pharmacology general anesthetics and anxiolytics

balanced anesthesia

• A combination of drugs to produce a reversible loss of consciousness and insensibility to painful stimuli while minimizing adverse reactions, taking into account the patient’s physical status, and preanesthetic and postanesthetic needs.

conscious sedation

• General dentists (and dental hygienists in some states) use nitrous oxide to provide conscious sedation and pain control)

history of general anesthetics

• Original methods  of producing general anesthesia involved strangulation or cerebral concussion

• Later opium, belladonna, hemp, and alcohol were used to render patients unconscious. Operations were quick and dirty

• Nitrous oxide was discovered in 1776

• Mid 1800’s true general anesthetics were discovered in the US.

• In 1846 surgically related mortality dropped dramatically with introduction of Ether

• Today anesthesiologists use a combination of inhaled and IV general anesthetics resulting in loss of consciousness, amnesia, immobility.

mechanism of local anesthesia action

• No theory completed explains the __ __ __ of various general anesthetics

• CNS depression is part of the explanation, however there is a lack of knowledge regarding arousal and unconsciousness

stage I analgesia

• Nitrous oxide as used in dental office, patient conscious and still responds to commands

• patient is unresponsive

• reduced sensation to pain

• can still respond to commands

• reflexes are present

• regular respiration

• some amnesia

• loss of consciousness

stage II delirium or excitement

• Uncomfortable stage for patient incontinence and vomiting can occur

• unconsciousness

• amnesia

• involuntary movement and excitement

• irregular respiration

• increased muscle tone

• sympathetic stimulation: tachycardia, mydriasis, hypertension

stage III surgical anesthesia

• return to regular respiration, muscle relaxation, and normal heart and pulse rates

• divided into four planes

  • 1: return to normal respirator movements, muscle relaxation, normal heart rate

  • 2: reflexes associated with eye diappear

  • 3: decreased skeletal tone, dilated pupils, tachycardia, hypotension

  • 4: diaphragmatic breathing, absence of reflexes, extreme muscle flaccidity

stage IV respiratory or medullary paralysis

• Complete cessation of respiration, circulatory failure

• cessation of respiration

• subsequent circulatory failure

• respiration must be artificially maintained

flaggs levels of anesthesia

• modern anesthetic techniques are more rapidly acting

• induction, maintenance, and recovery

flaggs induction phase

• All the preparation and medication necessary for a patient up to the time the operation begins

flaggs maintenance phase

• Begins with patient at a depth of anesthesia sufficient to allow surgical manipulation and continues to end of procedure

flaggs recovery phase

• Begins at termination of surgical procedure; continues through postoperative period until the patient is fully responsive

• important!!

gases

• nitrous oxide

volatile liquids

• halogenated ethers

  • sevoflurane

  • isoflurane

• ethers

  • diethyl ether

intravenous agents

• barbiturates

  • methohexital

Iv anesthetics

• a diverse group of CNS depressants

  • opioids, ultra short acting barbiturates, benzodiasepines, ketamine can be given IM

• depth and duration of anesthesia are less easily controlled than with inhalation agents

ultrashort-acting barbituates

• methohexital Sodium (Brevital), thiopental sodium (Pentothal), thiamylal sodium (Surital)

• Rapid onset (30-40 seconds) given IV

• Highly lipid soluble

• Blood and brain levels quickly decrease as drugs redistribute to skeletal muscle

• Complications: Laryngospasm and bronchospasm

• Some patients experience hiccups and delirium on recovery. Atropine and opioids may prevent this.

• Can cause cardiovascular and respiratory adverse effects

etomidate

• short acting IV anesthetic

• Used for conscious sedation and as part of rapid general anesthesia induction

• Rapid onset

• Safe cardiovascular profile

• Metabolized by liver

• Can cause adrenal suppression

propofol

• Unrelated to any other general anesthetic

• IV anesthetic onset of action is 30 seconds

• Duration of action is about 5 minutes

• Recovery patient’s feel better

• Produces little vomiting

• Can be used for induction and maintenance

• Metabolized by liver

• Can cause cardiovascular and respiratory depression (Michael Jackson)

ketamine

• Related to phencyclidine (PCP, angel dust) a hallucinogen

• Called dissociative (separates you from who you are) anesthesia appears to disrupt association paths in brain

• Patient appears to be catatonic and has amnesia

• Produces analgesia without loss of consciousness

• May be given IV or IM onset of 1-2 minutes

• Little respiratory change, pharyngeal and laryngeal reflexes intact

• Increase cardiac output

• Increase salivation, sometimes given with atropine for this salivation

opioids

• Used as adjunctive drugs to general anesthesia

• used: Morphine, fentanyl, sufentanil, and alfentanil

• Do not significantly alter cardiovascular function or peripheral resistance

• Prolonged respiratory depression is major disadvantage

• Naloxone can reverse respiratory depression of opioids

benzodiazepines

• Anxiolytic drugs

• Valium and Versed have been used for years

  • Versed is water soluble so eliminates thrombophlebitis found with diazepam

  • Versed has shorter duration, and better amnesic effect

induction and maintenance anesthesia

• inhalation anesthetics

• surgeon may use gas prior to general anesthesia

  • gases

  • volatile liquids

volatile liquids

• Liquids vaporized and carried to patient in the form of a gas

• Classified as halogenated hydrocarbons

• The less soluble the anesthetic is in body tissues the more rapid onset which allows anesthesiologist to adjust desired level quickly

nitrous oxide

• Colorless odorless gas

• Least soluble in blood of all inhalation anesthetics

• Provides anxiety relief. Rapid onset

• Technique involves increasing concentration to obtain desired level of sedation

• End of procedure 100% oxygen for 5 minutes

nitrous oxide contraindications

• Respiratory obstruction- if cannot breathe cannot inhale anesthetic

• COPD- respiration is driven by lack of oxygen rather than elevated carbon dioxide. Breathing higher oxygen levels could affect their breathing

• Emotional Instability- Some may experience euphoria a patient with emotional instability, depression, or severe anxiety may not respond to nitrous oxide

• Pregnancy- Some studies suggest there is a safety risk exposing a pregnant person to nitrous oxide, thus it is avoided. (if it is used must at LEAST have 50% oxygen and only used for 30 minutes, avoid constant introduction)

potential hazards of nitrous oxide misuse

• Numbness and paresthesia of the hands or legs

• This may progress to severe neurologic symptoms

• Liver and kidney problems have been mentioned with nitrous abuse

halogenated hydrocarbons

• isoflurane

  • Chemically related to enflurane

  • Low tissue solubility rapid induction and recovery

  • Respiratory depression, reduced blood pressure, muscle relaxation

  • Only a small amount undergoes metabolism; liver toxicity does not seem to be a problem

  • Most undesirable side effect is respiratory acidosis associated with deeper levels of sedation

goals of general anesthesia

• good patient control

• adequate muscle relaxation

• pain relief

balanced general anesthesi

• Guedel’s classification was developed when ether alone was used

• With balanced anesthesia patient readily passes from stage I to stage III skipping stage II.

dental hygiene considerations for general anesthesia

Review the patient’s medication/health history for evidence of contraindications to nitrous oxide, such as medical conditions and medications.

• Check equipment before use to ensure that it works properly.

•  Several states now allow dental hygienists to administer nitrous oxide. Table 11.5 reviews patient response at different concentrations of nitrous oxide.

• Patient response is the best indicator of the level of sedation.

• Make sure that the patient’s blood pressure and pulse are always within normal limits.

• Encourage the patient to refrain from making any major decisions while still feeling sedated from any of the anesthetics.

anxiolytic value of relaxation

• more productive dental appointments

• patient benefits

• dental team benefits

• fear, anxiety→ avoids dental care due to fear→ poor oral health→ feelings of shame and guilt due to fear of dentist

  • stops this cycle!

anxiolytics

• Sedative-hypnotic agents produce varying degrees of CNS depression

  • Sedation: small dose causes mild CNS depression (reduction of activity and simple anxiety)

  • Hypnotic dose: larger dose of the same drug produces greater CNS depression (induces sleep).

groups of anxiolytics

• Benzodiazepines (valium, Xanax)

• Barbiturates

• Nonbenzodiazepines-nonbarbiturate sedative hypnotics

sedation

• small dose causes mild CNS depression (reduction of activity and simple anxiety)

hypnotic dose

• larger dose of the same drug produces greater CNS depression (induces sleep).

benzodiazepine pharmacokinetics

• 1,4-benzodiazepine nucleus

• Well absorbed when administered orally

• Rapid Onset of action related to lipid solubility

• Storage in adipose tissue prolongs action

• Available as tablets, capsules, oral solution, rectal gel, and injectable form

• Cross the blood-brain and placental barriers to produce an effect on the CNS and adverse effects on the fetus

• Metabolized in liver

  • (valium, Xanax)

benzodiapepines mechanism of action

•Facilitate the action of the neurotransmitter γ-aminobutyric acid (GABA) a major inhibitory neurotransmitter in the CNS.

•Benzodiazepines act as agonists at the benzodiazepine receptor site, reducing the symptoms of anxiety

•Benzodiazepines act as agonists (facilitate) at the benzodiazepine receptor site, reducing the symptoms of anxiety

benzodiazepine behavioral effects

•Anxiety and panic reduction at low doses

•Drowsiness and sleep at higher doses

•Repeated doses reduce REM sleep

benzodiazepine antiseizure effects

• Diazepam used parenterally

  • Status epilepticus

  • Prevent seizures for LA toxicity

• Clonazepam used orally

  • Manages partial seizures

benzodiazepine muscle relaxation

•Effective for muscle spasticity secondary to pathological states such a cerebral palsy

benzodiazepine pharmacologic effects

• behavioral effects

• antiseizure effects

• muscle relaxation

benzodiazepine adverse reactions

• in general, when used alone have a wide margin of safety

• similar adverse reactions but differ in their frequency

  • can cause xerostomia, swollen tongue, bitter or metallic taste, thrombophlebitis

  • CNS depression with fatigue, drowsiness, muscle weakness, and ataxia in elderly patients

  • paradoxical CNS stimulation

  • psychiatric patients may experience anxiety, nightmares, tremulousness, hyperactivity, increased muscle spasticity

  • anterograde amnesia

  • contraindicated for narrow angle glaucoma, can cause blurred vision, diplopia, nystagmus

  • no adverse cardiovascular or respiratory effects

  • increased risk of congenital malformations, floppy infant syndrome, FDA category D drugs, avoid giving to pregnant, could be pregnant, and nursing mothers

thrombophlebitis

• inflammation of veins

paradoxical CNS stimulation

• when a substance meant to slow the brain causes excitement

• hyperactivity, agitation, insomnia

benzodiazepines abuse and tolerance

• can be abused

• Physical dependence and tolerance have been documented

• Addiction and abuse potential is less than other sedative-hypnotic agents

• Very wide therapeutic index, rare to overdose

• Overdose treatment

• Emesis if recently ingested

• Activated charcoal

• Romazicon-antagonist, could lead to withdrawal in long-term abuser

benzodiazepine drug interactions

• Additive effect with other CNS depressants

• Enzyme inducers increase their metabolism

• Enzyme stimulators decrease their metabolism

• Smoking reduces their effectiveness

  • Raises the rate of metabolism

• Cimetidine, disulfiram, isoniazid, and omeprazole increase their effects

• Selective serotonin uptake inhibitors greatly raise diazepam levels by altering its clearance

• Reduce effectiveness of levodopa

• May increase the effect of digoxin, phenytoin, and probenecid

benzodiazepine medical uses

• Short-term treatment of anxiety, panic attacks

• Conscious sedation, general anesthesia, or during surgery

• Insomnia management

  • Long term use can lead to tolerance

  • Can interrupt REM sleep

• Acute treatment of seizures

• Treatment of alcoholism

• Prevent alcohol withdrawal symptoms

• Control of muscle spasms

benzodiazepine dental relevance

• Premedication before surgical procedures to allay anxiety

• Oral or parenteral

  • Parenteral has an amnesic affect

• Conscious sedation

  • IV administration for muscle relaxation, amnesia

barbituates

• original sedative-hypnotic agents

• they are chemically similar to each other but differ in their onset and duration of action

• high rate of abuse

  • complete cardiovascular and respiratory depression with overdose

• benzodiazepines are safer and have mostly replaced _

• may be used as anticonvulsant for general anesthesia but are primarily not used

barbiturates pharmacokinetics

• Well absorbed orally and rectally

• Injectable solutions are irritating: IM route avoided, IV administration used

• IV agents Inactivated by redistribution from site of action in the CNS, to muscles, and adipose tissu

  • Short- and intermediate-acting _ are rapidly and almost completely metabolized by the liver

  • Long-acting _ are largely excreted through the kidneys

barbituates mechanism of action

• Enhance GABA-receptor binding

• Prolong the opening of chloride channel

• Higher doses Act directly on chloride channels without presence of GABA

• Mechanism of action is less specific than benzodiazepines (more generalized effect)

barbituate pharmacological effects

• CNS depression

  • principal effect

  • normal dose> relaxation

  • larger dose> disinhibition and euphoria. if excitation occurs it is from depression of inhibitory paths

• no analgesia effect

• anticonvulsant effect (phenobarbital used for epileptics)

barbituates adverse reactions

• Exaggerated sedative or hypnotic reaction

  • In elderly, debilitated patients, and patients with liver or kidney impairment

• Stimulation- idiosyncratic, usually elderly

• Fetal harm

• Can be lethal- Higher doses

• Coughing and laryngospasm- with IV use

• Depress liver and kidney function

• Reduce gastrointestinal motility

• Lower body temperature

• Acute poisoning- ingesting 10 times the hypnotic dose

• Death from an overdose is due to respiratory failure

barbiturates chronic long-term use

• physical and psychological dependence

• tolerance develops most effects but not to the lethal dose

• cross tolerance occurs

barbiturates contraindications

• Patients with intermittent porphyria or a positive family history of porphyria

• Absolute contraindication

• Genetic disorder

• Barbiturates can stimulate and increase the synthesis of porphyrins, which are already at an excessive level in this disease

barbiturates uses

• Ultrashort-acting _: used intravenously for induction of general anesthesia

• Short- and intermediate-acting _: little medical use; replaced by benzodiazepines

• Long-acting _: used for treatment of epilepsy

nonbenzodiazepine- nonbarbiturate sedative-hypnotics

• buspirone (buspar)

• Anxioselective

  • Selective anxiolytic effects, no hypnotic effects

• Onset of action: 1 week

• Undergoes 1^st pass metabolism

• No effect on GABA and lacks CNS depressant activity

• Does not cause dependence or tolerance

nonbenzodiazepine receptor hypnotics

• Zolpidem (Ambien)

  • Short term management of insomnia Rapid onset

  • Fewer muscle relaxant and anticonvulsant effects

  • Side effects: headache, drowsiness, dizziness, and diarrhea.

  • Reports of “sleep-driving” and Binge eating

• Zaleplon (Sonata) less potent and shorter duration than ambien. Lower next-day effects

• Eszopiclone (Lunesta) longest half-life. No reports of tolerance.

• Used to treat insomnia only

  • Schedule IV can have physical and psychological dependence

melatonin receptor agonist ramelteon (rozerem)

• for treatment of insomnias characterized by difficulty falling asleep

• MT1 receptor regulates sleep

• MT2 receptor may mediate the phase shifting effects of melatonin on a 24 hour biologic clock

• produced small improvements sleep latency, no effect sleep maintenance

melatonin

• Naturally occurring hormone made by the pineal gland that is released as the day ends and darkness takes over

• Manufactured synthetically

• Used to treat insomnia

• Can cause daytime sedation, morning grogginess, depression, headache, stomach cramps, and irritability

centrally acting muscle relaxants

• Exert their effects on the CNS to produce skeletal muscle relaxation

  • Carisoprodol (Soma)

  • Chlorzoxazone (Parafon Forte DSC)may discolor urine red

  • Methocarbamol (Robaxin)

  • Orphenadrine (Norflex

  • Cyclobenzaprine (Flexeril)-stongest and most sedative

  • Diazepam (Valium)

• Some degree of sedative effect

• Xerostomia common with these agents

• Dominate over selective muscle relaxants

orexin receptor antagonist

• Suvorexant (Belsomra)

• Blocks orexin neuropeptides from binding to their receptors

• Orexin neurons active during wakefulness, dormant during sleep

• Narcolepsy has been associated with a loss of orexin signaling

• Can impair next-day performance of activities that require mental alertness and motor coordination

general precautions: analgesic sedation combinations

• Both sedation and analgesia can be obtained from opioid analgesics alone

• Prescribing an opioid to add sedation to analgesia is undesirable unless the analgesic potency is required

special considerations

• Patient education

• Transportation to dental appointment

• Not a substitute for patient management

precautions for anxiolytics

• Exaggerated effects of medications

• Additive depression

• Accompanied by a responsible adult

• No making life-changing decisions

• Psychic and physical dependence

• Suicide

• Should not be given to pregnant women unless Potential benefit to the mother outweighs the risk to the fetus

• Sedatives do not provide analgesia

1860

• Niemann isolated cocaine

1884

Koller: cocaine in eye produced complete anesthesia

1905

• Einhorn synthesized procaine (ester)

1952

Amide lidocaine (Xylocaine)

1960

• Mepivacaine (Carbocaine) developed→ bupivicaine→ articaine

ideal properties of ideal local anesthetic

• Potent local anesthesia

• Reversible local anesthesia

• Absence of local reactions

• Absence of allergic reactions

• Rapid onset

• Satisfactory duration

• adequate tissue penetration, low cost, stability in solution, sterilization by autoclave, ease of metabolism and excretion

free base local anesthetics

• Viscid liquids or amorphous solids

• Fat soluble

• Unstable

• Alkaline, Uncharged, nonionized

• Penetrates nerve tissue

• Form present in tissue (pH 7.4)

salt form local anesthetics

• Crystalline solids

• Water soluble

• Stable

• Acidic, Charged, cation (ionized)

• Active form at site of action

• Form present in dental cartridge (pH 4.5-6.0)

local anesthetics pharmacokinetics

• Absorption depends on its route

• Rate of absorption depends on vascularity of the tissue

• Degree of inflammation present

• Vasodilating properties of the local anesthetic agent

• Presence of heat and use of massage

vasoconstrictor

• added to local anesthetic to reduces the blood supply to the area

• Limits systemic absorption

• Reduces systemic toxicity

higher concentration of anesthetics

• highly vascular organs…

• local anesthetics cross the placenta and blood-brain barrier

• lipid solubility affects the potency of the agent

metabolism of local anesthetics

•Esters are hydrolyzed by plasma pseudocholinesterases and liver esterases
•Procaine is hydrolyzed to para-aminobenzoic acid (PABA)

•Amides are metabolized by liver

•Prilocaine > orthotoluidine > methemoglobinemia

•Cimetidine > reduce hepatic blood flow can interfere with metabolism of amides

local aensthetic excretion

•Metabolites and some unchanged drug of both esters and amides are excreted by the kidneys

•Both parent drug and metabolites can accumulate with end-stage renal disease

local anesthetic adverse reaction

• Drug: Inherent toxicity and amount of vasodilation

• Concentration: Higher concentration=higher amount entering circulation

• Route of administration

• Rate of injection

• Vascularity

• Patient’s weight

• Rate of metabolism and excretion

• Children, elderly, debilitated more susceptible

local anesthetics: adverse reaction toxicity affecting the CNS system

• CNS stimulation due to depression of inhibitory fibers

  • Restlessness

  • Tremors

  • Convulsions

• CNS depression depression of both inhibitory and facilitative fibers

  • Respiratory and cardiovascular depression

  • Coma follows

local anesthetics adverse reaction toxicity affecting cardiovascular systems

• Myocardial depression

• Cardiac arrest with peripheral vasodilation

• Usual concentrations not expected to result in any of these adverse reactions

• Death has been reported (rarely) believed LA agent may cause a fatal arrhythmia in these rare cases

local anesthetics adverse reactions locally

• Result of injection technique

• Result of administration of an excessive volume too quickly

• Hematoma

local anesthetic malignant hyperthermia

• is not related to amides

• An inherited disease that is transmitted as an autosomal-dominant gene with variable expression, and reduced penetrance

• Acute rise in calcium > muscular rigidity, metabolic acidosis, and extremely high fever

• Treatment includes supportive measures and the administration of dantrolene (Dantrium)

• Halothane and succinylcholine are contraindicated

local anesthetics pregnancy and nursing considerations

•Elective dental treatment should be rendered before a patient becomes pregnant

• lidocaine and prolocaine FDA category B

• Mepivicaine, Articaine, and Bupivicaine FDA category C

• if local anesthesia is needed, use lidocaine in smallest effective dose possible

local anesthetic allergies

• Obtain allergy history, reactions range from rash to anaphylaxis

• Esters have a much greater allergic potential

• Unknown if amides produce allergic reactions

• Diphenhydramine (Benadryl)

  • 1% plus 1:100,000

• Methylparaben- not in single-dose cartridges

• Sulfite- acute asthmatic attack

vasoconstrictor

• epinephrine

antioxidant

• Sodium metabisulfite, sodium bisulfite, acetone sodium bisulfite

sodium hydroxide

• adjusts pH

sodium chloride

• makes solution isotonic

methylparaben and prophylparaben

• not in single dose cartridges

composition of local anesthetics

• vasoconstrictor

• antioxidant

• sodium hydroxide

• sodium chloride

• methylparaben and propylparaben

lidocaine

• Introduced in 1948: xylidine derivative

• Rapid onset

• Good distribution

• 2% with vasoconstrictor: Medium duration 1-1.5 hours pulpal 3-4 soft tissue

• Adverse reactions:

  • Hypotension

  • Positional headache

  • Shivering

mepivacaine

• introduced in 1960: xylidine derivative

• its rate of onset, duration, potency, and toxicity are similar to those of lidocaine

• Not effective topically

• Used for infiltration, block, spinal, epidural, and caudal anesthesia

• 2% with 1:20,000 levonordephrin (Neo-Cobefrin) as a vasoconstrictor

• 3% solution without vasoconstrictor

prilocaine

• Related chemically and pharmacologically to lidocaine and mepivacaine

• Toluidine derivative

• Less potent and less toxic than lidocaine

• Has a slightly longer duration of action

• Orthotoluidine (a metabolite) > methemoglobinemia in large doses

• 4% with/without 1:200,000 epinephrine

bupivicaine

• Related to lidocaine and mepivacaine

• More potent and toxic

• Advantage: Prolonged duration of action

• pulpal anesthesia longer than 1.5 hours

• Expect post operative pain

• Longer onset than lidocaine

• 0.5% with 1:200,000 epinephrine

articaine (septocaine)

• Approved for use in U.S. in 2000

• Derived from thiophene

• Greater lipid solubility

• Hydrolyzed by plasma esterase

• Metabolized mainly in blood

• Excreted by kidneys

• Half-life is 20 minutes

• May cause methemoglobinemia: no cases reported

• Paresthesia

• Used for local, infiltrative, and conductive anesthesia

• 4% 1:100,000 epinephrine

• 4% 1:200,000 epinephrine introduced in 2006

local anesthetic agents esters

• No esters are currently available in a dental cartridge

• Benzocaine: Commonly used topically

vascoconstrictors

• Prolong the duration of action

• Increase the depth of anesthesia

• Delay systemic absorption

• Reduce the toxic effect in the systemic circulation

• Reduce the bleeding in the area of injection and improve visibility at surgical site

• The decision about whether epinephrine should be used is made by weighing the risks and benefits

  • Caution in patients with uncontrolled HBP, hyperthyroidism, angina pectoris, cardiac arrhythmias, have had MI or cerebrovascular accident in past 6 months

vasconstrictor drug interactions

• are adrenergic agonists, or sympathomimetics

• Two drug interactions with most clinical significance (not absolute contraindications):

• Tricyclic antidepressants

  • Administration of epinephrine may produce an exaggerated increase in blood pressure

• Nonselective β-blockers

  • Administration of epinephrine may produce hypertension and reflex bradycardia