I.V (only for
short periods of sedation because of inhibition of corticosteroid
synthesis.
Pharmacological action of Etomidate:
• The primary action of Etomidate is hypnosis, which is achieved
in one arm-brain circulation.
Mechanism:
• The mechanism by which Etomidate produces hypnosis:
• May be in part related to the GABA adrenergic system, because
its action may be antagonized by GABA antagonists.
• It reduces cerebral blood flow, CMRO2, without altering means
arterial pressure and Cerebral Perfusion Pressure is maintained.
• It may lower the intracranial pressure in previously increased
ICP.
• It also decreases the intra ocular pressure.
Respiratory System:
• It has minimal effect on Ventilation.
• Do not include histamine release.
• Ventilator response to carbon dioxide is depressed.
• On induction it produces brief period of hyperventilation.
• Hiccups (or) coughing may be seen during induction.
• An induction dose of 0.3 mg/kg results in almost no change in heart
rate, mean arterial pressure, stroke value (or) systemic vascular
resistance and cardiac output.
• Patients with valvular heart disease may exhibit a 20% fall in
systemic blood pressure hence administration to acutely
hypovolemic patients results in sudden hypotension.
• It decreases 50% myocardial blood flow and oxygen consumption
and a 20% to 30% increase in coronary sinus blood oxygen
saturation.
• The myocardial oxygen supply / demand ratio is thus well
maintained.
• The hemodynamic stability seen with Etomidate may be due to lack
of effect both on the sympathetic nervous system and baroreceptor
function.

27
Endocrine effect:
• Endocrine effect is due reversible inhibition of the enzyme 11-B-
hydroxylase, which converts 11-deoxycortisol to cortisol and
relatively minor effect on 17-alpha, -hydroxylase.
• This results in an increase in the cortisol precursor 11-
deoxycortisol and 17-hydoxy-progesterone as well as increase in
Adrenocorticotrophic hormone (ACTH)
• This results in inhibition of ascorbic acid synthesis, which is
required for steroid production in humans.
• The blocked of the Cytochrome P-450-dependant enzyme 11-B-
hydroxylase also results in decreased mineralocorticoid
production.
• Hence vitamin-C supplementation restores cortisol levels to
normal.
Metabolism:
• Etomidate is rapidly metabolized by hydrolysis of the ethyl ester
side chain to its carboxylic acid ester, resulting in water soluble
and inactive compounds.
• Metabolized by M-dealkylisation.
Uses:
It is most appropriate in patients with
• Cardiovascular disease (coronary artery bypass, valve surgery)
• Reactive airway disease (do not release histamine)
• Intra cranial hypertension
• For cardio version (rapid onset and quick recovery)
Adverse Effects:
• Pain on intravenous injections (phlebitis, thrombosis and
thrombophlebitis)
• Abnormal muscular movements of a myoclonic nature.
(Myoclonus, dystonia and tremor)
Mechanism:
• Mechanism of Etomidate induced myoclonus appears to be
disinhibition of sub cortical structures that normally suppress extra
pyramidal motor activity.
• Adrenocortical Suppression: Inhibits conversion of cholesterol to
cortisol. Patients experiencing sepsis (or) hemorrhage, who might
require an intact cortisol response, would be at disadvantage.
• Nausea and Vomiting
• Laryngospasm and unexpected Apnea.

28
METHOHEXITONE:
History:
• It was synthesized in 1932 by Weese and Scharpff.
Basic pharmacology:
• It is a methylated oxybarbiturate.
• Chemically it is alpha-dl-1 methyl-5-ally-5-1 mrthyl-2-pentynyl.
• It is a white powder.
• PH of 10-11 and Pka of 7.9.
• Two asymmetrical carbon atoms, there are four possible
isomers, which are separated into 2 pairs.
• (Alpha) a-dl (High melting point) and (Beta) b-dl (low melting
point).
• The a-dl pair which is methexitone, produces hypnosis without
stimulation of skeletal activity and only this is now included in the
commercial formulation.
Pharmacological Activity:
• Most of the pharmacological actions are similar to that of
thiopentone.
• Inductions with Methohexital are frequently accompanied by
transient twitching of skeletal muscle, hiccup and Laryngospasm.
• It should never be given to patients with a history of epilepsy for
convulsion, (or) even status epilepticus can be precipitated.
• It does not cause bronchospasm.
Distribution Metabolism and Excretion:
• It is a lipid soluble drug.
• Is shows similar pattern of disturbance and elimination
• It is less sequestered in fat depots and much more rapidly
metabolized in the liver.
• The onset of anaesthesia is therefore less influenced by the bolus
effect.
• It is ultimately eliminated only after metabolic degradation in the liver,
the pathway involving: Side –chain oxidation N-demethylation and
ring splitting.
Dose:
• Induction of Anaesthesia: 1 to 2mg/kg.
• Continuous infusion: 3 mg/kg over 60 mins.
Uses:
• In outpatients needing Electro Convulsive Therapy (or) dental
extraction.
• In Caesarean section for which an induction dose of 1mg/kg, does
neither affect neonatal blood gases, nor reduces the Apgar score.

29
NEUROLEPT ANAESTHESIA
INNOVAR:
History:
• Droperidol and Fentanyl was synthesized by Janssen were used
by Decastro and Mundeleer.
Basic pharmacology:
• Innovar is a combination of Droperidol and Fentanyl in a ration
of5:1.
• Droperidol 2.5 mg/ml
• Fentanyl 50 micro g/ml
• Lactic acid is added for adjustment of PH to 3.5.
• Droperidol produced hypnosis, sedation and antiemetic effects.
• Fentanyl produces analgesia.
Dose:
Induction of General Anaesthesia: 0.1 to 0.15 ml/kg
Maintenance of General Anaesthesia.
• Fentanyl 1-2 micro g/kg.
• Fentanyl 0.01 to 0.05 micro g/kg/min.
Sedation and Analgesia
• 0.5 to 1.0 ml I.V repeated and titrated.
• 1 to 2ml I.M.
• Dose should be reduced in hypovolemic and other high –risk
patients.
Pharmacology:
Respiratory System:
• Produces Respiratory depression.
• Respiratory effect is peripheral and central and is due to
Fentanyl.
Cardio Vascular System:
• It decreases arterial blood pressure
Mechanism:
• Droperidol produces alpha-adrenergic blockade.
• Heart rate decreases.
Mechanism:
• Fentanyl induced increase in vagal tone,
• It causes vasodilatation and hypotension.
Uses:
• It is used for Neuroleptanaesthesia (NLAN).
• Droperidol also used as antiemetic component in general
anaesthesia. Dose producing antiemetic is between 10 to 20 micro g/
kg.(0.6 And 1.25 mg for a 70 kg person).
Mechanism:
The chemoreceptor trigger zone is the emetic centre and “red”
astrocytes transport neurolept molecules from the capillary to
dopaminergic synapses in the chemoreceptor trigger zone where they
occupy GABA receptors.
• Used for intravenous sedation during conduction anaesthesia (2 to
4ml) in divided doses.
• Its use is best in middle ear surgery as there will be high incidence of
postoperative nausea and vomiting.
• Used as sedative-analgesic for sedation during diagnostic and
surgical procedures.
Side Effects and Contraindications:
• Muscle rigidity (is a consequence of Fentanyl compound).
• Respiratory Depression (Due to Fentanyl).
• Hypotension (Due to Droperidol).
• Prolonged somnolence (due to Droperidol).
• Extra pyramidal complications (manifested by dyskinesia, especially
of the face, neck and pharyngeal muscles, with speech and
swallowing difficulties). Treatment is Diphenhydramine and
benztropine.
• Hallucinations, Weightlessness and loss of body image.
• Rare complication is malignant neuroleptic syndrome (characterized
by hyperthermia muscular rigidity and autonomic instability, muscular
hyper tonicity is lead-pipe). Treatment is Dantrolene, Bromocriptine
(2.5 to 10 mg PO TID).

30
STEROID ANESTHESIA:
ALTHESIN:
Basic pharmacology:
1. It is mixture of two steroids Alphaxalone (3 alpha-hydroxy-5
alpha-pregnane 11, 20 dione) and alphadolone acetate (21-
acetoxy -3 alpha-hydoxy-5 alpha –pregnane -11, 20-dione)
2. Althesin is a clear, colourless, viscid solution, containing 9 mg
of alphaxalone and 3mg of alphadolone acetate per ml.
3. Althesin are solubilized in cremophor EL, which is then diluted
in water.
4. It has high therapeutic index.
Dose of Althesin:
• Induction dose: 40 to 125 micro g/kg
• Supplementation: Single dose of 100 micro g, regardless of
bodyweight.
Pharmacological Effects:
• Mild respiratory stimulation (increases respiratory rate)
• Significant fall in PaCO2 during air breathing.
• Mild sinus tachycardia, decreased in peripheral vascular
resistance.
• Hypotension is seen (20% fall in systolic pressure)
• Rapid induction of anaesthesia and high potency are known to
be associated with the free 3 alpha-hydroxy group as the steroid
molecule.
• Rate of recovery is faster; there is some euphoria on recovery.
The mean time is 25 mins.
COMMENT:
• They represent an unusually mechanism in the production of
anaesthetics state.
• Their clinical utility has been poor
• They are no more used.
EUGENOL DERIVATIVES:
PROPANIDID:
History:
• Synthesized by Hiltmann and designated as Bayer 1420.
• Introduced into clinical investigation in 1961.
Basic Pharmacology:
• It is extremely short acting
• Chemically the drug is 3-methoxy 4 (N-diethyl-caemidomethoxy)
phenylacetic acid –n-propylester.
• It is a yellow oil with boiling point of 210 degree C. PH of 7.0 to 7.4
• It is insoluble in water but is available in 10 ml vials as a 5% solution.
Dose:
• The recommended dose is 10mg/kg as initial and subsequent dose
being 5mg/kg.
Pharmacological Action:
• It is extremely rapid-acting agent.
• It produces unconsciousness and anaesthesia
• It produces excitatory side effects such as tremor (or) muscle
movement.
• Pupillary and corneal reflex remains active.
Respiratory System:
• There is marked hyperventilation and being followed by short period
of apnea.
• Increase in heart rate
• Hypotension

31
PROPANIDID.Continuation:
Metabolism:
It is rapidly inactivated by pseudocholinesterases found in blood
and liver.
• There is enzymatic splitting at the ester bond
• Excretion is rapid and 755 to 90% of the injected dose are
eliminated with 2 hrs.
• It may prolong the effects of succinylcholine because both these
drugs are metabolized by pseudocholinesterases.
Uses:
• As a sole agent in short procedures.
• Tooth extraction.
Side Effects:
Involuntary muscle movements.
Hiccoughs.
Hypersensitivity reactions
Prolongation of succinylcholine.
Type to enter text

32
2. Anti Hypertensive drugs & pharmacology.
Classification of Severity of Hypertension in Adults:
Severity Range (mm of Hg) Diastole
Normal <140 <90
Mild hypertension 140-159 90-99
Moderate hypertension 160-179 100-109
Severe hypertension 180-209 110-119
Very severe
hypertension
>210 >120
General Classification of Hypertension:
Systolic and Diastolic Hypertension:
• Essential Hypertension- Unknown aetiology
• Renal: Acute and Chronic G.N, Hydronephrosis, Reno-vascular
stenosis, renin producing tumours.
• Endocrine: Adrenal (Cushingʼs syndrome, Congenital adrenal
hyperplasia.)
• Phaeochromocytoma Carcinoid tumours, Corticosteriods.
• Neurogenic: GB syndrome, Increased ICP, Psychogenic.
• Miscellaneous: Coarctation of Aorta, Increased intravascular
volume PIH.
Systolic Hypertension with wide pulse pressure.
• Increased Cardiac Output – Arterio Venous Fistula,
Thyrotoxicosis, Fever,
• Rigidity of aorta – Arteriosclerosis.
• Systolic BP is known to rise with age, averaging about 1mm of
Hg rise each year age between 40 to 55 yrs. In women this
increase is greater averaging 1 to 2mm per year.
Classification of Anti Hypertensive Drugs:
1. Central adrenergic Blocking agents
a.Methyldopa b. Clonidine C. Guanabenz.
2. Alpha – Adrenergic receptor blocking agents
a.Prazocin b. Terazosin C. Phenotolamine d. Phenoxybenzamine.
3. Beta –Adrenergic receptor blocking agents
I. Propranolol. Metoprolol. Atenolol
II. Labetolol – Combined Alpha and Beta Blocker.
4. Vasodilator drugs.
• Arteriolar –Hydralzine, Minoxidil, diazoxide.
• Arteriolar + Venous –Sodium Nitroprusside, Pinacidil.
5.Calcium channel blockers.
• Verapamil b. Diltiazem c. Nifedepine d. Amlodipine Nitrendipine Laxidipine.
6. Angiotensin converting enzyme inhibitors
a.Captopril b. Enalapril c. Lisinopril d.Ramipril.
7. Diuretics
• Loop diuretic –Frusemide
• Thiazides –Hydrochlorothiazide
• Potassium Sparing – Spironolactone, Triamterene, Amiloride.
8. Angiotensin antagonist.
• Losartan
9. Adrenergic neuron blockers
• Reserpine, Guanethidine.
10. Ganglion blocking agents
• Pentolinium
11. Serotonin antagonist
• Ketanserin

33
Anti Hypertensive drugs & pharmacology.Continuation:
Central Adrenergic Blocking Agents:
• This group comprises a relative new approach to therapy of
hypertension. They act on the central alpha-2 receptors.
Methyldopa:
• One of the oldest and most widely used.
• It is the alpha-methyl analogue of dopa, the precursor of
dopamine and nor-adrenaline. The alpha-methyl nor-adrenaline
formed from methyl dopa in the brain is a potent alpha-2-
adrenergic agonist and it decreases the efferent sympathetic
activity.
Pharmacokinetics:
• Only less than 1/3rd of oral is absorbed.
• Dose -0.25mg-0.5mg BD/QID
• Duration of action 12-24hrs.
Clonidine:
• It is a synthetic central anti hypertensive that stimulates alpha-2
adrenergic receptors within the CNS.
• It stimulates alpha-2 adrenergic receptors and causes decreases
in sympathetic outflow →fall in BP and bradycardia.
• It also causes reduction in SVR, HR and Stroke volume.
Pharmacokinetics:
• Well absorbed orally
Dose -
• Start with 100 µgm OD/BD (300 µgm-max)
• Peak action 2-4 hours t ½-8 to12 hours.
• Duration of action -6 to 24hrs.
• Sudden withdrawal of oral clonidine causes a hypertensive crisis
that can be life threatening.
Alpha-Adrenergic Antagonist:
PRAZOSIN:
• It is a α-blocking drug that has specific α1-adrenergeic antagonist
properties it reduces mean arterial pressure and systemic vascular
resistance and heart rate is unaltered.
• Very effective in the treatment of patients with HTN an associated
renal failure.
Dose & Duration:
• starting dose 0.5mg HS and gradually increased upto 10mg BD.
• Onset of action 2-4hrs.
• Duration of action 8-10hrs.
Uses:
• Improves carbohydrate metabolism and counteracts insulin
resistance so suitable for DM patients.

34
Vasodilators drugs (peripheral):
HYDRALAZINE:
1. It causes direst relaxation of vascular smooth muscle
producing decrease in SVR and concomitant increased in HR
and contractility.
2. The vasodilation is due to nitric oxide generation and mediated
through cyclic GMP
Pharmacokinetics:
• Subjected to first pass hepatic metabolism
• 25mg to 50mg OD-PO. Peak effect 1-2hrs
• 10 to 20mg IM/IV very slow in hypertensive crisis
• Hypotensive affects lasts for 10-12hrs.
MINOXIDIL:
• It is a potent vasodilator and
• Its adverse effect was fluid retention and hypertrichosis.
Sodium Nitroprusside: (arteriolar and venous dilator)
• It is rapidly and consistently acting vasodilator. It relaxes both the
resistance and capacitance vessels. It reduces SVR and cardiac
output (decreased venous return). Myocardial work load is
reduced. Plasma renin is increased.
• The endothelial cells and RBC split the nitroprusside to generate
nitric oxide which relaxes vascular smooth muscle.
Dose:
• In hypertensive emergencies – 50mg added in 500ml of bottle.
• Infusion rate – 0.1mg/min titrated to response.
• It decomposes in alkaline PH and exposure to light so bottle
should be covered with black paper. It is converted to
thiocyanate in liver which is excreted slowly. If larger doses are
infused for more than 1 to 2 days excess thiocyanate may
accumulate and produce toxicity.
ACE inhibitors:
CAPTOPRIL:
• If effectively decreases BP in patients with renal vascular
hypertension
• It decreases BP by lowering SVR with little effect on cardiac output.
(Plasma renin activity increases sharply because the negative
feedback inhibition or angiotensin II is no longer presented).
• Marked drop in plasma aldosterone (All is a potent stimulation for
aldosterone)
• It can also increase plasma kinin levels and potentiate the
hypotensive action (but it doesnʼt inhibit the enzyme kinase I which
degrades the bradykinin).
Pharmacokinetics:
• 70% of oral administration is absorbed.(food in stomach reduces it
bioavailability)
• T ½ → 2hrs.
• Duration of Action → 6-12hrs; Peak action -1 hr
ENALAPRIL:
It is a prodrug converted in the body to enalaprilat (tripeptide analogue)
it is not used orally because of poor absorption. It has same
pharmacological and therapeutic effects of captopril. The other
advantages are.
• More potent
• Absorption not affect by food.
• Slow onset of action and longer duration of action (24hrs)
• Dose: 5 to 20mg OD. Peak action 4 to 6 hrs. T ½ -11hr >24hrs.

35
ACE inhibitors.Continuation:
LISINOPRIL:
• It is the lysine derivative of enalaprilat. Oral absorption is slow
and unaffected by food. However short term treatment (10wks)
causes a significant reduction in cardiac output.
• There is a decrease in venous return and intravascular volume is
redistributing from pulmonary bed to the periphery. There may
also be a negative inotropic effect.
Dose:
• 10 to 40mg OD. Peak action 6 to 8hrs, duration of action >24hrs.
Adverse effects:
• Hypotension-occurs in patients treated with diuretics.
• Hyperkalemia –decreased aldosterone → Na+ excretion and K+
retention.
• Cough –Brassy cough within 1 to 8wks.
Diuretics:
• Medium Efficacy Diuretics (Inhibition of Na+-Cl-symport)
• Benzothiadiazines –Chlorothiazide, hydrochlorothiazide, clopamide.
• Thiazide like-Indapamide.
Chlorothiazide (Benzothiadiazines):
• It is synthesized as a chronic anhydrase inhibitor variant in which
urine produced was rich in chloride ions.
• The primary site of action is cortical diluting segment or early distal
tubule (site 3). They inhibit the Na+-Cl- symport at the luminal
membrane.
• Under their action the Na+ reabsorption in the DT exchanges with K+
so that urinary K+ excretion is increased in parallel to the natriuretic
response.
• They tend to reduce GFR so that not effective in patients with low
GFR. They decrease Ca2+ excretion and increase Mg2+ excretion.
Pharmacokinetics:
Dose:
• 50-100mg morning (pts with oedema)
• 25-50 mg/day morning (pts with HTN)
Onset of action →1hr. undergoes hepatic metabolism and excreted.
Indications:
• HTN
• Hypercalciuria
• Oedema
• Diabetis insipidus
Contra indications: Renal failure.

36
ANGIOTENSIN ANTAGONIST:
LOSARTAN:
• It is a competitive antagonist of AT II and more selective for AT1.
It blocks al overt actions of AT II viz vasoconstriction, central and
peripheral sympathetic stimulation, release of aldosterone and
renal actions promoting salt and water reabsorption.
• Losartan causes fall in BP in HTN patients which lasts for 24 hrs
while HR remain unchanged. There is no significant effect on
plasma lipid profile, carbohydrate tolerance and insulin
sensitivity.
Pharmacokinetics:
• Oral absorption is not affected by food. Bioavailability is about
35% due to high 1st pass metabolism.
Dose:
• 50 mg OD
Use:
• Treatment of HTN but its maximum effect seen after 3-6 wks.
ADRENERGIC NEURON BLOCKERS:
RESERPINE:
• This class of drugs derived from plants of the genus
RAUWOLFIA, SERPENTINA (SARPAGANDHA)."
• It depletes stores of catecholamines and serotonin in many
organs including brain and medulla.
• It causes a slow decrease in BP, frequently associated with
Brady cardia.
• Chronic administration results in a reduced cardiac output.
Dose
• 0.25 mg/day.
• Major drawback being incidences of nightmares and psychic
depressions.
Hypertensive emergencies
• Neurologic conditions such as hypertensive encephalopathy and
cerebrovascular accidents may be the result of hypertension.
Hypertension may be exacerbated by CVA. Head injury and
intracranial mass often induce hypertension. Eclampsia is
characterized by marked hypertension, convulsions etc.,
• Cardiovascular conditions like dissecting aortic aneurysms, angina,
acute LVF, myocardial infarction with refractory hypertension,
postoperative hypertension – all require prompt management.
• Renovascular hypertension and hypertension due to chronic renal
failure need therapy. Hypertension after renal transplant, due to
stenosis at anastamotic site, will jeopardize the graft.
• In catecholamine – related crises as is Phaeochromocytoma which
can cause serious dysrhythmias and pulmonary oedema, the use of
beta blockers, vasodilators, alpha blockers and magnesium sulfate
before the during surgery are of vital importance. Rebound
hypertension may occur after cessation of therapy especially with
clonidine and ganglion blockers.
Management of hypertensive emergencies:
• Calcium Channel Blockers: Sublingual nifedipine 5-10mg should not
be used; the intravenous preparation is unavailable for commercial
use as it is photodegradable and hence short half-life. – Sublingual
not used any more.
• Sympathetic inhibitors: Labetolol shows great promise and is used
as a mini bolus or continuous infusion which is effective within
5-10min average preoperative effective dose being 200mg.
orthostatic hypotension is observed. Transition to oral therapy is not
difficult.
• Beta Blockers: Esmolol is probably the fastest acting drug to control
blood pressure. Dose. 25-300μg/kg/min.
• ACE Inhibitors: Captopril 0.5-1.0mg/kg. Bolus has its onset of action
in 3-5min., peak action at 20min. and duration of action of hours.

37
3. Preoperative usage Antihypertensives:
• These drugs have been used extensively in both acute as well
as chronic control of hypertension.
• In essential hypertension calcium channel blockers, beta
blockers and ACE inhibitors should be continued on the morning
of surgery; most patients are on combination therapy.
• Ischaemic Heart Disease: Coronary Vasodilation is achieved
using calcium channel blockers. Beta blockers, by reducing the
heart rate and oxygen consumption, help in decreasing
myocardial ischemia and reducing arrhythmias.
• Dysrhythmias. Calcium channel blockers and beta blockers are
useful to control supraventricular dysrhythmias and digitalis
toxicity. They reduce automaticity and delay conduction in A-V
node. Verapamil is used in a dose of 0.1mg/kg. Infused over
3-5min.magnesium is useful for intractable ventricular
dysrhythmias.
• Calcium channel blockers are useful as adjuvant for inducing
hypotension in neuro surgery and cardiac procedures.
Premedication with Metoprolol followed by infusion of esmolol
25-300µg/kg/min. has been used to control blood pressure and
reflex tachycardia.
• Tachycardia and hypertension due to laryngoscope intubation,
sternotomy, skin incision, and manipulation of organ etc., can be
minimized with esmolol and verapamil. Magnesium sulfate has
also been useful especially during laryngoscopy at 40mg/kg
bolus.
• Calcium channel blockers have been used to prevent malignant
hyperthermia, bronchospasm, and cerebral arterial spasm.
• To control postoperative hypertension following CABG, apart
from SNP, NTG, or labetalol, esmolol can also be used, in a dose
of25-300µg/kg/min.
• Calcium channel blockers, magnesium sulfate and beta blockers
have been used for myocardial protection in cardioplegia.
Type to enter text

38
4. Anti Hypertensive Classification according to the site of action.
Drugs acting centrally α2 adrenergic agonists:
• methyldopa, clonidine.
Drugs acting on autonomic ganglia:
• Hexamethonium
• Trimethaphan
Drugs acting on post ganglionic sympathetic nerve endings:
• Adrenergic neuron blockers – Guanethidine
• Catecholamine depletors – Reserpine
Drugs acting on adrenergic receptors
• α adrenergic blockers à phentolamine (α1) Prazocin doxazocin,
Phenoxybenzamine (α1 and α2)
• β adrenergic blockers à propronolol, atenolol etc
• α and β adrenergic blockers à labetolol, carvedilol
Drugs acting directly on vascular smooth muscle (vasodilators)
• Arteriolar vasodilator à Ca+2 Ch blockers, hydralazine,
diazoxide, minoxidil
• Arteriolar venular vasodilator à SNP
Potassium channel activators
• diazoxide, minoxidil, nicorandil
Drugs which block renin-angiotensin-aldosterone axis
• Block renin release - β blockers
• ACE inhibitors – captopril, enalapril etc
• Angiotensin II receptor blockers – Losartan
• Counteract action of aldosterone – spironolactone
Diuretics
• Thiazide
• Potassium sparing diuretics
• Loop diuretics
I. Noradrenaline:
• α1 + α2, β1 + β3
• (no β - 2 action)
Dose:

• 2
to
4
µg/min

• I.V.
infusion

II. Adrenaline:
• α1 + α2, β1 + β2
Dose:
• 0.2
to
0.5
mg
s/c
(or)

I.V. infusion:
0.01 to 0.5 µg/kg/hr

39
5. Anti Anginal Drugs and its pharmacology.
Anti-anginal drug classification
I. NITRATES
• Short acting: Glyceryl trinitrate (NTG)
• Long acting: Isosorbide dinitrate. Isosorbide mononitrate
II. BETA-BLOCKERS
• Propranolol, Metoprolol
III. CALCIUM CHANNEL BLOCKERS
• Phenyl alkylamine - verapamil
• Benzothiazepines - diltiazem
• Dihydropyridines - nifedipine, nicardipine, amlodipine,
nimodipine
IV. POTASSIUM CHANNEL BLOCKERS
• Nicorandil, pinacidil
Nitroglycerin
• It is a smooth muscle relaxant causing vasodilatation. It
interacts with the sulphydryl group (SH) present on the surface
of smooth muscle cells and cause vasodilatation.
Mode of Action with Physiological Effects:
• The important effect of systemic and regional venous dilation.
Since 70-75% of blood is stored in venous capacitance
system, venodilation markedly reduce venous pressure.
Venous return to heart and cardiac filing pressures. Primarily
venodilation occurs in the splanchnic capacitance system.
• At low doses it increases the distensibility and conductance of
large arteries with no change in SVR.
• At higher doses it dilates arteries. This is important so that
when after load decreases preload also decreases. In MI
patients NTG preferentially reduce cardiac preload while
maintaining systemic perfusion pressure.
• NTG causes venodilatation of pulmonary artery and veins and
decreases RA, pulmonary artery and pulmonary capillary wedge
pressure. Renal artery, cerebral artery and cutaneous vessels also
dilate with NTG.
• In coronary circulation NTG is a potent epicardial coronary artery
venodilator (normal and diseased vessel).
• A stenotic lesion dilates with NTG thus reducing resistance to
coronary blood flow and improves myocardial ischaemia.
• Smaller coronary artery dilates more than large ones.
• Effective in preventing or reversing coronary artery vasospasm
(stenotic arteries).
• Increases coronary collateral vessel diameter and enhances
collateral flow.
• Initial short lived increases in coronary blood flow, later reduction in
coronary blood flow as MVO2 decreases.
Preparation and Dosage.
• Sublingual NTG.
• Sublingual bioavailability - 80%
• Bypasses and high first pass biodegradation in liver by nitrate
reductance to glycerol dinitrate and nitrite.
• Plasma half life - 4-7min.
• A tablet which adheres to buccal area between the upper lip and
teeth has rapid onset and longer half life than sublingual doses.
Dose OA Peak
Action
Duration
of

action
Sublingual NTG O.03-0.8mg 2-5 min 4-8min 10-30min
Sublingual ISDN 2.5-10mg 5-20min 15-60min l-3hrs
Oral NTG 0.4mg 2-5min 4-8min 10-30min
Buccal NTG l-3mg 2-5 min 4-10min Vi -4hrs.

40
Anti Anginal Drugs and its pharmacology.Continuation:
a. NTG Ointment and patches:
• Readily absorbed through skin - longer lasting effects.
• Adequate blood level concentration - 20-30min.
• Duration of action - 4-6hrs
• It is administered as inches. 15mg/inch (four times daily).
• Patches - contain either liquid NTG or NTG bonded to polymer
gel.
• Adequate blood level cone: 20-30min.
• Steady state after 2hrs and may be maintained upto 24hrs.
• It contains NTG concentration / cm2 and total dose varies from 5
and 30mg.
• Doses of 15mg or higher / day are usually required for relief of
myocardial ischaemia.
b. Intravenous NTG:
• It is available since early 1980's an injectable form with stable
shelf half life in a 5mg/ml solution of 70% alcohol.
• Blood levels are achieved instantaneously and arterial dilating
doses with resulting hypotension may occur quickly. Dose of
5-10µg/min (Arterial dilation - 150µg/min).
• The dosage of NTG available in less when administered in
plastic bags and polyvinyl chloride tubing because of absorption
by the bag and tube.
Indication:
Myocardial ischaemia
• Decreased LV preloaded.
• Decreased LV after loaded.
• Increases coronary circulation.
Myocardial infarction.
• Limits infarct size.
• IV - NTG over 48hrs may improve overall mortality
Effective in treatment of pulmonary edema.
• Reducing ventricular volume and pressure.
• Improve ventricular function by reducing ischaemia induced
wall motion abnormality.
Acute mitral regurgitation improves with NTG (Arterial dilation - good
forward stroke volume and reduces regurgitation fraction).
• Arrhythmias - Myocardial ischemia is a common cause for
arrhythmia. NTG have some anti arrhythmic properties and reduce
ventricular fibrillation.
• Congestive heart failure - the reduction in preload and afterload
improve CHF symptoms and forward stroke volume. Nitrates
maintain their effectiveness in reducing cardiac filling pressure,
exercise capacity improves and vasodilator therapy reduces
mortality.
Contraindication:
1. Hypotension 2. Raised ICP 3. Glaucoma
Drug Interaction:
• With calcium channel blocker - orthostatic hypotension
• With anti HTN and alcohol - severe hypotension
Side effect:
• Meth-Haemoglobinuria (dose of 5mg/kg/day should be avoided).
• Tolerance to NTG.
• Rebound phenomena causesʼ coronary vasospasm, myocardial
ischemia infarction.
• Interferes with platelet aggregation - ability to get adhered with
damaged intima is reduced.
• NTG may induce resistance to the anticoagulant effect of heparin.
• Flushing, headache, tachycardia, nausea, vomiting.

41
Anti Anginal Drugs and its pharmacology.Continuation:
ISOSORBIDE DINITRATE:
• It has similar properties of that of GNT. It can be used
sublingually at the time of attack. It is having a slight slower
action than GTN, peak effect at 5 to 10 min elimination half life
being 40min, but sustained release formulation may afford
protection for 6 to 10 hrs.
ISOSORBIDE MONONITRATE:
• This is a active metabolite of Isosorbide dinitrate. When
administered orally it undergoes high first pass metabolism.
POTASSIUM CHANNEL BLOCKERS:
• Minoxidil and diazoxide are K+ channel openers which have
been used since long in severe HTN and hypertensive crisis. K+
channel openers like Nicorandil, Pinacidil have been developed
recently.
• Diazoxide and some other reduce insulin secretion while
sulphonylureas cause hypoglycemia by blocking potassium
channel in pancreatic beta cells and releasing insulin.
NICORANDIL:
• This drug activates ATP sensitive potassium channels -
hyperpolarizing vascular smooth muscle. It also acts as a nitric
oxide-relaxes blood vessels by increasing cGMP. Thus the
arterial dilatation is coupled with venodilatation. Coronary flow is
increased. It does not alter the cardiac contractility and
conduction properties.
• Dose: 5 to 20mg BD.

42
Porphyrias:
• Inborn error of metabolism
• Essential for many vital physiologic functions of oxygen transport
storage.
• Aminolevulinic acid synthetase (ALA synthetase) present in
mitochondria.
• Controlled by endogenous concentration of heme
Sign & Symptoms:
• Abdominal pain
• Autonomic nerves system instability.
• Electrolyte imbalance
• Neuropsychiatric manifestations
• Skeletal muscle weakness (Quadriperesis)
• Cranial Nerve palsies, UMN
• Seizures
• Tachycardia and increase BP
Diagnosis- increased blood concentration of ALA synthetase
Treatment:
• Removal of triggering factor
• Adequate hydration and carbohydrates
• Opioids for pain
• Antiemetic (N and V)
• Beta Adrenergic blocker (to control tachycardia and systemic
hypertension)
• Anticonvulsants
• Benzodiazepines
• Haematin 3 to 4 mg/kg over 20 m.
6. Porphyrias.

43
7. Cardiac Glycosides
DIGOXIN"
One drawback of Vaughan Williams Classification scheme is that it
fails to incorporate the anti-arrhythmic drug effects to cardiac
glycosides. Primary therapeutic use of this group is
1. Increases the force of cardiac contraction.
2. Slowing of ventricular response rate during AF / atrial flutter.
3. Inhibition of membrane bound sodium-potassium dependent
Atelectasis.
• Binds to the sodium potassium ATPase and produce complete
inhibition of transport process.
• The elevated intracellular sodium increases the
availability of calcium to contractile proteins and increases
contractility.
• Digitalis exerts its positive inotropic effect independent
of catecholamine liberation.
CVS effects:
1. Augments both force and velocity of concentration in failing
heart and in non failing heart without increase in cardiac output.
2. Ventricular end diastolic pressure and volume is decreased.
3. Heart size decreases so decreased myocardial wall tension,
decreases myocardial oxygen consumption and angina.
4. Digitalis increases systolic arterial pressure, pulse pressure,
PVR in normal patients.
5. It decreases systemic resistance and venomotor tone in
patients with heart failure.
6. Appears to normalize the baroreceptor and other
neuroendocrine responses to heart failure.
7. Because of its weak inotropic effect digitalis is used adjuvant to
ACE inhibitors and diuretics to increase ejection fraction and
exercise tolerance in chronic CHF.
8. Digoxin therapy wonʼt improve survival but reduce rate of
hospitalization for worsening heart failure.
Indications for digoxin therapy:
Digoxin beneficial
1. Patients with moderate or severe systolic LV dysfunction.
2. Patients with acute MI and atrial fibrillation.
3. Patients with CHF associated with atrial fibrillation
Unclear Digoxin indication
• Patients with decreased LV ejection fraction after acute MI. Digoxin
probably not indicated
• Patients with acute MI with sinus rhythm and mild heart failure.
• Patients with isolated RV failure. Dosages
• For rapid digitalization in un-digitalized patients in heart failure
Dose:
• Oral dose à 7.5µg/kg in 3 divided doses
• Maintenance dose à 0.125-0.5mg daily
• IV à 0.5-0.75mg (l-3hrs)
• Increment dose à 0.125 -0.250mg upto 2mg
• Maximum effect seen à l-3hrs
• Complete digitalization à with in 12hrs
• IM à pain at injection site and delayed absorption and low
concentration
Contraindication
• Hypoxia
• SA node dysfunction
• Decreased potassium concentration
• Increased calcium
• Hypertrophic cardiomyopathy

44
Cardiac Glycosides. Continuation:
Anesthetic significance
Anesthetic agents which increase tolerance to digoxin are
• Ketamine
• Isoflurane
• Euflurane
• Methoxyflurane
• Diethylether
Toxicity
• Can occur in any patients. Hypothyroid patients are more prone.
• It is enhanced by hypoxia, decreased magnesium, increased
calcium and decreased potassium concentration.
• Enhanced by administration of propranolol, diuretics,
amiodarone, and verapamil.
Symptoms
Cardiac symptoms to toxicity
• Enhanced automaticity
• AV block
Extra cardiac symptoms
• Nausea, vomiting, anorexia, diarrhea, confusion, dizziness,
syncope.
Management:
1. Discontinue the treatment
2. Diuretic causing potassium loss and infusion of carbohydrates
which cause intra cellular movement of potassium should be
avoided.
3. In digitalis induced arrhythmia à lignocaine, phenytoin, and
propranolol or DC shock.
ADENOSINE
• It is an endogenous molecule produced as an intermediate
metabolite of adenosine monophosphate; adenosine has a short half
life in plasma (l-2sec) because of metabolites. It exerts its cardiac
and venous effects by binding with G proteins. Cardiac
electrophysiological effect:
• Mediated through A1 receptor and consists of negative chronotrophic,
dromotropic, inotropic actions.
• It decreases SA node activity and AV nodal conductivity and
ventricular automaticity.
• It ventricular myocardium adenosine antagonizes the stimulation of
inward calcium current produced by catecholamines.
• The primary anti arrhythmic effect of adenosine is to interrupt re-
entrant AV nodal tachycardia.
Dose:
• Rapid IV bolus à 100-200µg/kg
• Continuous infusion à 150-300µg/kg/min
• In adults (practical purposes) à IV of 6mg given bolus followed by
second dose 12mg after 1min of 1st dosage if 1st dosage is not
effective.
• This therapy rapidly interrupts SVTs caused by re-entry mechanisms
• Faster onset of action and rapid elimination

45
8. Anti-Arrhythmic Drugs & its pharmacology.
Classification of anti-arrhythmic drugs (Vaughan Williams
Classification)
CLASS I MECHANISM
Membrane stabilizers
Blocks the inward sodium current in tissue
with fast response action potentials.
Drugs that reduce maximal velocity of
phase of depolarization
CLAS S IA
- Quinidine
- Procainamide
- Disopyramide
- Diphenylhydantion
Decrease V max at all heart rates
Increases AP duration
CLASS IB
- Lignocaine
- Phenytoin
- Tocainide
- Mexiletine
Decreases V max in partially depolarization
cells.
Little effects at slow rates on V max in normal
tissue
No changes in AP duration
CLASS IC
- Felcainide
- Propafenone
- Moricizine
Minimal effect on action potential
Profoundly slows conduction velocity
Decreases V max at normal rates in normal
tissues
CLASS II
Beta Adrenergic receptor
antagonist
- Propranolol
- Metoprolol
- Esmolol
Decreases S.A. nodal automatically
Increases A.V. nodal refractoriness
Decreases A.V. nodal conduction velocity
CLASS III
Drugs Prolonging Depolarization
- Bretylium
- Amiodarone
- Sotalol
1. Prolong A.P. duration in tissues with fast
response action potential
CLASS IV
Calcium Antagonists
- Verapamil
- Diltiazem
Decreases conduction velocity
Increases refractoriness in tissue with slow
response action potentials.
FOR A-V BLOCK - Atropine
DRUGS THAT CANNOT BE CLASSIFIED BY THIS SCHEME:
• Digitals " "
• Adenosine"
• Alinidine
CLASS-1A
QUINIDINE:
• It is an alkaloid from cinchona bark. Class-IA drug effective in acute
and chronic SVT. Clinically it is used in oral forms to treat both atrial
and ventricular arrhythmias.
• It decreases the slope of phase 4 diastolic depolarization and
increase threshold potential.
• It depresses the cardiac contractility and high doss dilates blood
vessels there by vasodilatation.
• Infra-nodal conduction is slowed at high doses and cause bundle
branch block, complete heart block or asystole.
• This drug abolishes re-entry tachyarrthmias.
• Prolonged ERP in atria.
Dose: It can be given orally and parenterally. The hypotensive effect is
the principal limitation to its IV route.
• 300 to 600mg PO. Half life elimination - 6 to 7hrs.
Side effects:
• Most serious is of cardiac mainly affecting its conduction. Monitoring
with ECG is a useful guide to its therapy. Various degrees of
conduction block at both atria and ventricular level seen.
• Quinidine syncope - ventricular tachyarrhythmias produced
by Q-T interval prolongation.
• Thrombocytopenia and hypersensitivity.
• Tinnitus, visual disturbances, headache, confusion.

46
Anti-Arrhythmic Drugs & its pharmacology. Continuation:
Indications of QUINIDINE:continuation:
• Prevent recurrence of SVT and to suppress ventricular
premature beats.
• SVT with WPW syndrome are effectively suppressed.
Contraindications:
• Persons with pre-existing prolongation of Q-T interval or A-V
block in ECG. Anesthetic implication: It accentuates the effect of
NMJ blockade.
PROCAINAMIDE:
• It is an amide derivative analogue of local anesthetic procaine. It
is effective treating ventricular tachyarrhythmias but not effective
in abolishing atrial tachyarrhythmias.
• It decreases the maximum velocity of phase of depolarization.
• Decrease amplitude during phase O and rate of phase 4
depolarization.
• Prolongs ERP in atrial and His-purkinje portion.
Dose:

• 500 to 600mg Q4H or 500mg/kg/day PO. Onset of action 1 to
2hr T 1/2-3to4hr.
• IV- 1.5mg/kg given at 5min interval up to therapeutic level. Onset
of action within maintenance infusion - 20 to 80 gm/kg/min.
Indications:
• Premature ventricular contraction and paroxysmal ventricular
tachycardia.
DISOPYRAMIDE:
• Although chemically different from quinidine and procainamide it is
effective in suppressing atrial and ventricular tachydysarrhythmias. It
has prominent cardiac depressant and anticholinergic actions, but
not alpha adrenergic blocking properties.
• Conduction through AV node may be facilitated because of its
indirect vagolytic effect.
• Potent negative inotropic drug and after IV use systemic vascular
resistance reflexly increases.
Disadvantages:
• The marked negative inotropic and anticholinergic effects limit the
usefulness of the drug.
• Should not be used for ventricular tachyarrhythmias caused
by prolonged repolarization.
Dose:
100-200mg Q6H: t½ à hrs: Onset of action à 30 - 60min

47
Anti-Arrhythmic Drugs & its pharmacology. Continuation:
CLASS IB:
LIGNOCAINE
• It is a widely used cardiac anti arrhythmic and local anesthetic
(molecular weight -288; Pka - 7.86). It is an amide group of drug.
It is white or slightly yellow crystalline powder with a
characteristic odour. Solutions are very stable. It has become the
clinical standard of treatment for ventricular arrhythmias,
effective in suppressing re-entry cardiac disarrhythmias (PVC).
1. Occurs more frequently than 5/min
2. Are closely coupled to T wave.
3. Originate in multiple foci.
4. Appear in groups of 2 or more.
Lignocaine is useful when used prophylactically for acute MI to
prevent life threatening ventricular arrhythmias such as VF and VT.
• Therapeutic blood concentration depresses the slop of phase 4
diastolic depolarization in purkinje fibres.
• It interferes with SA nodal activity when there is a pre-existing
SA node disease.
• Lignocaine increases VF threshold.
• In purkinje fibres it increases transmembrane potassium
conductance.
• In partially depolarized initial membrane potentials, lignocaine
decreases fast channel sodium response.
• Lignocaine may be ineffective in hypokalemia patients.
• Conduction velocity is significantly decreased in ischaemia tissue
and not affected in normal tissue.
• In therapeutic doses of lignocaine no significant effect on QRS
and Q-T interval seen.
Routes of administration and Dosage:
• Initial bolus dose of 1 - 1.5mg/kg followed by infusion dose of
20-50µg/kg/min.
• 50% reduction of initial bolus dose should be given to patients with
decreased CO, decreased hepatic blood flow or CCF.
• Lignocaine for IV purpose is different from others because it contains
no preservative.
Metabolism and Excretion:
• Plasma protein binding à 65%
• Hepatic excretion - 60-70%
• Metabolites
1) Monoethylglycine à Possess anti arrhythmic effects
2) Glycine
Metabolic products eliminated from kidney.
Side effects:
• CNS manifestations à Drowsiness, dis-orientation, muscle -
twitching hearing abnormality and culminating in seizures.
Anesthetic significance:
• Prolong the action of Succinylcholine (inhibition of Ach release and
post junctional effects inhibit plasma Cholinesterase activity).

Pharmacology DNB Q & A.pdf

Recommended

Recommended

More Related Content

Similar to Pharmacology DNB Q & A.pdf

Similar to Pharmacology DNB Q & A.pdf (20)

Recently uploaded

Recently uploaded (20)

Pharmacology DNB Q & A.pdf