Speaker : Dr.

Vijaylakshmi
THIOPENTONE SODIUM
Rapidly acting barbiturate IV induction agent.

Chemical structure:
5 ethyl ( 1-methyl butyl )- 2 thio barbituric acid.

 First used in human beings on march 8th 1934 by Dr.

Ralph M Waters.
 In june 1934 John S Lundy started the clinical trial at
Mayo clinic at the request of Abotts.
 Physical properties:
 pH -10.5, pKa -7.6.

 Preservative:
 6% sodium carbonate – prevents precipitation of barbituric
acid by atmospheric CO2.
 Space above the powder in the vial is filled with nitrogen
instead of air to prevent precipitation.

 Shelf life:
 powder form of thiopentone is stable at room temperature
indefinitely. After reconstitution, refrigerated solutions are
stable for upto 2 weeks and at room temperature they are
stable for 6 days
Structure activity relationship:
side chain at no.5 carbon position is responsible for
hypnotic activity.
Sulphur atom at no. 2 carbon position is responsible for
increased potency, increased lipid solubility, rapid and short
duration of action.

Mechanism of action:
it activates the GABA receptor complex, opens the
chloride channels and hyperpolarizes the post synaptic
membrane therby inhibits the post synaptic neurons (GABA
mimetic).
also decreases the rate of dissociation of GABA from the
receptors and increases the duration of GABA activated
chloride channel opening (GABA facilitatory).
 Pharmacodynamics:

 Central nervous system:

 decreases cerebral blood flow (CBF), CMRO2,
 thereby decreases the ICP.
 It acts as a free radical scavenger,
 has anti epileptic properties,
 produces burst suppression of EEG
 hence used as a cerebral protective agent
 Produces hypnosis.
 Cardiovascular system:

 In therapeutic induction doses,(3 – 5 mg/kg), when given

slowly in normal persons it doesnot produce myocardial
depression and doesnot decrease peripheral vascular
resistance but produces venodilatation and increases heart
rate. Doesnot produce significant change in cardiac output.

 But when given rapidly or in high doses and in patients with

cardiac diseases and hypovolemic states, produces severe
myocardial depression, decreases peripheral vascular
resistance and venodilatation producing severe reduction in
cardiac output.
 Respiratory system:
 it’s a central respiratory depressant, brief period of apnoea is
very common with induction doses.
 In lighter planes, it sensitizes the laryngeal & bronchial
reflexes thereby producing laryngospasm and
bronchospasm.

 Other effects:
 decreases hepatic blood flow,
 renal blood flow and GFR.
Pharmacokinetics:

 causes unconsciousness in 30 sec.

 consciousness returns due to rapid redistribution from the
brain to the inactive tissues in about 5 – 8 mins
 highly lipid soluble,protein binding – to albumin, 72 – 86%.

Metabolism

 10 -25% is metabolized each hour.

 Metabolized to hydroxy thiopentone and carboxylic acid
derivatives.
Indications:
 Most popular IV induction agent.
 As a sole anaesthetic agent for short procedures.
 As a cerebral protective agent in head injuries.
 As an antiepileptic.
 Narcoanalysis.

Contra indications:
Absolute:
 acute intermittent porphyria (enzyme inducing property in
liver)
 Low cardiac output states: hypovolemia, shock, valvular
heart diseases, cardiac failure, constrictive pericarditis.
Dosage:

 IV induction – 3 – 5 mg/kg, children – 5 - 6 mg/kg, infants - 7

– 8 mg/kg.

 Infusion for brain protection – 150 – 200 µg/kg/min after

loading dose of 25 mg/kg.

 Anti epileptic dose – 1mg/kg

Side effects:
 Accidental intra arterial injection- produces crystallization,
blocking of the arterioles, release of kinins and vasospasm
leading to severe pain and gangrene of the limb.
 Prevention
 donot use anticubital veins for injection,
 use only 2.5% of the drug.
 Treatment:
 Stop further injection,
 retain the needle in the artery,
 drug dilution using saline,
 injection of vasodilators like papaverine, lignocaine ;
 stellate ganglion block or brachial plexus block
PROPOFOL

ultra short acting non barbiturate IV anaesthetic

agent.

 Chemical structure
 2,6 – di isopropyl phenol – a derivative of phenol oil at
room temperature and non soluble in water.

 Propofol emulsion contains

 1% propofol with
 soyabean – 10%,
 glycerol – 2.25%
 egg phosphatidyl 1.2%
 Milky white in colour due to preservative.

 Propofol emulsion readily supports bacterial growth.

 Bacteriostatic agent is added – either

 EDTA (0.005%) or
 sodium metabisulphite (0.025%) or
 benzyl alchohol (0.1%).

 Once opened, the vial should be discarded after 6 hrs.

Pharmacodynamics

 Central nervous system – effects similar to thiopentone.

 Acts on GABAA receptors.
 Decreases CMRO2, cerebral blood flow and intra cranial
pressure.
 Has neuroprotective properties like thiopentone, but increased
hypotension can decrease cerebral blood flow & cerebral
perfusion pressure.
 Sedative doses unlike thiopentone doesnot produce hyperalgesia.
 Also produces significant amnesia.
 Induction doses causes non epileptic myoclonic movements.
Respiratory system

 depresses respiratory center,

 induction doses produce apnoea for a few minutes.
 Airway reflexes are obtunded & incidence of cough &
laryngospasm are greatly reduced ,useful for LMA insertion.
 Produces bronchodilatation and hence advantageous in
hyperactive airway diseases.
Cardiovascular system

 produces greater decrease in blood pressure than thiopentone.

 Decreased myocardial contractility,
 decreased venous & arteriolar peripheral vascular resistance
leads to decrease in both preload & afterload.
 Blunts barostatic reflex – slower heart rate for a given decrease
in blood pressure.
Other effects

 decreased renal blood flow & hepatic blood flow.

 Decreased PONV,
 has antipruritic effect,
 has arrhythmic effect.
 Safe in patients with porphyria & malignant hyperthermia.
Pharmacokinetics

 Lipid siolubility – most lipid soluble drug used in medicine.

 Oil/water partition co-efficient is 4700 – 10 times higher than
thiopentone.
 High lipid solubility & increased blood flow to the
brain→faster onset of action.
 Protein binding – 98% protein bound. To be given in lesser
doses in patients with hypoproteinemia.
 Redistribution – redistribution half life is 1 – 2 min. effect is
terminated due to redistribution from brain to skeletal system in
3 – 5 min
Metabolism & elimination

 terminal half life – 4 – 6 hrs.

 Undergoes hydroxylation & conjugation in liver.
 Has high hepatic extraction ratio.
 60% metabolism in liver & 40% in the kidneys.
Factors affecting pharmacodynamics and
pharmacokinetics

 elderly patients require less dose - ↓sensitivity of the brain & ↓

plasma protein concentration & ↓hepatic blood flow.

 Hypovolemic patients and cardiac patients require titrating

doses.
Dosage
 Induction – 1.5 – 2.5 mg/kg body wt.
 Maintenance of anaesthesia -
 following induction bolus – 100 – 200 µg/kg/min.
 doesnot accumulate like thiopentone.
 Context sensitive half life – rule of thumb is to take the value
of 11 min for a 1 hr infusion & add to that 4 min for each
additional hour of infusion.
 Sedation – loading dose of 0.5 to 1 mg/kg, followed by an
infusion of 25 – 75 µg/kg/min.
Adverse effects
 Pain on injection – probably due to the free concentration of
propofol in the aqueous phase of emulsion. Free propofol
exerts painful effect by stimulating kallikrein kinin system →
bradykinin release →stimulates intravascular nociceptors.
 IV lidocaine (0.5 mg/kg) given 30 to 120 sec before with a
rubber tourniquet on the forearm, decreases pain. This method
is surerior to mixing lidocaine with propofol.
 Long term infusion can result in hypertriglyceridemia &
pancreatitis.
 Propofol infusion syndrome – long term infusion
→rhabdomyolysis, metabolic acidosis, cardiac & renal failure.
KETAMINE

 Phencyclidine derivative.
 Weak base – pKa – 7.5
 Racemic mixture of 2 isomers, s – isomer is more potent
anaesthetic with fewer side effects.
 Preservative – benzalkonium chloride.
Pharmacodynamics

 Central nervous system

 produces dissociative anaesthesia.
 Dissociates thalamocortical system from limbic system
 . Patients appear to be dissociated from the environment.
 Depresses CNS by blocking the NMDA receptors.
 Ketamine causes profound analgesia.
 ↑cerebral blood flow, CMRO2, & intracranial pressure – not ideal
for neurosurgery & patients with raised intracranial pressure.
 Produces emergent phenomenon, can be prevented by prior
administration of benzodiazepines – not recommended in patients
with h/o psychiatric disease.
 Can stimulate seizure focus – not indicated in epileptic patients.
 Cardiovascular system

 ↑myocardial contractility, heart rate, systemic vascular

resistance, blood pressure & cardiac output → indirect
effects of increased centrally mediated release of
catecholamines from adreal medulla –
 not indicated in patients with coronary artery disease and
hypertension.
 Drug of choice in patients with hypovolemia and low
cardiac output states and also in patients with rt →lt shunts.
 Respiratory system
 little effect on ventilatory drive in normal persons.
 Can produce apnoea in infants & neonates when given
intravenously.
 Produces Bronchodilatation – useful in patients with bronchial
asthma.
 Near normal airway reflexes are preserved.
 Induces copius salivation, hence an anti sialogogue drug has to be
administered.

 Other effects:
 High risk of PONV.
 Prevents post operative shivering.
 Per operative analgesic dose decreases post operative morphine
requirement.
Pharmacokinetics

 IV induction – rapid loss of consciousness, awakening much

slower.
 Redistribution half life – 11 to 17 min.
 Metabolized to nor Ketamine then to inactive glucuronide in
liver. Nor Ketamine is 1/4th as potent. Small fraction is bound
to plasma proteins.
Clinical use:

 For induction – IV 1- 2 mg/kg. IM – 5 – 10 mg/kg

 For analgesia – 0.15 – 0.3 mg/kg – extensively used for burns

dressing.
 Oral premedication in children – 3 – 6 mg/kg keatmine + 0.25
– 0.5 mg/kg midazolam.
 Ketamine and midazolam are the only two induction agents
which have reliable and predictable absorption with minimal
pain following intramuscular injection.
 Can also be used for epidural analgesia at 0.5 - 1 mg/kg
body wt.
 Intrathecal route – 1 - 1.5 mg/kg body wt – can be used as the
sloe drug for superficial surface surgeries like skin grafting.
side effects

 emergence reaction.
 contraidicated-
 pts with high icp, icsol,
 open eye injury,,
 vascular anneurysms,
 pts with psychiatric disorders(schizophrenia)
BENZODIAZEPINES

 midazolam was synthesised in 1976

 history: diazepam was first described for iv anesthetic

induction in 1965.
MIDAZOLAM

 physicochemical properties:

 midazolam solution (1-5mg/ml) contains 0.8% sodium cl,

0.01% disodium edetate,1% benzyl alcohol as preservative.
 ph-3.
 highly lipid soluble accounts for rapid CNS effect and large
VD
Metabolism:

 biotransformation of bzds occur in liver. hepatic microsomal

oxidation and glucuronide conjugation.
 age, smoking, no effect on midazolam biotransformation.
 alcohol consumption increases biotransformation of
midazolam.
 excreted largely by kidneys, can cause profound sedation in
patients with renal impairment.
 Pharmacokinetics:

 midazolam is a short acting drug with clearance rate 6-

11ml/kg/min, as compared to lorazepam .8-1.8ml/kg/min, and
diazepam .2-.5ml/kg/min.
 termination of action is primarily by redistribution.
 age, gender, race, enzyme induction, hepatic and renal diseases
are factors influencing pharmacokinetics.
 in obese pts VD is increased as drug accumulates in adipose
tissues, elimination ½ life prolonged.
Pharmacodynamics
 Central nervous system:
 dose related reduction in cmro2 , cerebral blood flow by 34%
with induction dose of 0.15mg/kg.
 increases seizure threshold.
 Respiratory system
 dose related central respiratory depression.
 co2 response curve slope is flatter,
 0.13-0.2mg/kg dose of midazolam produces ventilatory
depression depends on the rate of administration.
 Cardiovascular system
 reduction in arterial blood pressure due to decrease in
systemic vascular system.
 Heart rate, cardiac output, ventricular filling pressure is
maintained.
Uses:
 induction : midazolam is the bzd of choice for induction,
 0.2mg/kg dose induces anesthesia in 28sec
 above 55yrs and ASA status iii .require 20% or more
reduction dose.
 iv sedation: pre-op medication, intra-op regional/local
anesthesia. post-op.
 oral sedation
 ponv.
Dosage :
 induction- 0.05-0.15mg/kg.
 maintainance- 0.05mg/kg.
 sedation -0.5-1mg.

Side effect :
 respiratory depression.
NEUROMUSCULAR BLOCKING DRUGS

Definition
 Neuromuscular blocking drugs principally act by
interrupting the transmission of nerve impulses at the
neuromuscular junction (NMJ).
History:
The use of neuromuscular blocking drugs in anesthesia has its
origin in the South American Indians arrow poisons or
curares.
Curare was known to man for a long time in the form of arrow
poison used by tribes men to hunt animals, which is an
alkaloid obtained from the plant “Chondrodendron
Tomentosum”.
Classification of
Neuromuscular Blocking Drugs
 Depending on the mechanism of action and duration of
action

1.Depolarizers – mimic actions of acetylcholine

Decamethonium
Suxamethonium
2.Non depolarizers
SUCCINYLCHOLINE / SUXAMETHONIUM /
DIACETYLCHOLINE (SCh)
It is the only depolarizing neuromuscular blocker in clinical use.
Structure: It is composed of two acetylcholine molecules linked back to
back through the acetate methyl groups. It’s a quartenary ammonium
compound.

CH3 O O CH3
H3C-N-CH2-CH2-O-C-CH2 - CH2-C-O-CH2-CH2-N-CH3
CH3 CH3
succinylcholine
Pharmacokinetics and Pharmacodynamics:

Sch is endowed with two unique and critically

important characteristics:

1. produces intense paralysis rapidly.

2. effects are likely to wane before a
pre oxygenated patient becomes hypoxic.
It’s a quaternary ammonium compound, highly ionized
and water soluble with less lipid solubility.
Rapid onset of action:
30-60 seconds following intravenous injection.
Duration of action:
ultra short 3-5 minutes.
Dose: 1mg/kg i.v.

These characteristics make succinylcholine a very

useful drug for providing skeletal muscle
relaxation to facilitate tracheal intubation.
Recovery:
spontaneous breathing- observed within 5
minutes

Sch undergoes rapid hydrolysis in plasma by

Pseudocholinesterase/ Plasmacholinesterase /
Butyrylcholinesterase, synthesized by liver.
Breakdown of Sch takes place in two stages, both stages
mediated by pseudoChE:
1st stage:
Succinylcholine----------------------->
Succinylmonocholine + choline
(weak NMB)

2nd stage:
Succinylmonocholine-------------------> Succinic acid +
choline
 Mechanism of action
 Sch attaches to one or both of the alpha subunits of
nicotinic acetylcholine receptors and mimics the action
of acetylcholine (partial agonist),
thus depolarizing the post junctional membrane
(muscle end plate).
 Unlike Ach, the hydrolysis of SCh in synaptic cleft is
slow resulting in sustained depolarization of the muscle
end-plate.
 Continuous end-plate depolarization causes muscle
relaxation because opening of the lower gate in the
postjunctional sodium channels is time limited.
 After the initial excitation and opening, these sodium
channels close and cannot reopen until the end-plate
repolarizes. The end-plate cannot repolarize as long as
the depolarizing muscle relaxant continues to bind to
Ach receptors;
this is called PHASE I BLOCKADE
 CLINICAL USES of Succinylcholine:

1) Bolus i.v dose 1mg/kg

a) facilitate intubation
b) to provide brief muscle relaxation for closed
reduction of fractures.
c) to prevent adverse muscle contractions in
Electroconvulsive therapy.
d) for miscellaneous short surgical procedures.

2) Small dose given i.v bolus as a last resort to break

laryngospasm.
3) Intermittent i.v dose

- when short surgical procedures are unexpectedly

prolonged and extended, for extended periods of
relaxation.
- Intermittent fractional dose given after loading dose.
Each subsequent dose should be one half of the
previous dose.
Not practical for >30minutes
4) Continuous i.v drip in adults
Solution used is 0.1% concentration of SCh in 5%
dextrose; in geriatric 0.2% concentration.
For induction of relaxation- 5 to 10 mg/min (50-150
drops/min) for 2-5minutes.
For maintenance- 0.5-5 mg/min (12 drops/min)-
1mg/min to begin with.
5) Continuous i.v infusion in paediatrics
Neonates <10 days: unpredictable dose range.
7-10weeks: 25mg/kg/hr
20-30weeks: 8.7mg/kg/hr
Children 1-15years (mean age 6.5yr): 6.5mg/kg/hr
6) IM SCh in children
4mg/kg into deltoid / quadriceps femoris given 1-2min
after induction with halothane in children.
SCh given alone i.m, HR increases transiently to 110bpm
(10-15% above preanaesthetic level) decrease at 2min
to 80bpm, remains at this level for 5min. This sequence
occurs whether or not atropine (0.2mg) given with SCh.
But if larger dose of atropine (0.3mg) given similar
sequence till 2min 1 min later HR 110bpm (10% above
preinduction).
7) SCh given first may enhance the depth of block
induced by a subsequent dose of NDMR. However, the
effect on duration of action is variable.
Increases the duration of atracurium, rocuronium; no
effect on pancuronium, pipecuronium, mivacurium.
Adverse side effects:

1. CVS effects- cardiac dysrhythmias

2. hyperkalemia
3. fasciculations
4. myalgia, myoglobinuria
5. increased intraocular pressure
6. increased intragastric pressure
7. increased intracranial pressure
8. masseter spasm/ sustained skeletal muscle
contraction
9. malignant hyperthermia
10. phase II blockade
11. histamine release and anaphylactoid reaction.
Classification of NDMR’s
By chemical structure
 Steroidal compounds:
Pancuronium Rocuronium
Vecuronium Rapacuronium
Pipecuronium
 Benzylisoquinolium compounds:
d-Tubocurarine atracurium
metocurine cisatracurium
doxacurium mivacurium
 Phenolic ether: Gallamine
 Strychnos alkaloid: Alcuronium.
 Classification by duration of action
a. long acting relaxants – [> 1 hour]
d-Tubocurarine pipecuronium
Metocurine Gallamine
Doxacurium Alcuronium
Pancuronium
b. Relaxants of intermediate duration (30-60 mins)
vecuronium rocuronium
atracurium cisatracurium
c. short acting relaxants (12-20 mins)
Mivacurium
Rapacuronium
d. Ultrashort acting(< 10 mins)
430A
TAAC 3
PANCURONIUM
 Aminosteroid, long acting, methyl group in the structure
produces cumulative effect and cardiac effects.
 Cardiac effect - ↑ heart rate & ↑ blood pressure due to
parasympathetic & sympathomimetic effects.
 Doesnot release histamine
 Metabolism – 40 % in liver & 60% excreted via the
kidneys unchanged.
 Metabolites – 3 hydroxy, 17 hydroxy & 3, 17 hydroxy
metabolites.
 Dose – ED 95 is 0.05 mg/kg
 Intubating dose – 0.08 – 0.12 mg/kg
 Cumulative and hence cannot be used in infusion.
VECURONIUM
 Aminosteroid, intermediate acting.
 Noncumulative – can be used in infusion
 Demethylation of 2 position of the D - ring of Pancuronium –
½ to 1/3rd duration of action.
 Cardiostable, doesnot release histamine.
 Metabolism – 40% in liver & excreted via bile. 60% excreted
via kidneys.
 Metabolites – 3 desacetyl, 17 desacetyl & 3, 17 desacetyl
Vecuronium metabolites. Metabolites have ½ the potency of
Vecuronium.
 Dose – ED 95 – 0.05 mg/kg
 Intubation dose – 0.08 to 0.1 mg/kg
 Infusion rate – 0.8 - 2 µg/kg/min
 Drug interactions – when used with fentanyl without
anticholinergic, can produce cardiac asystole.
ATRACURIUM
 Benzyl isoquinolium group, intermediate acting.
 Releases histamine when administered rapidly or given 3 times
the intubating dose.
 Metabolism – Hoffmann’s elimination – (pH dependant
degradation n plasma) and ester hydrolysis.
 Metabolite – laudanosin – tertiary ammonium compound –
CNS stimulant.
 Doesnot require liver or kidney for metabolism & excretion –
hence safe in patients with hepatic or renal disorders.
 Non cumulative – can be given as infusion.
 Dose:
 ED 95 – 0.3 mg/kg
 Intubating dose – 0.5 mg/kg
 Infusion dose –
 Opioids
 “Opos” meaning -- Juice (Greek).

 “Opium” is a Greek word meaning “juice,” or the extract from the

poppy - Papaver somniferum.

 “Opiate” is a drug extracted from the poppy.

 “Opioid” is a natural or synthetic drug which binds to opioid

receptors.

 “Narcotics” those drugs which possess both an analgesic and

sedative properties. 58
 Terminology
Natural opioids occur in two forms:
 In the juice of the opium poppy (morphine and codeine)
as endogenous endorphins.

All other opioids are prepared from;

 Morphine (semi synthetic opioids such as heroin)
OR
 Synthesized from precursor compounds
(synthetic opioids such as fentanyl)

59
 On the basis of efficacy and potency opioids are
classified as agonists, partial agonists or mixed
agonist antagonists.

1. Based on intrinsic activity

• Agonists: Morphine, Fentanyl.

• Partial agonists: Buprenorphine.

• Mixed agonist-antagonists: Nalbuphine, Butorphanol.

• Pure antagonists: Naloxone, Naltrexone.

60
 Classification of OPIOIDS
 Natural
 Phenanthrene (basic structure)
 Morphine 10%
 Codeine 0.5%
 Thebaine 0.2%

 Semisynthetic
 Heroin
 Oxymorphone
 Hydromorphone

 Synthetic
 Meperidine
 Methadone
 Morphinians
 Benzamorphans.

61
Intrathecal opioids
 Hydrophilic opoids  Lipophilic opioids

-morphine -fentanyl.
-codeine -papaverine
-dihydrocodeine -diamorphine
-Pethidine -Buprenorphine.
 Mechanism of action
 Modulation of pain sensation
 There is a descending (efferent) system for the
physiological modulation of pain, involving the
periaqueductal or periventricular gray matter.

 Endogenous opioid peptides: neurotransmitters or

neuromodulators for inhibitory neurons in pathways
operating for pain sensation, probably acting at
Substance P/glutamate synapses.

63
 An epidurally administered opioid not only produces
action at local site of application at spinal cord but also at
distant CNS sites of medulla and PAG area.
 The Substantia Gelatinosa of spinal cord possess a dense
collection of opiate receptors and application of opiates at
these sites creates intense analgesia.
In the spinal cord, opioids act at synapses either

64
 Presynaptically as neuromodulators or
Postsynaptically as neurotransmitter blockers.
Analgesia produced by opioid agonists are
predominantly presynaptic. There is
substantial overlap between µ & K receptors in the
descending pain control circuits,

◦ the µ receptor action are always analgesic where

as
◦ the K receptors action can be analgesic or
antanalgesic
 Clinical Uses
1. Sedation and analgesia. 2. Premedication.

3.Balanced anaethesia. 4.Neuroleptanalgesia/anaesthesia

5.Total intravenous anaesthesia(TIVA)

6.High dose Opioid anaesthesia.

7.Treating chronic pain.

8.Left ventricular failure and pulmonary oedema.

9.Treatment of shivering.

10.Antitussive action. 66
Morphine

Pentacyclic alkaloid:
 O2 bridge at position 4 & 5,

 Phenolic hydroxyl (OH)

groups at position 3 & 6,

 Tertiary +vely charged N and

a quaternary carbon.

67
 Opioid Agonists
 Morphine and its derivatives
 Morphine
 L-isomers are active form

 Extract of Papaver somniferum;

 Chief phenanthrene alkaloid in opium

 Standard analgesic for moderate to severe

pain. 68
 CNS effects
 Analgesia
 Selectively interfere with nocioception of pain
 Also Interferes with forebrain mechanisms for
affective reaction to pain.

 Action mediated via receptors in

 Dorsal horn of spinal cord (substantia gelatinosa)

 Periaqueductal gray (PAG)

 Dorsal raphe nuclei and

 Limbic regions

69
 CNS effects (cont.)
 Behavioral effects: dysphoria as initial experience followed
by euphoria – major contributor to abuse liability as well as
relief of pain and anxiety.

 Sedation, drowsiness, and mental clouding.

 Emetic:
 direct stimulation of CTZ.
 High doses depress vomiting center.

 Antitussive: direct action on medulla cough center to

suppress cough reflex.
70
 Pupil size
 Morphine causes miosis (pinpoint pupils) --kappa
receptor effect.

 Pinpoint pupils still responsive to bright light.

 Oculomotor nerve (CN3) is stimulated by kappa receptor

site. If kappa receptor is blocked, mydriasis from sigma
effect will result.

 Atropine partially blocks effect indicating

parasympathetic system involved.
71
 Effects of morphine on respiration
There is a primary and continuous depression of respiration
related to dose;

 Decrease rate..

 Decrease volume..

 Decrease tidal exchange..

72
Cardiovascular system –
 Most opioids have little direct effect on the heart but may produce
bradycardia.

 Peripheral vasodilation and orthostatic hypotension as a result of CNS

actions, and histamine release.

 Cerebral vasodilation, ↑ intracranial pressure..

 Indirect effect due to histamine release

 Itching, sweating, redness of eyes.
 Bronchoconstriction, ↓ bronchial secretions.

73
 Peripheral actions

 GI tract - ↑ tone, ↓ peristalsis, (↑risk of regurgitation in pre op pts) –

constipation (need to prevent and/or treat constipation specially in
patients taking opioids chronically)

 Biliary tract – gall bladder or bile duct spasm due to ↑ biliary

pressure.

 Urinary tract - ↑ muscle tone → urinary retension.

74
Gastrointestinal system

 Nausea and vomiting – Stimuation of CTZ, in area postrema of

medulla.

 stimulation by stretch receptors causes nausea and vomiting.

 has afferents from gut and ear.

 involved in motion sickness due to labyrnthine stimulation.

75
Morphine effects on various smooth muscles
 Biliary tract
 marked increase in the pressure in the biliary tract
 10 fold increase over normal (normal is 20 mm H20 pressure)
 increase due to contraction of Sphincter of Oddi

 Urinary bladder
 tone of detrusor muscle increased
 feel urinary urgency
 have urinary retention due to increased muscle tone where
sphincter closed off

 Bronchial muscle
 bronchoconstriction can result
 **contraindicated in asthmatics, particularly before surgery
 Uterus
 contraction of uterus can prolong labor.
76
 Neuroendocrine Effects: Stress free state
Inhibit the release of
 Gonadotropin releasing hormone (GnRH)
 Corticotrophin- releasing factor(CRF) & hence
 Luteinizing hormone (LH)
- Follicle-stimulating hormone (FSH)
-ACTH.

77
Tolerance to morphine develops for Nausea,
Analgesia, Sedation, Respiratory depression,
Cardiovascular and Euphoric effects.

 But Not to Miosis, Constipation .

High doses (overdose situation) of morphine

 excitatory and spinal reflexes
 high doses of many OPIOID cause convulsions
due to stimulation at sigma receptor.
78
Pharmacokinetics:
Absorption-
 Readily absorbed from GI tract, nasal mucosa, lung
subcutaneous, IM, and IV route.
Distribution-
 widely distributed
 Unbound morphine accumulates in kidney, lung, liver,
and spleen
 CNS is primary site of action (analgesia/sedation)
 Crosses placenta in limited amount slowly enters brain.
Elimination-
 Primarily biotransformation.
 ~ 90% via kidney (as glucuronide)~10% in feces via bile.
79
 Metabolism
-Rapid glucuronide conjugation in liver and intestine
 80 - 90% may be metabolized during the first pass
through the liver after an oral dose.
 Morphine-6-glucuronide (an active metabolite)
 4 – 6 times more potent than morphine.
 may contributes significantly to analgesia when
morphine given chronically by oral route or with
renal failure.
 Morphine-3-glucuronide lacks analgesic effect but can cause
dysphoric side effects or seizures.

80
 Acute toxic symptoms:
 Triad
 Coma, Pinpoint pupils, Respiratory depression.

 Treatment:
 Maintain respiration.

 Opioid antagonist, preferably IV Naloxone

(may precipitate withdrawal symptoms),

 Repeat as needed (Naloxone is short acting)

81
 Codeine
 Less potent than morphine.
 Analgesic equivalent
 32-65 mg orally = 650 mg aspirin
 120-130 mg sc = 10 mg morphine sc
 Difficult to obtain same level of analgesia.

 Lower abuse potential, constipation, sedation,

 respiratory depression < morphine.

 Relatively mild withdrawal symptoms.

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 Methadone:
 Primarily a μ agonist with actions similar to morphine
except
 Also glutamate antagonist at NMDA receptors
 Greater oral effectiveness.
 Extended duration of action in suppressing withdrawal.
 Slow onset.Long duration (T1/2 22 hr) accumulate.
 Propoxyphene:
 Weak analgesic,Only administered orally
 Overly prescribed propoxyphene has been involved in
many drug-related deaths (mostly suicides) Overdose
– cardiotoxicity, seizures, toxic psychosis.

83
 Meperidine
1939- By Eisieb and Schquman –synthetic opioid.
Anticholinergic, weak local anesthetic property.

Potency -1/10th of morphine.

Negative inotropic at 2-2.5mg/Kg, less effect on biliary
sphincter and renal tract.

Effective in control of shivering from diverse causes…

Metabolised to desmethyl(nor)meperidine - meperidic acid

Normeperidine has ½ potency, 2 times CNS stimulant and

4-5 times half-life Meperidine.
Cumulative actions- Tremulousness, myoclonus &
seizures. 84
 Meperidine Congeners
(extremely potent synthetic drugs)
 Fentanyl

 Sufentanil

 Alfentanil

 Remifentanil

85
 Fentanyl
1960- synthesised as phenylpiperidine derivative
Potency-75-125 times tht of morphine.Highly lipid soluble- onset in
2-3 min IV. Less effect on haemodynamics

Duration is short- redistribution- <60min With 50µg/kg

Elimination half life is longer than morphine

Metabolised by N-delkylation to norfentanyl- OH to hydroxy propionyl

derivatives

Chest wall rigidity (wooden chest) – effect on µ receptors on GABA

interneurones.

Analgesia: 1-2µg /kg

Adjuvant to inhalational: 2-12µg/kg
Sole anaesthetic: 50-150µg /kg
Epidural bolus dose of 25-50µg- within 10-15 min onset and lasts 2-4
hrs.
Epidural infusion: 0.5-1µg /kg/hr 86
 Sufentanil
A thenyl derivative of fentanyl by Von Bover et al in 1976.

Potency 2000-3000 times of morphine, 10-15 times of fentanyl.

Biochemical behaviour similar to fentanyl.

Higher ionization and protein. Binding- VD is smaller, shorter elimination time(2.5hr)

Metabolised to norsufentanyl and desmethyl sufentanyl.

Excetion is 60% in urine and 10% in bile.

 Sedation: <0.5µg /kg.

Sugrical anesthesia: 10-15µg /kg.

Balanced anesthesia: 0.25- 1.0µg /kg

87
 Alfentanil
 By Niemgeeners and Janseen in 1981…

Potency 10- 20 times of morphine, 1/5th – 1/10th less potent than

fentanyl.

Less lipid soluble but more unionized. Onset of action 90sec.

Duration of action 5-10 min.

Bio behaviour similar 2 fentanyl. Metabolised to noralfentanyl by N-

delkylation.

90% excreated in urine. Oxidised in liver N-dealkylation,

desmethylalfentanil.

Induction: 165-175 µg/kg

Maintenanace: 1.0-1.5µg /kg/min infusion

Premedication: 10-15µg /kg
88
Attenuator of intubation: 30µg /kg
 Remifentanyl
 Synthetic anilido-piperidine derivative. Ultra short acting µ agonist
 Potency similar to fentanyl, peak effect 1-3 min.
 Vials has glycine- not for epidural/intrathecal
 Solution in dextrose is stable for 24hrs. (20µg/ml in 55 dextrose)

 Metabolised by nonspecific tissue and blood esterases

 Metabolites 300-1000times less potent, limitless metabolism
 Terminal half life 10min.-is by metabolism and elimination not
redistribution.

 Context –sensitive half life. Clearance & distribution r independent of

dosage.
 Adverse effects are similar to other opioids

Truncal muscle rigidity avoided slow incremental doses rather than
boluses. Not associated with histamine release.

 Co-induction: 0.5-1µg /kg/min

 Anaesthesia: 0.25-0.4µg /kg/min or
89
 Analgesia: 0.05- 0.1µg /kg/min
 Agonists and Antagonists
Buprenorphine:
Synthetic derivative of thebaine alkaloid

Partial agonist at µ receptor

High affinity but low intrinsic activity at kappa receptor

Potency 25-50 times of morphine

Due to high affinity difficult to antagonise by naloxone

Due to stability of binding , onset and offset are slower w.r.t plasma conc.

Terminal half life is 4hrs. Duration might last for about 8hrs.

Metabolism –liver- dealkylation and conjugation 90

 Nalbuphine
Semi synthetic phenanthrene derivative.

Equipotent to morphine.

Partial agonist at kappa, antagonist/weak agonist at µ.

Somnolence. Effective in morphine tolerated subjects.

VD 162-498L.

Metabolism – liver- 2 inactive metabolites-excreted in feces

Clearance- 0.8-2.3L/min., elimination t1/2 is 110-160 min.

Useful in managing postoperative shivering.

91
 Pentazocine
A bezomorphan derivative. Agonist at kappa and delta
receptors

Partial agonist/antagonist at µ receptor.

Potency 1/3rd of morphine. Less nausea vomiting, less

marked rise in biliary pressure.

Increases in catecholamine conc.

May cause vivid and unpleasant hallucinations.

Metabolism – liver- oxidation and glucuorinidation.

60-70% protein bound, VD= 4.9L/Kg, clearence

1320mL/min. Elimination t1/2 =2hr. 92
 Butorphanol
Partial agonist at kappa and ? antagonist at µ receptor

Potency 5-8 times of morphine

Pronounced sedation effect mediated by kappa receptor.

Does not interfere with biliary pressure.

Does effective in treating shivering.

Metabolised –liver-OH and nor derivatives, 80%

protein bound.

Elimination half-life is 2.1 – 8.8 hrs.

93
 Tramadol
Synthetic opioid of aminocyclohexanol group.
Racemic mixtures of enatiomeres.

Non –selective agonist at µ, κ and δ receptors.

Inhibits noradrenaline uptake and enhances serotonin action.

Potency almost equal to meperidine.

Therapeutic effect in clinical doses on CVS and ventilation are
negligible….

Dosage….orally absorberd with 70% availability, multiple doses

reduces first pass metabolism effects.
VD2.9-4.37L/Kg., protein bound 20%.

Elimination half life is 270-450min.

Metabolised –liver- demethylation and conjuagation.

O-demethyltramadol- active metabolite high µ affinity, t1/29hr.(10%)

Clearance of 6.7 – 10.1 ml/Kg/min.
94
 Adv. Effcts.: Nausea, vomiting, sedation ,diaphoresis and least incidence of
constipation.

 Peak action 2-4 hr, MAO inhibitor and tramodol potentiate each other to cause
excitation.

Opi0ids for diarrhea

 Diphenoxylate:
 Derivative of meperidine.
 Combined with atropine (Lomotil) for treatment of diarrhea.

 Loperamide (Imodium):
 Derivative of diphenoxylate.
 Effective antidiarrheal drug with little abuse potential.

95
Antagonists

96
 Naloxone
A substituted oxymorphone derivative.

Competitve antagonist at µ, δ, κ and sigma receptors.

Short acting: onset in 1-2 min. with duration of 30-60

min.

VD 2L/kg, 2% bioavaialbility, 46% prt. Bound.

Metabolised –liver- conjugation

Clearance 25ml/min/kg, plasma half-life 1.2hr.

In unrelieved pain- ppt. sympathetic drive-tachycardia,

hypertension and arrhythmias.
Usage in shock. 97
 Naltrexone

Orally effective for 24hr. –longer half-life.

Used in opioid addiction, compulsive eating and morbid

obesity.

Methylnaltrexone:

•Quarternery opioid antagonist, does not cross BBB

•Used In attenuating peripheral morhine-induced changes
in rate of gastric emptying and incidence of nausea.

98
 Nalmefene

6- methyl analogue to naltrexone.

Pure opioid antagonist.

Longer duration of action – half-time 10.8 hr.

Metabolised –liver-conjugation.

99
Thank u.