11. pharmacology (autosaved)

Pharmacology of Commonly Used Drugs in Conscious Sedation

PHARMACOLOGY OF COMMONLY

USED DRUGS IN CONSCIOUS

SEDATION

Conscious Sedation 67


BARBITURATES

Barbiturates are those agents that may pharmacologically be described as “sedative-

hypnotics”. Chemically, they are derivatives of barbituric acid or malonyl urea, which is a

combination of malonic acid and urea. Barbituric acid itself has no hypnotic properties, but

replacement of hydrogen by various radicals produces many different drugs processing hypnotic

characteristics. The new compounds are varied in their actions, both the potency and duration of

action being markedly affected by the different substitutions.

The barbiturates may be divided into two categories based on the chemical structure.

Those compounds having oxygen attached to the carbon of the urea component are properly

termed barbiturates. They are frequently referred to as oxybarbiturates to distinguish them from

those of the second category, the thiobarbiturates - which have a sulfur atom in place of the

oxygen. Although the pharmacology of all barbiturates is essentially similar they differ in

potency, duration, and intensity of effect. Thiobarbiturates possess a greater degree of fat

solubility, and are more rapid in onset, have shorter duration of action, and are somewhat more

toxic than the oxybarbiturates. 93

The barbiturates are general depressants; they depress the activity of nerve, skeletal

muscle, smooth muscle, cardiac muscle, and the central nervous system. However, it must be

emphasized that the central nervous system is exquisitely sensitive to depression by barbiturates;

as a result, when these drugs are administered in therapeutic doses, the effects on other structures

are absent or negligible. All degrees of depression of the central nervous system are possible,

ranging from mild sedation to general anesthesia or to coma.



Drugs in this category appear to act at all levels of neuraxis. There is a complex,

interrelated group of pathways coursing through the reticular formation of the midbrain and

medulla and extending anteriorly into the thalamus and hypothalamus – the “reticular activating

system.” This system is very sensitive to the depressant effects of sedative hypnotic drugs. It is

their effect on the reticular system that seems to be responsible for the inability to maintain

wakefulness under the influence of these compounds. The cerebral cortex is among structures

most sensitive to these drugs, since they do depress cerebral function as evidenced by release of

inhibitions and the production of amnesia in the conscious patient. 93

Barbiturates can be classified based on the time of onset and duration of action into

four groups: 93

1. Ultra short acting: The ultra short acting barbiturates most commonly used are thiopental

sodium, thiamylal sodium, and methohexital sodium. With the exception of thiopental

these drugs are administered exclusively by the intravenous route for the production of

conscious sedation. They possess the shortest duration of action and are also the most

potent barbiturates available. With all drugs in this group the peak effect after intravenous

administration will be realized in 30 to 60 seconds. Sedative effect will be present for 5 to

7 minutes for methohexital, the shortest acting and most potent barbiturate, and for 10 to

15 minutes with thiopental and thiamylal.

Thiopental is the only agent in this group that may be administered by any

route other than the intravenous. A rectal suspension is available that when instilled

rectally in doses of no more than 10 to 14mg. per pound will produce sedation in 8 to 10

minutes. This method is particularly useful in apprehensive children. Duration will be

about 30 to 60 minutes.



2. Short acting barbiturates: The short acting barbiturates most commonly used are

pentobarbital and secobarbital. They may be administered orally, intramuscularly, or

intravenously. These drugs are particularly useful via the intravenous route for the

production of conscious sedation, either as a sole agent or in combination with other

central nervous system depressants. When used alone intravenous dose range usually is

from 50 to 100 mg. lower doses must be employed when used these drugs are used in

conjugation with psycho sedatives and / or narcotic analgesics. Duration of sedation via

the intravenous route will range from 2 to 3 hours.

Short acting barbiturates are also of value when administered via the

oral route to provide the patient with a restful sleep the night before his dental

appointment. Depending on the individual, the oral dose will range from 50 to 200 mg.

the drug will require 30 to 45 minutes for its maximum effectiveness and will have

duration of 4 to 6 hours. Providing the patient with a restful sleep the night before his

appointment will allow him to arrive at the office well rested and thus with an elevated

pain reaction threshold.

3. Intermediate acting barbiturates: The intermediate acting barbiturates most commonly

used are amobarbital, aprobarbital, and butabarbital. They are administered via the oral

route only and effective in 45minutes to one hour. Duration will range from 6 to 8 hours.

They may be used to best advantage on the night before the appointment to aid the patient

in obtaining a good night‟s rest.

4. Long acting barbiturates: The long acting barbiturates most commonly used are barbital

sodium and Phenobarbital. These agents are indicated for oral administration only and,



because of their long duration of 8 to 10 hours, are seldom if ever indicated in dental

practice.

PENTOBARBITAL

Pentobarbital is an oxybarbiturate and is one of the most frequently used barbiturates for

pediatric sedation. Pentobarbital is a barbiturate with no inherent analgesic properties that

produces profound sedation, hypnosis, amnesia, and anticonvulsant activity in a dose dependent

fashion. With intravenous titration, sedation is evident in 3–5 min with duration of roughly 30–

40 min. Like other barbiturates, pentobarbital can lead to respiratory depression and hypotension.

In many centers, pentobarbital is the intravenous sedative of choice for diagnostic imaging in

children, and is regarded as better than midazolam or chloral hydrate for this indication. 95

METHOHEXITAL AND THIOPENTAL

When given intravenously, both methohexital and thiopental produce effective sedation within 1

min and induce potent respiratory depression in the same manner as propofol and intimidate.

Clinical recovery is rapid (about 15 min). The depth of sedation achieved in existing small series

is not well described, but seems to be at or beyond levels consistent with deep sedation.

Barbiturates are rapidly absorbed rectally and methohexital or thiopental given by this route can

reliably produce anxiolysis and sedation suitable for CT or MRI scanning. Although respiratory

depression is unusual with typical doses, it can occur.

When transporting patients who have received pentobarbital, methohexital, or thiopental

from a more controlled location such as the emergency department to a radiology suite, vigilance

is required to maintain adequate monitoring and to ensure that skilled personnel remain available



to manage airway complications. Barbiturates are rapidly absorbed rectally and methohexital or

thiopental given by this route can reliably produce anxiolysis and sedation suitable for CT or

MRI scanning. Although respiratory depression is unusual with typical doses, it can occur.95

BENZODIAZEPENES

Mode of action:

Binding of gamma – aminobutyric acid (GABA) to its receptor on the cell membrane triggers an

opening of a chloride channel, which leads to an increase in chloride conductance. The influx of

chloride ions causes a small hyper polarization that moves the post- synaptic potential away from

its firing threshold and thus inhibits the formation of action potential away from its firing

threshold and thus inhibits the formation of action potentials. Benzodiazepines bind to specific,

high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for

GABA.93

The benzodiazepine receptors are found only in the central nervous system, and their

location parallels that of the GABA neurons. The binding of benzodiazepines enhances the



affinity of GABA receptors for this neurotransmitter, resulting in a more frequent opening of

adjacent chloride channel. This in turn results in hyper polarization and further inhibition of

neuronal firing. Benzodiazepines and GABA mutually increase the affinity of their binding sites

without actually changing the total number of sites. The clinical effects of the various

benzodiazepines correlate well with each drug‟s binding affinity for the GABA receptor-

chloride ion channel complex.93

At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety

by selectively inhibiting neuronal circuits in the limbic system of the brain. All of the

benzodiazepines used to treat anxiety have some sedative properties. At higher doses, certain

benzodiazepines produce hypnosis.

Uses:

Primary therapeutic effects of benzodiazepines include sedation, anxiolysis, and anterograde

amnesia – all beneficial for the treatment of the fearful pediatric dental patient. These drugs

possess muscle relaxant and anti-convulsant properties as well. 93



Adverse Effects:

Benzodiazepines demonstrate a wide margin of safety and a wide therapeutic index which

represents the dosage difference between an effective dose and a lethal dose. Its onset and

duration of action are relatively short when compared with other orally administered sedatives.

Minimal adverse reactions are associated with these drugs, and a reversible agent is available.

Benzodiazepines administered alone can cause respiratory depression, an effect that is amplified

when given in combination with opioids. Moreover, this synergistic effect causing significant

respiratory depression can also occur when benzodiazepines are administered in the presence of

other CNS depressants such as a patient‟s own medications.

Physiological effects may include nausea, vomiting and/or unsteady movements

(ataxia). This latter condition can manifest as a loss of head control, leading to a compromise of

the patient‟s airway. Other undesirable responses may include a paradoxical or angry response,

whereby the patient appears irritable, agitated and/or combative. Benzodiazepines should be

avoided in patients with acute narrow angle glaucoma, and are contraindicated for patients with a

known allergy or hypersensitivity to them or any of their components. 93

DIAZEPAM

Diazepam is a benzodiazepine derivative. The chemical name of diazepam is 7-chloro-1, 3-

dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one. It is a colorless to light yellow

crystalline compound. The empirical formula is C16H13ClN2O and the molecular weight is

284.75. The structural formula is as follows:96



A benzodiazepine that is lipid soluble and water insoluble. It is readily absorbed from the

gastro intestinal tract, reaching peak levels at 2 hours. Biotransformation of the drug occurs quite

slowly and it has a half life of 20 to 50 hours. The drug has three active metabolites, one of

which is also very lipophilic and has a half life of 96 hours. These metabolites are anxiolytic than

sedative.

After intravenous administration, diazepam is redistributed within 30 to 45 minutes,

and the patient seems not to be sedated although free from anxiety. The patient should not be

considered recovered from the drug. It has simply been redistributed. In fact stored drug can be

redistributed to the CNS by a fatty meal consumed sometime later and the patient will suddenly

feel resedated. This is referred to as rebound effect.

Diazepam has strong anticonvulsant activity and provides some prophylaxis against this

adverse reaction of other drugs during the operative procedure. Diazepam can be administered

orally, rectally, or parenterally. If the intravenous route is selected, use of a large vein and slow

administration is recommended because the drug‟s propensity to cause irritation of the vein, with

resultant thrombophlebitis. In addition rapid administration may result in apnea. Ataxia and

prolonged CNS effects are the only common adverse reactions that can be anticipated when

diazepam is used for conscious sedation. 97



Dosage:

Oral or rectal – 0.2to 0.5 mg/kg to a maximum single dose of 10mg

Intravenous – 0.25mg/kg

Supplied as:

Tablets – 2, 5, and 10 mg

Suspension- 5mg/ml

MIDAZOLAM

Midazolam HCL first was synthesized by Fryer and Walser in 1976. Midazolam is a short-

acting, water-soluble benzodiazepine. It has anxiolytic, sedative, hypnotic, anticonvulsant,

muscle-relaxant, and anterograde amnesic effects. The drug has been used as a preanesthetic

sedative in adults, and more recently in children. Chemically, midazolam HCl is 8-chloro-6-(2-

fluorophenyl)-1-methyl-4 H -imidazo [1, 5-a] [1, 4] benzodiazepine hydrochloride. Midazolam

hydrochloride has the molecular formula C18H13ClFN3•HCl, a calculated molecular weight of

362.25 and the following structural formula: 96

Midazolam is imidazo benzene with unique properties when compared with other

benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo.

Midazolam also has a relatively rapid onset of action and high metabolic clearance when



compared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and anti

anxiety effects when administered orally, intramuscularly, or intravenously. There are many uses

for midazolam in the peri operative period including premedication, anesthesia induction and

maintenance, and sedation for diagnostic and therapeutic procedures. Clinical advantages of

midazolam are: 98

1. Water soluble

2. Rapid onset

3. Short acting

4. Anticonvulsant, muscle relaxant

5. Anterograde amnesia

6. Clinically inactive metabolites

7. Relatively high margin of safety

8. Reversal agent available

9. May be administered intra nasally

Like most drugs, its onset of action varies greatly depending upon its route of

administration. Intravenous administration will result in the most rapid onset of action due to its

immediate deposit into a patient‟s circulation. However, when administered orally, the drug is

exposed to metabolic clearance mechanisms in the intestine and liver, and will take longer to

produce its pharmacological effects pending its eventual deposit into the circulatory system and

action at receptors.

For pediatric dental patients, it is commonly administered orally, in doses of 0.25 –

0.75 mg/kg, with an upper limit of up to 1.0 mg/kg. An effective dose is usually 0.5 mg/kg and

should not exceed the maximally recommended dose of mg. In obese children, the dose should



be calculated based on ideal body weight. When supplied as an oral formulation, the bitter taste

often requires an accompanying flavoring agent, (i.e. apple juice) for patient acceptance. In order

to enhance analgesia, the sedative can be mixed with an acetaminophen elixir, at a dosage of 15

mg/kg. The oral form of midazolam has a cherry flavored vehicle that can be mixed with

children‟s flavored aspirin or acetaminophen to increase the palatability.84

Intravenous midazolam is highly lipid soluble and redistributes rapidly.

Consequently intravenous midazolam can be titrated to effect with fractionated doses of 0.05-0.1

mg/kg that may be repeated at intervals of 3 to 4 minutes. As opposed to the oral route of

administration, intravenous midazolam reaches peak effect in 2 to 3 minutes. Slow intravenous

administration is recommended with close observation for respiratory depression. When

combined with intravenous opioids for painful procedures, midazolam has potent sedative effects

and the use of cardio-respiratory monitoring is imperative. A maximum intravenous dose of 0.05
88
mg/kg has been recommended when combining the drug with narcotics.

Anterograde amnesia is even more prominent than when the drug is used orally.

Slurred speech has been shown to coincide with the onset of anterograde amnesia. Certain

underlying conditions or medications may prolong the effects of midazolam. Heparin decreases

protein binding and increases the free fraction. Hepatic metabolism is inhibited by cimetidine,

which prolongs the elimination half-life. Intravenous midazolam is an excellent agent for

sedation and anxiolysis in patients for minor procedures when an intravenous line is in place. It

provides complementary sedation for patients receiving opioids for very painful procedures due

to synergy but extreme caution is warranted when combining the drugs due to respiratory

depression.



Midazolam may be given as an intramuscular bolus of 0.08-0.1 mg/kg. Good

sedation and cooperation scores were recorded at 15 minutes after this dose in one study.

Persistent sedation is minimal 60 minutes after the dose. Midazolam gives reliable sedation after

intramuscular dosing - a useful alternative for children who will not accept oral medications,

particularly where residual sedation is a concern.84

Midazolam may be given by the intranasal route at doses of 0.2-0.4mg/kg. Onset

time is intermediate between the oral and intravenous routes of administration (10-15 minutes).

The effectiveness of this route of administration is well established as a pre - medicant for

anesthesia but its use is limited by burning on application to the nasal mucosa which most

children find very objectionable, as well as the bitter taste of midazolam reaching the

oropharynx. Adverse effects including respiratory depression and synergy with opioids are

similar to those mentioned above. For sedation and anxiolysis in young children who either

refuse or cannot take an oral dose of midazolam. Onset is reliable but most children will only

accept this route of administration once.97

Midazolam may be administered rectally at doses of 0.3-0.75 mg/kg. A dose of 0.3

mg/kg has been shown to give reliable levels of sedation with a mean time of 16 minutes to

maximal blood level. Rectal administration is generally not as well tolerated in children > 3 years

of age. After thirty minutes, blood levels were generally low but sedation and anxiolysis effects

remain.84

Dosage: Oral – 0.25 to 1.0 mg/kg to a maximum single dose of 20mg;

Intramuscular – 0.1 to 0.15 mg/kg to a maximum dose of 10 mg;

Intravenous – slow titration;



Supplied as: Syrup-2mg/ml;

Injectable – 1- and 5mg/ml vials

BENZODIAZEPINE ANTAGONIST: FLUMAZENIL

One of the benefits of using benzodiazepines is the ability to reverse possible undesirable effects

such as oversedation. Flumazenil is a benzodiazepine antagonist, acting competitively at the

benzodiazepine site of the GABA receptor, but without altering its morphology. Chemically,

flumazenil is ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a] (1, 4)

benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated

molecular weight of 303.3, and the following structural formula: 96

Flumazenil is a white to off-white crystalline compound with an octanol: buffer partition

coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous

solutions.

This reversal agent is typically administered intravenously and its onset of action is

usually within 1 minute. The first dose administered is 0.01 mg/kg with a maximum dose of 0.2

mg. Doses should be administered slowly over 15-30 seconds, and may be repeated every minute

at 0.01 mg/kg for up to 5 doses or a maximum cumulative dose of 1.0 mg. The duration of action

of flumazenil is about 30 minutes, less than the half life of the benzodiazepine being reversed.

Therefore, the patient should be carefully monitored after its administration for any signs of



resedation and hypoventilation. If such undesirable signs occur, another dose may be required or

an infusion may need to be initiated.97

For reversal of sedation, the initial dose should be 0.01 mg/kg (up to 0.2 mg) given over

15 seconds. If the desired level of consciousness does not occur after waiting an additional 45

seconds, another dose of 0.01 mg/kg (up to 0.2 mg) should be administered and dosing repeated

at 60-second intervals to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. Most

patients respond to doses in the range of 0.6 to 1.0 mg. A series of injections is preferable to a

single bolus to titrate to a desired end point and thus manage the problem with the minimally

effective amount of drug. Onset of reversal is usually seen within 1 to 2 minutes. 88

The duration and degree of reversal are related to dose and plasma concentration of

the sedating benzodiazepine, as well as that of the antagonist given. This coupled with the fact

that the duration of effect is shorter for flumazenil than for most benzodiazepines, means that

resedation can occur. Patients should be carefully monitored for re-sedation and respiratory

depression throughout that period of reversal. The longer the period of sedation, the longer that

period required for monitoring and surveillance for re-sedation. If re-sedation occurs, repeated

doses of flumazenil at no less than 20-minute intervals may be used.

Dosage: intravenous – as described above

Supplied as: 5-and 10ml multiple-use vials containing 0.1 mg/ml in boxes of 10

CHLORAL HYDRATE

Chloral hydrate, the oldest member of the hypnotic group of drugs, was discovered by Liebig in

1832.It is produced by the hydration of chloral (trichloroacetalydhyde -CC, CHO). The chloral

hydrate produced is a crystalline substance readily soluble in oil or water. Chloral Hydrate is



classified as a non-barbiturate, a hypnotic that has been widely used as a sedative in pediatric

dentistry for decades.96

Its mechanism of action is unknown, yet its depressant effects on the C.N.S. are

primarily due to its active metabolite, trichloro ethanol (TCE), a carcinogen in mice. Following

oral administration, chloral hydrate is absorbed into the bloodstream and the major portion of

this drug is reduced by liver alcohol dehydrogenase to trichoroethanol. The trichloroethanol may

then be conjugated to glucoronides of urochloralic acid and excreted in the urine and bile. A

small portion of the chloral hydrate as well as a small portion of trichloroethanol is oxidized in

the kidney and liver by a DPNH-dependent enzyme system to the inactive metabolite,

trichloroacetic acid.

It may be administered orally at a dose of 25-50 mg/kg, with a maximal total dose of

1,000 mg. Its onset of action is 30-60 minutes and duration of up to 5 hours. A major

disadvantage of this medication is that of all the orally administered sedative medications, it may

have the worst taste. Moreover, its liquid concentration is a mucosal irritant that can cause

nausea, vomiting or even laryngospasm. 84

Compared with other agents, other notable side effects include its delayed onset, prolonged

recovery, possible cardio-irregularity at higher doses, and no analgesic properties. Chloral

hydrate depresses genioglossus activity causing hypotonicity of the tongue which can lead to it

falling backward against oropharyngeal structures, depressing respiration and compromising the

patient‟s airway. Moreover, it has no reversal agent.88



Nordenberg, et al., reported that the recommended hypnotic dose of chloral hydrate

depresses the cerebral hemispheres and induces sleep without significant changes in respiration,

blood pressure or heart rate. With higher doses the respiratory rate may be depressed and the

blood pressure reduced due to medullary depression and peripheral cutaneous vasodilation.

However, because of its therapeutic ratio, these and other known untoward effects are not seen

following the ingestion of sedative quantities.

It is particularly effective for non-painful procedures requiring sedation or sleep in

children younger than 2 years of age who do not require an intravenous catheter. Some

practitioners recommend sleep deprivation for children prior to giving chloral hydrate. Chloral

hydrate should be given in a quiet, calm and dimly lit environment to be most effective.

Chloral hydrate is well established as a sedative for painless procedures such as for

radiographs, CT and MRI scans. Usefulness in painful procedures is limited by patient

movement and agitation that occurs during a painful procedure even when the child may appear

to be much sedated. The long elimination half-life of chloral hydrate (trichloroethanol) often is

an indication for prolonged supervision prior to discharge.84

PROPOFOL

Propofol is 2, 6 diisopropylphenol, a phenol derivative with sedative, hypnotic and anesthetic

properties. 96



Propofol is a clear colourless insoluble phenolic compound supplied in an isotonic, oil-in-

water, Intra-lipid emulsion that came into use as a useful, short acting, IV anaesthetic in 1984. It

is unrelated, chemically, to any other anaesthetic agent, but behaves rather like ketamine (q.v.).

Recovery from propofol is, however, rather more rapid, and „hangovers‟ are less common. The

drug is rapidly redistributed into fat and other body tissues and more than half leaves the

circulation within 10 minutes even after neonatal IV administration. It is then conjugated and

metabolized in the liver, the elimination half life being 5–10 hours although, with sustained use,

elimination from deep stores may take 2–3 days.96

Propofol‟s primary mechanism of action is through the GABAA receptor. Through

this mechanism propofol results in neuronal cell membrane hyper polarization, inhibition of the

action potential and a reduction in cell activity. Propofol is not teratogenic or fetotoxic in

animals but crosses the placenta readily, and the manufacturers do not recommend use during

pregnancy or delivery, although no problems have been encountered with use for Caesarean

delivery.97

Propofol can be administered by either bolus dosing or bolus dosing followed by a

continuous infusion. Because of propofol‟s short duration, procedures exceeding 15 to 20

minutes are often best managed by a bolus dose followed by continuous infusion to maintain the

desired plasma concentration and clinical effect. As noted above onset of action is extremely

rapid and induction of sedation or anesthesia may be achieved with 2-3 mg/kg in 95% of patients

within 60-90 seconds. Typical induction doses for sedation include infusing propofol at 0.5-2

mg/kg/min until the child is asleep. Infusion of 100-150 mcg/kg/min maintain sleep in close to

100% of patients. Doses of propofol following induction can be used at 0.5-1 mg/kg if the patient
84
awakens.



The three properties of propofol that make it such a useful sedative-hypnotic are high

lipid solubility, large volume of distribution and high metabolic clearance. In fact clearance of

propofol exceeds hepatic blood flow. Propofol is metabolized by the liver through

glucuronidation pathways to inactive conjugated metabolites. It is highly protein bound. Its

pharmacokinetics is summarized best by a 3-compartment model. Infants have a larger volume

of distribution and a greater metabolic clearance than older children. Consequently bolus doses

required to achieve clinical effect is higher in infants. Similarly because the metabolic clearance

is higher in infants, continuous infusions rates are greater.

Propofol is particularly effective as a sole agent for noninvasive radiologic procedures. For

MRI and CT scans infusions of 100-150 mcg/kg results in a very high success rate. Propofol is

also very effective either as a sole agent or combined with opioids/ketamine for brief painful

procedures. As a single agent propofol is effective for invasive oncology procedures89,90 and

gastrointestinal procedures84

KETAMINE

Ketamine is chemically related to phencyclidine (PCP) and cyclohexamine; it has a molecular

weight of 238 and a pKa of 7.5. Although ketamine hydrochloride is water soluble, ketamine's

lipid solubility is ten times that of thiopentone. The molecular structure (2-(O-chloropheny l)-2-

methylamino cyclohexanone) contains a chiral centre at the C-2 carbon of the cyclohexanone

ring so that two enantiomers of the ketamine molecule exist: s (+) ketamine and r (-) ketamine.96



The mechanism of action of Ketamine includes:99

1. Noncompetitive antagonist of the central nervous system NMDA receptors

a. NMDA receptor is a calcium-gated channel receptor

b. NMDA receptor agonists are excitatory amino acids: glutamic acid, aspartic

Acid and glycine

c. Agonist binding to receptor results in opening of ion channel and depolarization

Of the neuron

d. NMDA receptor is involved in sensory input at the spinal, thalamic, limbic, and

Cortical levels

e. Ketamine blocks sensory input and impairs limbic functions

2. Agonist at α- and β-adrenergic receptors

3. Antagonist at muscarinic receptors of the central nervous system

4. Blocks reuptake of catecholamines

5. Agonist at opioid sigma receptor

Ketamine is one of the most versatile sedative-analgesic agents and results in a

number of desired clinical effects that are dose-dependent.At the lowest of doses anxiolysis and



analgesia occur. Antegrade amnesia occurs at slightly higher doses and is often accompanied by

perceptual changes. Higher doses result in a sedated state that is described as a “dissociative

sedation”. Typically spontaneous respirations and airway reflexes are maintained although may

not be totally normal. Ketamine generally causes an increase in heart rate, blood pressure and

cardiac output. 100

Because of concerns of potentially increasing intracranial pressure, ketamine should be

used with caution in patients with suspected increased intracranial pressure as well as open globe

injuries. Ketamine‟s neuropsychiatric effects include visual hallucinations that may be

accompanied by emergence phenomena and agitation. Oral secretions are typically only mildly

increased but may require antisialogogues. The single most severe adverse effect with ketamine

sedation is laryngospasm. Ketamine is clinically effective by a number of different routes.

Oral/Rectal Ketamine:

Oral and rectal doses of ketamine are 4-10 mg/kg. Onset of sedation occurs in 15-30 minutes and

effects may be prolonged by the oral or rectal route lasting 3 to 4 hours. Ketamine‟s active

metabolite norketamine predominates with oral/rectal administration typically in a ratio of

norketamine to ketamine of 5 to 1 and 3 to 1 respectively. Norketamine is approximately one-

third as potent as ketamine. Following oral administration (10 mg/kg), peak effects occurred in

30 to 40 minutes in children undergoing painful cancer procedures. Typically, higher doses of

oral ketamine (8-10 mg/kg) are more effective as a premedication than lower doses (3-6

mg/kg).84

Intramuscular (IM) Ketamine:

Intramuscular ketamine reaches peak blood levels and clinical effect in five minutes after 3 to 10

mg/kg. Recovery from dissociation occurs within 15 to 30 minutes with coherence and



purposeful neuromuscular activity returning in 30-120 minutes. A smaller dose of 3 mg/kg has

been employed to facilitate intravenous catheter placement or acceptance of a mask for

anesthesia induction, with no delay in discharge compared to control patients after 60 minutes.

The 100 mg/ml formulation of ketamine is preferred for IM administration in older

children to minimize volume related injection site discomfort. Experience with intramuscular

ketamine is extensive. Sedation is accompanied by the excellent analgesia. Intramuscular

administration of ketamine is an excellent means of sedating the “out of control” patient for IV

placement or mildly painful procedures. Deep sedation may occur. 84

Intravenous Ketamine:

Ketamine is typically given in doses of 0.5 to 1 mg/kg although doses of 2 mg/kg can be used.

Peak concentrations occur within 1 to 2 minutes and rapid absorption by the highly perfused

cerebral tissues allows almost immediate induction of clinical effects. Ketamine then slowly

redistributes into the peripheral tissues; thus decreasing central nervous system levels that

correlate with return of coherence, generally 10-15 minutes if no additional doses are given.

Deep levels of sedation may be achieved. Remarkably painful procedures are tolerated well

following administration of ketamine because of its profound analgesic effects as well as the

dissociative sedation it affords.

Intravenous ketamine is well established as a safe and efficacious agent in pediatric

patients. Because of higher blood levels with intravenous use, ketamine administered by this

route may have more problems than oral or intramuscular administration. Oral secretions may be

avoided by the administration of an antisialogogue (atropine 0.01-0.02 mg/kg or glycopyrrolate

0.005 mg/kg intravenous). 84



Although patients will continue to breath and maintain airway tone, silent pulmonary

aspiration of oral contents has been reported with deep levels of sedation. Patients may continue

to move during sedation and eyes remain open. Emergence delirium is much less common in

children than adults and may be prevented or treated by the administration of a small dose of a

benzodiazepine or preparing the patient by discussing the clinical effects of ketamine prior to

administration.

Ketamine alone is particularly effective for procedures with moderate to severe

discomfort and pain. Initial doses of 0.5 mg/kg followed by repeat doses of 0.25-0.5 mg/kg were

effective for 97% of pediatric patients undergoing invasive emergency department procedures. In

combination with midazolam, ketamine doses of 0.5-1.5 mg/kg was superior in efficacy and

safety to an opioid-midazolam combination in children undergoing painful pediatric oncology

procedures.

Similarly the combination of propofol and ketamine 1 mg/kg resulted in less restlessness

during burn dressing changes compared to a propofol-fentanyl combination. Ketamine should be

used cautiously if at all in individuals with intracranial hypertension, systemic hypertension or

neuropsychiatric disorders and/or any child with visual or auditory. 84

NARCOTICS

Narcotics are the “heavy artillery” of pediatric sedation. They are not employed with any

great consideration for their analgesic properties. They do produce sedation and euphoria to a

greater degree in children than in adults. Local anesthesia is still required for intra-operative pain

control. Local anesthetics are also CNS depressants.



A significant drug-drug and drug-physiologic interaction can occur when narcotics or

other drugs that depress respiration are combined with local anesthetics. In usual doses, local

anesthetics are CNS depressants and will provide additive depression when combined with other

CNS depressants. In addition, when drugs that depress respiration are used (particularly

narcotics), varying degrees of hypercarbia can occur, with a resultant decrease in serum pH. As

the respiratory depression continues to deepen, respiratory and metabolic acidosis results in an

increase in the availability of lidocaine to the CNS. This occurs as a result of less serum protein

binding of lidocaine along with central vasodilation and an increase in blood flow to the CNS inn

an acidotic state. 97

Consequently the threshold for CNS lidocaine toxicity is lowered. Lidocaine toxicity

results in CNS excitation and seizures and ultimately coma and death. As a result, the maximum

dosage of local anesthetic must be reduced when used in combination with a CNS and/or

respiratory depressant. This very important and significant interaction is often overlooked and is

the cause of many of the adverse incidents reported in pediatric sedation. The maximum local

anesthetic does in children may allow for the use of only one or two dental cartridges, which is

quite different than for adult patients.

Combination with other sedative drugs, including nitrous oxide-oxygen, reduces the need

for larger doses of narcotics and thus reduces the potential for unwanted effects from these

potent drugs. A practitioner employing narcotics should be thoroughly familiar with their actions

and interactions and should have had some supervised experience in their use as well as in

management of the airway and patient resuscitation procedures.88



FENTANYL

Fentanyl is a synthetic opiate agonist in the same chemical class as meperidine. It is a potent

narcotic analgesic. A dose of 0.1 mg is approximately equivalent to 10 mg of morphine or 75 mg

of meperidine. Fentanyl has a rapid action, and after a submucosal or intramuscular injection the

onset occurs in 7 to 15 minutes; duration of effects is 1 to 2 hours. The drug is metabolized by

the liver and is excreted in the urine.97

Fentanyl produces little histamine release and has much less emetic effect than morphine

or meperidine. Fentanyl can be administered by the intramuscular, intravenous, or submucosal

route. When it is used with other CNS depressants, the dose should be reduced. The drug works

well with orally administered diazepam and nitrous oxide-oxygen. It is not recommended for use

in children younger than 2 years of age.

The oral transmucosal preparation of fentanyl has never become popular for procedural

sedation and analgesia because titration is difficult, effectiveness is variable, and the incidence of

emesis is high (31–45%).89 Like all opioids, fentanyl can cause respiratory depression. Because

of the lack of histamine release with fentanyl, nausea and vomiting are less common than with

morphine or meperidine. In the absence of substantial ethanol intoxication, hypovolaemia, or

concomitant drug ingestion, hypotension is rare, even with very large doses of fentanyl (doses of

50 _g/kg are common in adult and pediatric cardiac surgery). A common reaction to fentanyl is

isolated nasal pruritus.97

A widely-described but rare adverse effect of fentanyl with potential for respiratory

compromise is chest-wall rigidity. This complication is associated with much higher doses (_5



_g/kg as a bolus dose) than those used for procedural sedation and analgesia; indeed, this adverse

event has not been reported in this setting.

Dosage: 0.002 to 0.004 mg/kg

Supplied: 0.05 mg/mL in 2-and 5-mL amples

MEPERIDINE

Meperidine is a synthetic opiate agonist. It is water soluble but is incompatible with many other

drugs in solution. Meperidine may be administered orally or by subcutaneous, intramuscular, or

intravenous injection. It is least effective by mouth. It is bitter and requires taste masking by a

flavoring agent. By the oral route, peak effect occurs in 1 hour and lasts about 4 hours. Parenteral

administration shortens the time of onset and duration. High doses that lead to an accumulation

of normeperidine, a primary metabolite of meperidine, have resulted in seizures. Meperidine

should be used with extreme caution in patients likely to accumulate or be sensitive to this

metabolite (e.g., patients with hepatic or renal disease, or history of seizures).

Dosage: Oral, subcutaneous, or intramuscular-1.0 to 2.2 mg/kg, not to exceed 100mg

when given alone or 50 mg when in combination with other CNS depressants 97

Supplied: Oral tablets-50 and 100 mg;

Oral syrup-50mg/5mL;

Parenteral solution-25, 50, 75, and 100 mg/mL.



NARCOTIC ANTAGONIST

A semi synthetic opiate antagonist used for the sole purpose of reversing the effects of narcotic

drugs. Naloxone is a pure antagonist, with no agonist activity even in large doses. It acts in 2 to 5

minutes after subcutaneous or intramuscular injection and 1 to 2 minutes intravenously. After

intravenous administration the duration of reversal about 45 minutes; it is slightly longer when

the drug is administered intramuscularly or subcutaneously. This is an important difference,

because the duration of reversal is about 45 minutes; it is slightly longer when the drug is

administered intramuscularly or subcutaneously. This is an important difference, because the

duration of effect of the opiate is in all likelihood longer than that of the antagonist.

Consequently, patients undergoing reversal of sedation with naloxone should be kept

under continual surveillance until it has been determined that the narcotic will not produce a

rebound effect. The time period will vary depending on the duration of action of the narcotic.

Repeated doses of naloxone may be necessary to establish patient stability. If the decision has

been made to administer an antagonist, other resuscitative measures must be available and must

be used as necessary. Naloxone administration should never take precedence over basic

resuscitative measures. There is no evidence to support the contention that naloxone will reverse

respiratory depression but not the sedative action of the opiate.97

Adverse reactions include nausea, vomiting, sweating, hypotension, hypertension,

ventricular tachycardia and fibrillation, and pulmonary edema. None of these effects, however,

has been reported with its use in pediatric conscious sedation.

Dosage: Intravenous, subcutaneous, intramuscular-initial dose: 0.01 mg/kg; subsequent doses:

0.1 mg /kg (2 mg maximum) every 2 to 3 minutes



Supplied: Parenteral solution-0.02, 0.4, 1.0 mg/kg

NITROUS OXIDE

Nitrous oxide is an inorganic inhalation agent that is colourless, odorless to sweet-smelling, and

non-irritating to the tissues. It is non-flammable but will support combustion. It is slightly

heavier than air, with a specific gravity of 1.53, and has a blood: gas partition coefficient of 0.47.

Because of its low solubility in blood, it has a very rapid onset and recovery time.

Nitrous oxide has multiple mechanisms of action. The analgesic effect of nitrous oxide

appears to be initiated by neuronal release of endogenous opioid peptides with subsequent

activation of opioid receptors and descending Gamma-amino butyric acid type A (GABAA)

receptors and noradrenergic pathways that modulate nociceptive processing at the spinal level.

The anxiolytic effect involves activation of the GABAA receptor either directly or indirectly

through the benzodiazepine binding site.

Unlike other anaesthetics, nitrous oxide produces a mild analgesic effect at subanesthetic

concentrations. The mechanism for this effect most likely involves an interaction with the

endogenous opioid system because it is abolished by administration of the opioid antagonist,

naloxone. The strongest evidence is that nitrous oxide stimulates release of enkephalins, which

bind to opioid receptors that trigger descending noradrenergic pathways.

Inhaled nitrous oxide provides anxiolysis and mild analgesia and sedation. It is commonly

dispensed at concentrations between 30% and 70% with oxygen composing the remainder of the

mixture. Nitrous oxide has rapid onset (30–60 s), maximum effect after about 5 min, and rapid



recovery upon discontinuation. At typical procedural sedation and analgesia concentrations there

is preservation of hemodynamic status, spontaneous respirations, and protective airway reflexes.

Nitrous oxide has an excellent safety profile; however as a sole agent it does not reliably produce

adequate procedural conditions, and in many cases is supplemented with an opioid or local or

regional anesthesia. Administration can also be useful for intravenous access or venipuncture in

frightened children.

The safest method of nitrous oxide administration is via a self-administered demand-valve

mask, which needs negative inspiratory pressure to activate gas flow. If the patient becomes

somnolent, the mask will fall from their face and gas delivery will cease. The main limitation of

self-administration is that it is ineffective in uncooperative patients, including most frightened

young children.

Continuous-flow nitrous oxide has been used in this population with a mask strapped over

the nose, or over the nose and mouth producing moderate or deep sedation and necessitating an

additional physician dedicated to continuous gas titration. This technique is associated with

more frequent emesis than self-administration (0% vs. 4%), posing a potential hazard when a

mask is strapped over the child‟s mouth.

Several minor adverse effects can be evident, including nausea, dizziness, voice

change, euphoria, and laughter. Because of its high diffusibility, nitrous oxide should be avoided

in patients with potential closed-space diseases such as bowel obstruction, middle ear disease,

pneumothorax, or pneumocephaly. A scavenging system must be in place to ensure compliance

with occupational safety regulations as occupational exposure to nitrous oxide has been

associated with increased rates of spontaneous abortions.



ANTIHISTAMINES

HYDROXYZINE

Hydroxyzine hydrochloride is designated chemically as 2-[2-[4-(p-Chloro-?-phenylbenzyl)-1-

piperazinyl] ethoxy] ethanol dihydrochloride. Hydroxyzine hydrochloride occurs as a white,

odorless powder which is very soluble in water 96

Hydroxyzine is an antihistamine with mild sedative and antiemetic properties. In

normal doses, it has no cardio vascular or respiratory depressant effects. It is rapidly absorbed

from the gastrointestinal tract with clinical effect seen in 15 to 30 minutes, peak levels occur at 2

hours, and mean half-life is 3 hours. Administration is preferably by the oral route. Intramuscular

injections must be deep in a large muscle mass. The drug should not be injected subcutaneously

or intravenously because of potential tissue necrosis and hemolysis. Adverse reactions include

extreme drowsiness, dry mouth and hypersensitivity.97

Dosage: Oral-1 to 2mg/kg;

Intramuscular-1.1mg/kg

Supplied as: Tablets-10, 25, 50 and 100mg;

Syrup- 10mg/5ml;

Injectable-25 or 50mg/ml;



DRUGS USED FOR PROCEDURAL SEDATION AND ANALGESIA


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