IntrVen Pharmac Lect 2

Dr.
Vithal Dhulkhed
Professor and Head Department of Anesthesiology KIMSU,Karad,
19/04/2012 Dr. Vithal Dhulkhed 1
Historically, anaesthesia was by inhalation However, patients frequently passed through stage
of hyperexcitability Guedel termed this stage 2. Chloral hydrate was first IV agent(1870s) IV route not popular until 1930s, with the use of barbiturates.
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INTRA VEnoUS ANAESTHETIC AGENT
Objectives
Properties of the ideal IV anesthetic agent Classification The present commonly used agents Target-controlled Infusions Chirality New drugs and technologies
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IDEAL IV ANAESTHETIC AGENT

Rapid onset: A- un-ionized at blood ph(7.35 7.45) B- highly lipid soluble these properties permit penetration of the BBB 2-rapid recovery -by redistribution from brain
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analgesia at sub anesthetic concentrations minimal cardiovascular and resp. depression No emetic effects No excitatory phenomena No emergence phenomena No interaction with neuromuscular blocking
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No pain on injection, no venous sequelae No toxic effects on other organs No release of histamine No hypersensitivity reactions Water soluble formulation Long shelf life : No stimulation of porphyria
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Pharmacokinetics basics
By knowing VD ,T1/2 calculate dose required and dosing
interval to attain serum therapeutic level VD (Vol of distrn) = dose/conc of drug; after bolus (VC) at steady state (SS) after infusion (Vss). Clearance = Elimination * VD. The desired conc for therapeutic effect (Cp) Loading dose = Cpss * VC ;Bolus = (Cnew - Cactual) * VC Inf rate to maintain SS= Cpss * Clearance
M: LBM = 1.1 * wt - 128 * {wt/ht} F: LBM = 1.07 * wt 148 * {wt/ht}
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Intravenous anaesthetic agents

Barbiturate Sodium thiopental non barbiturate Propofol (newly introduced) Ketamine (infrequently used) Etomidate Other adjuvant IV agents (benzodiazepines, midazolam, diazepam,)
Sodium thiopental (pentothal)
Ultra short acting IV anesthetic-hypnotic Yellow powder,-highly lipid soluble,2.5% soln used Combined with sodium carbonate,(30mg) it becomes water soluble.When injected ,sodium carbonate is neutralized and the thiopental is converted to its lipid soluble non ionazed form (40% ionized at pH=7.4) Bacteriostatic ,and has a pH of 10.6 to10.8 It is highly protien bound by albumen(75%)
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Derived from Barbituric acid (2,4,6-trioxohexahydropyrimidine, condensation of malonic acid and urea) Alkyl/aryl groups at C5 (i.e.CH2)-sedative hypnotic activity Sulfa group (C2-S)increase lipid solubility Phenyl group at C5, or on N - anticonvulsant activity (e.g. phenobarbital), Long alkyl side chains at C5 increase hypnotic potency from 5 to 6 C atoms length (above this, convulsant properties may result)

Pharmacokinetics Induces liver enzymes, increasing cyto P450 activity
Metabolism primarily in the liver (apprx 10 to15%per hour

Desulfuration to pentobarbital which is oxidised to inactive thiopental carboxylic acid Less than 1% unchanged urine excretion If large doses or infusions are used, metabolism becomes zero order and delayed recovery.

Acts on Cl-channels,hyperpolarise post synaptic membrane Facilitates inhibitory neurotrasmitter GABA, mimics its actions Inhibits synaptic transmission of Glutamate,Ach Decrease both cerebral electrical & metabolic activity Anticonvulsant,reduction of ICP and IOP Anti-analgesic effect

Thiopental causes a dose related depression of myocardial function -venous tone decreases Depression of the respiratory response to hypercarbia and hypoxia
Laryngospasm and bronchoconstriction FRC is reduced by 20% with induction
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Sodium thiopental (pentothal) indications

Induction of anesthesia Maintenance of anesthesia for short procedures Control of convulsive states For supplement of regional anesthesia or low potency anesthesia
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Absolute contraindications Airway obstruction , porphyria,H/O hypersensitivity Precuations
CVS disease , severe hepatic disease ,renal disease
Rarely, intra-arterial injection can occur
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Physical and chemical properties

Intravenous anaesthetic/hypnotic. (2,6-diisopropylphenol) Akylphenol white oil-in-water emulsion, pH of 7 1% propofol 10mg/ml,10% soyabean oil. 2.25 %glycerol,1.2% purified egg phosphatide. Acts on B1 subunit of GABA NMDA receptor
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Propofol
Physical and chemical properties

Propofol is a highly lipid soluble.
Has No effects on muscle relaxants.

Associated with low incidence of nausea &
vomiting. Metabolism to glucurone metabolites excreted in urine.
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Propofol Dosage
For healthy unpremedicated 2.5-3 mg/kg. For premedicated 1.5-2 mg/kg. Elderly patients <= 1 mg/kg.
Maintenance of anesthesia (50-150 mcg/kg/min)
combined with N2O and Opioids (Continuous Infusion: Total intravenous Anesthesia TIVA)
For IV conscious sedation for operative procedures
with local anaesthesia 25-75 mcg/kg/min.

Propofol
Propofol has antiemetic, antipruritic, and anticonvulsant properties. Hypotension secondary to a drop in systemic vascular resistance, contractility, and preload. Hypotension is more pronounced than with thiopental. Propofol markedly impairs the normal arterial baroreflex response to hypotension. excitatory side effects such as myoclonus.
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Propofol
Causes profound respiratory depression. Depression of upper airway reflexes exceeds that of thiopental. Venous irritation: Pain on injection is more common than with thiopental.Reduced by Concomitant lidocaine, administering through more proximal IV line. not licensed for use in children < 3 years-reports of unexpected deaths -due to metabolic acidosis and myocardial failure after long-term use in ICU.
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Propofol
indication Initiation and maintenance of Monitored Anesthesia Care sedation Combined sedation and regional anesthesia Induction of General Anesthesia Mainenance of General Anesthesia Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Approved Patient Population Adults only Adults only (See Precations ) Patients 3 years of age Patients 2 months of age Adults only
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Ketamine
Its a dissociative anesthetic
agent.
by dissociative we mean that
the patient is unconscious but

appears awake and doesnt feel pain.
It has anesthetic and
analgesic effect
Ketamine
Physical & chemical Properties chemically related to the psychotropic drug

( e.g. phencyclidine).Racemic mixture,Smore analgesia,rapid metabolism,fewer emergence reactions.MW 238
Water soluble, and 10x more lipid soluble than thiopental.
pH=3.5 - 5.5 Converted to norketamine(20-30% activity) then tohydroxynorketamine
Ketamine
Pharmacokinetics Dosage
IM 5 10 mg/kg. peak plasma level reach approx 15 minutes IV 1 2 mg/kg. dissociated stage is noted in 15 seconds. intense analgesia, amnesia & unconciousness occur within 45-60 minutes
subsequent IV doses of 1/3 of the initial dose maybe required

KETMINE METABOLISM
It has a rapid absorption and distribution to the
vessel rich groups like THIOPENTAL

Hepatic metabolism is required for elimination
<5% excreted unchanged in urine
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KETMINE Mechanism of action There are 3 theories explains the MOA of ketamines :
1 N-methyl aspartate receptor theory : NMDA receptors may represent a subgroup of the sigma opiate receptors (the PCP site) that blocks spinal pain reflexes. 2 Opiate receptor theory : Ketamine may have some affinity for opiate receptors,mu,kappa,delta; but its effect cant be reversed with naloxone. 3- Miscellaneous receptor theory : It reacts with muscarinic, cholinergic and serotonergic receptors. Ketamine is a potent analgesic at subanesthetic plasma concentrations. It has a wide margin of safety ( up to 10x the usual dose )
CNS :
KETMINE Pharmacodynamics
1. ketamine increases cerebral oxygen consumption, cerebral blood flow, and intracranial pressure 2- generalized increase in the muscle tone and purposful movements. 3- Unpleasant dreams, hallucinations or frank delirium (esp. females & large doze of ketamine). incidence of dilirium in 15-35 year old pts is approx. 20%
Respiratory system:
It preserves laryngeal &pharyngeal airway reflexes. Ketamine is a potent bronchodilator
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CVS:
It produces central sympathetic stimulation,
which increases: 1. arterial blood pressure, heart rate, and cardiac output. 2. Pulmonary artery pressure. 3. Coronary blood flow. 4. Myocardail oxygen uptake. It may cause myocardial depression if the sympathetic nervous sys is exhausted or blocked.
GI GU
Minimal anorexia, nausea & vomiting.
Placental transfer does occur, but neonatal depression hasnt been observed if the doze is limited to < 1 mg/kg.
Muscle system
Generalized increase in skeletal muscle tone. Increases the effects of muscle relaxants.
Endocrine Sys.
Increased sympathetic stimulation increased blood
glucose, increased plasma cortisol, increased heart rate.

KETMINE Indications
1- sole anesthetic for diagnosis and surgical procedures
2- induction of anesthesia
3- to supplement regional or local anesthetic techniques

4- for anesthetic induction in severe asthmatic pts. Or patients with cardiovascular collapse requiring emergency surgery
1- lack of knowledge of the drug
KETMINE Contraindications
2- lack of resuscitative equipment 3- inability to maintain a patent airways 4- allergy to ketamine 5- history of psychosis 6- cerebro-vascular disease 7- Patients. For whom hypertention is hazardous
ETOMIDATE
Carboxylated imidazole.watersol at phys pH
Only D-isomer is actve 0.2%soln.35% propylene glycol,pH 8.1-painful,little
risk of pptn. 10ml ampoule,2mg/ml Acts on GABA,no intrinsic analgesic activity 75% prot binding,rapid onset 30sec, Metabolised to inactive carboxylic acid metabolitehepatic enzymes and plasma esterases, kidney elimn. Dose .3mg/kg
Cardiostable,not sympathomimetic like ketamine

Pain on injection,no histamine release. increases epileptogenic activity in patients with seizure
foci. frequent myotonic activity during induction, decreased by opioid or benzodiazepine premedication. The incidence of nausea and vomiting seems to be more common with etomidate than others inhibition of corticoid synthesis by reversible block of 11-beta-hydroxylase.
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Benzodiazepines
Features which result in their popularity as
adjuvant IV anaesthetic agents: 1 amnesia 2 minimal cardiarespiretory depressant effect. 3 anticonvulsant activity. 4 low incidence of tolerance and dependence.
Benzodiazepines
They inhibit the actions of glycine (by increasing the
conc. Of a glycine inhibitory neurotransmitter) which will lead to antianxiety and skeletal muscle relaxant effects. 2 Bind to GABA ,increase Cl- conductance , facilitate the actions of the inhibitory neurotransmitter GABA
Benzodiazepines are highly lipid soluble. Midazolam (Versed) exhibits
significant lipid solubility, following injection, because the previously open imidazole ring closes at physiological pH (7.4).
They are highly protein bound (albumin). They are metabolized by the liver through conjugation with
glucoronic acid and excreted by the kidneys. Midazolam and Diazepam are the most commonly used benzodiazepines during operative procedures. cause anterograde amnesia
Benzodiazepines Midazolam and diazepam

They are commonly used to provide:
IV sedation.amnesia. reducing anxiety.

structure composed of a benzene ring, fused to a seven-member diazepine ring Both diazepam and lorazepam are insoluble in water, and therefore require solubilizing agents, while the imidazole ring renders midazolam water soluble
Midazolam and diazepam

THE DIFFERENCES BETWEEN THEM
Midazolam is 2-3 times more potent than diazepam: The dose for IV conscious sedation: 0.5 3 mg up to 0.1 mg/kg for midazolam, and 1-10 mg for diazepam. The dose for inducing anesthesia: 0.2 0.4 mg/kg for midazolam , and 0.15-1.5 mg/kg for diazepam. Midazolam has a more rapid onset, greater amnestic effect, less postoperative sedative effects than diazepam.
Benzodiazepines Midazolam and diazepam

THE DIFFERENCES
Pain on injection and thrombophlebitis is less likely with midazolam . Elimination half time for midazolam range from 1-4 hours, and for diazepam from 21-37 hours.
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Benzodiazepine antagonists (Flumazenil)

Its an imidazobenzodiazepine. Antagonizes by copetative inhibition. Its elimination half-time is1hour, considerably less
than most benzodiazepines; therefore we will need

repeated administrations of flumazenil to antagonize a benzodiazepine with a longer halftime.
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Benzodiazepine antagonists (Flumazenil)
The usual initial dose is 0.2 mg over 15 seconds, if the desired level of consiousness is not obtained within one minute of administration we can give repeated doses of 0.1 mg every minute up to the maximum of 2 mg, and if sedation recurs we can use infusions of 0.1-0.4 mg/hour. The most common side effect is nausea (4%)
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Narcotic Agonists
Opium derived
from dried juice of poppy plant which contains over 20 plant alkaloids. including morphine & codiene.
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Narcotic Agonists Site of Action

Opioid receptors are predominantly located in the: Brain stem (amygdala, corpus striatum, periaqueductal gray matter and medulla),Spinal cord(substantia gelatinosa), GIT
3 types of receptors: Mu receptors (): analgesia, resp depression, euphoria, & physical dependence. Kappa receptors (K): analgesia, sedation, resp depression, miosis. Sigma receptors(a): dysphoria, hallucination, tachypnea, tachycardia.
Narcotic Agonists Pharmacokinetics
Rapid distribution through the body
following IV injection.
Its metabolized by the liver and the
majority of the inactive metabolites are
excreted unchanged in the urine.

Narcotic Agonists Pharmacodynamics

Sedation through interfering with sensory perception of painful stimuli. Large doses produce unconsciousness but they are generally incapable of producing anesthesia and it cant guarantee total amnesia. It may produce nausea & emesis through stimulation of the chemoreceptor trigger zone.
Narcotic Agonists Pharmacodynamics Dose related depression of respiratory rate and minute ventilation and increase the tidal volume which will lead to a slow deep respiration. Reversed by naloxone administration.
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CVS
Opioids have little myocardial depressant effect With either N2O or benzodiazepines may depress
cardiac output. They decrease SVR,either by decreasing sympathetic outflow or by releasing histamine (as morphine) Synthetic opioids are less likely to release histamine. They produce bradycardia by stimulation vagal nucleus in the brain stem.

Slow GI mobility-constipation,post op ileus. Increase biliary tract tone -biliary colic with patients with bile stones. Increases the bladder sphincters tone urine retention. Anaphylactic reactions, bronchospasm, chest wall rigidity and pruritis.
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Narcotic Agonists Fentanyl and Morphine Fentanyl -most narcotic agent used during induction of anaesthesia due to its rapid onset (highly lipid soluble) and predictable duration of action (30 minutes). Morphine is used in the perioperative period to provide long lasting analgesia
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Narcotic Agonists Fentanyl and Morphine

Potency Ratio Analgesic dose Low dose
Morphine
10 mg
0.05 - 0.2 mg/kg
Fentanyl
100
100 mcg
0.5 3 mic g/kg
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Narcotic Antagonists (Naloxone)

Naloxone competes with opioids at the mu, delta,
kappa and sigma receptors. Ampules of 0.02, 0.4 and 1 mg/ml. Peak effect 1-2 min. Duration of action 30-60 min. Used in perioperative surgical patients with excessive sedation or respiratory sedation secondary to opioids.
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Narcotic Antagonists (Naloxone)

Given in small incremental doses. High doses of naloxone will result in sudden reversal of analgesic effects leading to abrupt return of pain resulting in hypertension, tachycardia, pulmonary edema, ventricular dysrhythmias and cardiac arrests. If sedation or respiratory depression recurs, continuous infusion of 3-10 micg/kg/hour of naloxone is required.
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Agents of research interest

Dexmedetomidine -alpha 2-adrenoreceptor agonist with sedative and analgesic properties. Used via infusion (for up to 24 hours). Antisympathetic effects -cardiovascular stability Used as an adjunct to other anaesthetics
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Current clinical practice - focused on two compounds, midazolam and propofol. Why then look for new compounds? The answer is both have limitations. Have relatively steep doseresponse curves Propofol causes pain on injection,also supports bacterial growth,causes haemodynamic depression,occasionally causes excitation
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Midazolam has a slow, time-to-peak effect has an active metabolite, 1-hydroxymidazolam CNS7056 is a new esterase-hydrolysed benzodiazepine with rapid onset, short duration of action, and a fast recovery profile in animal models JM-1232 () evaluated in man as MR04A3 is a novel isoindoline derivative benzodiazepine receptor site agonist fully reversible by flumazenil Both onset and offset times were faster than literature values for midazolam
Etomidate Derivatives
Improved understanding of action at a molecular level
chemical modification to allow esterase hydrolysis Potentiates GABAA receptor activation. receptors are pentameric with two binding sites Methanethiosulphate-etomidate (MTS-etomidate) forms covalent bond to one binding site Considered a molecular probe to interrogate the binding site
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Methoxycarbonyl-etomidate -MOC-etomidate-rapidly
metabolized. Only during infusion adrenocortical depression Anaesthesia induced by MOC-etomidate is doseindependent Infusion require a substantial mass of drug with subsequent metabolism to carboxylic acid and methanol Its proper evaluation requires human exposure
Carboetomidate
In contrast, offers a pharmacodynamic
solutionremoving the nitrogen atom from etomidate massively decreases adrenocortical depression
What is unclear is whether the unwelcome effects
of etomidatemyoclonus and nausea and vomiting remain unchanged
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AZD3043 - allosteric modulator of GABAA similar to
propanidid ,tested in man by bolus injection and infusion with 4 studies registered at www.clinicaltrials.gov,
PF0713, (R, R)-2,6-di-sec-butylphenol, similar to
propofol but with larger sidechain, slower onset of action and longer duration ,without pain on injection due to reduction in the aqueous phase concentration
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Fospropofol
Is a phosphate pro-drug for propofol -converted to
propofol in a few minutes of i.v. injection. -time-topeak effect is longer, recovery slower (FDA) approved for 'moderate sedation'. does not cause pain on injection ,water soluble However perineal pain or paraesthesia
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! One approach to containing drug costs

Use a cheap agent for induction and maintenance
switch to a more expensive short-acting agent towards the end of surgery for rapid recovery
Perhaps, a truly short-acting benzodiazepine agonist,
or one with a faster onset than midazolam, might allow benzodiazepine anaesthesia to be revisited.
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Target Controlled Infusion

Improved administration technique based on
pharmacokinetics Infusion pump technology, better estimations of effect site conc* facilitated TCI Set initial target blood (or effect site) conc required based on BWt Blood (or effect site) conc display estimates from large trials
*concentration of agent in the brain for any given blood concentration

Determine for each drug PK data set, simulation of
the conc obtained with a given dosage. choose the drug that servesbest. calculate optimal dosing schemes to obtain a blood or effect site conc in the therapeutic range rapidly with minimal overshooting. Couple the pharmacokinetic information with a computer-controlled administration device: TCI systems, blood conc or effect-site conc controlled.
Target conc are calculated, not measured. TCI maintain 3 superimposed infusions, one at a constant
rate to replace drug elimn and second exponentially decreasing infusions to match drug removed from central compartment to others At present there is no method of measuring drug concns real time analogous to the ET volatile concn
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Using Technology to Support Drug Administration

TCI of propofol has been adopted worldwide with the
exception of the USA Generic or 'open' TCI -implement published TCI remains strictly 'open loop', -No feedback of an effect measure to TCI system The Open TCI initiative, www.opentci.org, brings together academics and manufacturers to share data and develop best practice in TCI. Currently available
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The choice of math model and the question of its
appropriateness to the individual patient remain the responsibility of the anaesthetist Closed-loop anaesthesia has been the subject of considerable research but has not been developed commercially
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Sedasys(Ethicon Endo Surgery, Inc., Cincinnati, OH,
USA) new proprietary system for propofol delivers a fixed sedation protocol or a subset of it and reacts to protect patient safety. Provided satisfactory sedation without device-related adverse events during endoscopy It monitors ECG, SaO2, Et CO2, and patient responsiveness to auditory commands. Slow titration in small increments
chiral drugs
The configuration defined by Cahn-Ingold-Prelog
sequence rule
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This is an exciting time for anaesthetic drug
development Anaesthetics may be neuro-protective,effect (or not) preconditioning,[ alter immunity and cell proliferation, may cause neurotoxicity in infant brain. Researchers are working to clarify these and identify how to exploit beneficial effects and moderate or avoid harmful ones.
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Chirality and anaesthetic drugs

Enantiomers are molecules
that exist as Rt-handed and Lt-handed forms -nonsuperimposable mirror Dextro propoxyphene images. Analgesic Such compounds are also said to be chiral Diastereoisomers refer to stereoisomeric compounds not enantiomeric,
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Levo Antitussive
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more than half of
synthetic agents are chiral Administered as racemic mixture, i.e. two virtually separate drugs are being given at the same time with different pharmacodynamics and pharmacokinetics
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Group priority (atomic size) is indicated as A>B>C>D, A representing the largest size.
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Potential advantages -an increase in the selectivity,
improved therapeutic index and less drug interactions Total plasma Cl and the VDss were significantly greater for R-thiopental than for S-thiopental It has twice potentiation of gamma-amino butyric acid (GABA) at GABA A receptors Different adverse effect profiles
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Ketamine R(-) isomer is less effective but higher
side effects than S(+) enantiomer Etomidate is optically pure R(+) isomer, which is the active component Dexmedetomidine, an imidazole compound, is dextro-enantiomer acting on alpha-2 receptor, especially for the 2A subtype More effective than clonidine
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Dr.

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

INTRA VEnoUS ANAESTHETIC AGENT

Dr. Vithal Dhulkhed

IDEAL IV ANAESTHETIC AGENT

Dr. Vithal Dhulkhed

IDEAL IV ANAESTHETIC AGENT

Dr. Vithal Dhulkhed

IDEAL IV ANAESTHETIC AGENT

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

Intravenous anaesthetic agents

Sodium thiopental (pentothal)

Dr. Vithal Dhulkhed

Sodium thiopental (pentothal)

Metabolism primarily in the liver (apprx 10 to15%per hour

Sodium thiopental (pentothal)

Sodium thiopental (pentothal)

Dr. Vithal Dhulkhed

Sodium thiopental (pentothal) indications

Dr. Vithal Dhulkhed

Sodium thiopental (pentothal)

Rarely, intra-arterial injection can occur

Dr. Vithal Dhulkhed

Physical and chemical properties

Dr. Vithal Dhulkhed

Physical and chemical properties

Has No effects on muscle relaxants.

vomiting. Metabolism to glucurone metabolites excreted in urine.

Dr. Vithal Dhulkhed

Maintenance of anesthesia (50-150 mcg/kg/min)

with local anaesthesia 25-75 mcg/kg/min.

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

the patient is unconscious but

Physical & chemical Properties chemically related to the psychotropic drug

subsequent IV doses of 1/3 of the initial dose maybe required

vessel rich groups like THIOPENTAL

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

It produces central sympathetic stimulation,

Minimal anorexia, nausea & vomiting.

glucose, increased plasma cortisol, increased heart rate.

3- to supplement regional or local anesthetic techniques

1- lack of knowledge of the drug

Cardiostable,not sympathomimetic like ketamine

Dr. Vithal Dhulkhed

Benzodiazepines Midazolam and diazepam

IV sedation.amnesia. reducing anxiety.

Midazolam and diazepam

Benzodiazepines Midazolam and diazepam

Dr. Vithal Dhulkhed

Benzodiazepine antagonists (Flumazenil)

than most benzodiazepines; therefore we will need

Dr. Vithal Dhulkhed

Benzodiazepine antagonists (Flumazenil)

Dr. Vithal Dhulkhed

Dr. Vithal Dhulkhed

Narcotic Agonists Site of Action

Narcotic Agonists Pharmacokinetics

Rapid distribution through the body