PART V – DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEMChapter 21: Introduction to CNS Pharmacology *

Chapter 22: Sedative-Hypnotic Drugs *

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Benzodiazepines (BZs)

Short acting:

Midazolam, triazolam

Bind GABAA receptor subunits (BZ receptors) to facilitate chloride channel opening (↑frequency) • membrane hyperpolarization

Anxiety disorders (alprazolam, lorazepam, clorapezate, chlordiazepoxide, clonazepam, diazepam) • Panic disorder (alprazolam, clonazepam) • Tonic-clonic seizures, status epilepticus (diazepam, lorazepam, midazolam) • Absence seizure (clonazepam) • Insomnia (estazolam, triazolam, temazepam, flurazepam) • Alcohol withdrawal (chlordiazepoxide, diazepam) • General anesthesia (IV midazolam, often used with ketamine) • Muscle spasm (diazepam)

Metabolized by CYP3A4 and excreted in urine • Additive CNS depression with manydrugs (alcohol, antihistamines, antipsychoticss, opioids, and TCAs)

Cardiac depression, respiratory depression, decreased psychomotor skills, cognitive impairment, anterograde amnesia, paradoxical excitement • Tolerance & dependence liability • C/I: obstructive sleep apnea, myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, sleep apnea syndrome, acute narrow-angle glaucoma

Withdrawal signs (e.g. tremors, hyperreflexia, and seizures) occur more commonly with shorter-acting drugs • Effects on sleep pattern: ↓latency, ↑duration, ↓REM and slow wave sleep (stage III & IV), ↑stage II sleep • Should only be used for short-term treatment (<14 days of continued use) due to tolerance building • Safer than barbiturates due to higher therapeutic index

Intermediate acting:

Alprazolam, estazolam, lorazepam (Anxicam), temazepam

Long acting:

Chlordiazepoxide, chlorazepate,

clonazepam, diazepam (Valium), flurazepam

Newer BZ receptor agonists

Zolpidem, zaleplon, eszopiclone

Acts on the same site on GABAA receptor as BZs do (BZ1 receptor-specific)

Sleep onset insomnia Oral activity, CYP substrates • Additive CNS depression with ethanol and other depressants • Eszopiclone with longest h/l

Minimal effects on sleep patterns • Cause less daytime cognitive impairment

Less interruption on sleep pattern than BZs or barbiturates

BZD antagonist

Flumazenil Antagonist at benzodiazepine sites on GABAA receptor (i.e. BZ receptors)

Reversal of CNS depressant effects of BZs, eszopiclone, zolpidem, and zaleplon

IV form • Short half-life Agitation, confusion • possible withdrawal syndrome in patients with BZ dependence

Barbiturates

Pentobarbital, thiopental, methohexital,

Bind to GABAA receptor sites (distinct from benzodiazepines),

Induction of anesthesia (thiopental, methohexital) • Refractory seizures or status

Oral activity • hepatic metabolism by CYP3A4; induction of metabolism

Similar to BZs • Higher risks of cardiac and respiratory depression

Medications for convulsive status epilepticus: thiamine + dextrose (0-10’) →

phenobarbital, secobarbital, amobarbital

facilitating chloride channel opening (↑duration) • Decreases AMPA receptor activation by glutamate • Decreases activity of voltage-dependent Na+ channels

epilepticus (phenobarbital) • Induction of barbituric coma in IICP or status epilepticus (pentobarbital, thiopental) • Insomnia (secobarbital, amobarbital)

of many drugs than BZs • Higher tolerance & dependence liability than BZs

diazepam/lorazepam + phenytoin (10-30’) → phenobarbital (30-60’) → pentobarbital or thiopental (> 60’)

Melatonin receptor agonist

Ramelteon Activates MT1 and MT2 receptors in suprachiasmatic nucleus

Sleep onset insomnia Oral activity; forms active metabolite via CYP1A2 • Fluvoxamine and fluconazole inhibits metabolism

Dizziness, fatigue, endocrine changes • Minimal rebound insomnia or withdrawal symptoms • Minimal abuse liability

5-HT agonist

Buspirone Partial agonist of 5-HT1A subclass of brain serotonin receptors; exact mechanism for its anxiolytic effect is unknown

General anxiety disorder Oral activity • Slow onset (> 1 wk) • Forms active metabolite • interactions with CYP3A4 inducers and inhibitors

Dizziness, GI distress, tachycardia, paresthesias • Minimal CNS depressant effects • Minimal abuse liability

A selective anxiolytic and has no anticonvulsant or muscle relaxant properties • Often used with β blockers to treat ANS hyperactivity induced by anxiety

　　 　　

Chapter 23: Alcohols *

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Alcohols

Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways

Antidote in methanol and ethylene glycol poisoning

Zero-order metabolism by alcohol dehydrogenase • Duration depends on dose • Interactions: Induction of CYP2E1; increased conversion of acetaminophen to toxic metabolite

Acute: CV depression, CNS depression and respiratory failure • Chronic: damage to many systems, including liver, pancreas, gastrointestinal tract, and central and peripheral nervous systems

Aldehyde dehydrogenase is inhibited disulfiram, metronidazole, oral hypoglycemics, and some cephalosporins

Methanol Poisoning result in toxic levels of formate, which causes characteristic visual disturbance plus coma, seizures, acidosis, and death due to respiratory failure

Ethylene glycol

Poisoning creates toxic aldehydes and oxalate, which causes kidney damage and severe acidosis

Drugs used in acute ethanol withdrawal

Diazepam BDZ receptor agonist that facilitates GABA-mediated activation of GABAA receptors • See Chapter 22

Anxiety disorders, ethanol withdrawal symptoms; skeletal muscle relaxant; treatment of convulsive disorders

In case the patient has compromised liver function, a short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is preferred

Thiamine(vitamin B1)

Essential vitamin required for synthesis of the coenzyme thiamine pyrophosphate

Administered to patients suspected of alcohol dependence to prevent the Wernicke-Korsakoff syndrome (WKS)

Parenteral administration None WKS, which mainly causes vision changes, ataxia and impaired memory, is a manifestation of thiamine deficiency

Drugs used in chronic alcoholism

Naltrexone Nonselective competitive antagonist of opioid receptors

Reduced risk of relapse in individuals with alcohol-use disorders

Available as an oral or longacting parenteral formulation (see Chapters 31 and 32)

Gastrointestinal effects and liver toxicity • rapid antagonism of all opioid actions

Other

Acamprosate

Poorly understood NMDA receptor antagonist and GABAA agonist effects

Reduced risk of relapse in individuals with alcohol-use disorders

Oral administration Gastrointestinal effects and rash

Enzyme inhibitor

Disulfiram Inhibits aldehyde dehydrogenase • Causes acetaldehyde accumulation during ethanol ingestion

Deterrent to relapse in individuals with alcohol-use disorders

Oral administration Little effect on its own but severe flushing, headache, nausea, vomiting, and hypotension when combined with ethanol

Drugs used in acute methanol or ethylene glycol toxicity

Fomepizole Inhibits alcohol dehydrogenase • Prevents conversion of methanol and ethylene glycol to toxic metabolites

Methanol and ethylene glycol poisoning

Parenteral administration Headache, nausea, dizziness, rare allergic reactions

Ethanol Higher affinity for alcohol dehydrogenase, reduce metabolism to toxic products

Methanol and ethylene glycol poisoning

Chapter 24: Antiseizure Drugs

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Sodium channel blockers

Phenytoin, fosphenytoin

Use-dependent block of neuronal voltage-gated Na+ channels

Generalized tonic-clonic (grand mal) seizure, status epilepticus, partial (focal) seizures

Oral, IV (fosphenytoin) • Variable absorption, saturable metabolism (zero-order elimination at high doses) • A potent inducer of hepatic CYP enzymes

CV risk associated with rapid infusion rates • Nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral neuropathy, osteoporosis, purple glove syndrome • Fetal hydantoin syndrome: broad nasal bridge, cleft palate, microcephaly, mental retardation

Valproic acid, carbamazepine, and phenytoin are the drugs of choice for generalized tonic-clonic (grand mal) seizures. Lamotrigine and topiramate are alternative agents.

Carbamazepine, oxcarbazepine

Blocks voltage-gated Na+ channels and decreases glutamate release in CNS

GTC seizures, partial seizures, trigeminal neuralgia • Bipolar I disorder (manic or mixed episodes)

Oral • Well absorbed, linear metabolism, active metabolite 10,11-epoxycarbamazepine by CYP3A4 • Oxcarbazepine is a structural derivative of carbamazepine with less extensive hepatic metabolism

Risks of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) in Asians with HLA-B*1502 • Diplopia, cognitive dysfunction, drowsiness, ataxia, aplastic anemia, agranulocytosis • Fetal craniofacial anomalies and spina bifida

Carbamazepine, lamotrigine and phenytoin are the drugs of choice for partial seizures. Felbamate, phenobarbital, topiramate, and valproic acid are alternative agents.

Lamotrigine Blocks Na+ and Ca2+ channels and decreases glutamate release in CNS

GTC seizures, partial seizures, atypical absence seizure, myoclonic seizure • Bipolar I disorder (maintenance)

Oral • Not protein-bound, extensive metabolism through hepatic and renal glucuronidation

Dizziness, ataxia, nausea, rash (potentially fatal), rare SJS or TEN (not significantly associated with HLA-B*1502)

Zonisamide Blockade of Na+ and T-type Ca2+ channels • weak inhibitor of carbonic anhydrase

Partial seizures (adjunct), myoclonic seizure (adjunct)

Oral • Metabolized by hepatic CYP3A4

Dizziness, confusion, agitation, diarrhea, weight loss, rash, rare Stevens-Johnson syndrome

Calcium channel blockers

Ethosuximide

Decreases T-type Ca2+ currents in a voltage-dependent manner

Absence (petit mal) seizure

Oral • Long half-life GI distress, lethargy, headache, behavioral changes

Ethosuximide or valproic acid are the preferred drugs for absence seizure because they cause minimal sedation. Lamotrigine and clonazepam are alternative agents.

Valproic acid

Inhibits low-threshold T-type Ca2+ channel •

GTC seizures, absence seizure, partial seizures,

Oral, IV • Causes inhibition of hepatic drug metabolism

Drowsiness, nausea, tremor, alopecia, weight gain,

Valproic acid is particularly useful in patients with multiple

shows use-dependent block of voltage-gated Na+ channel • causes increased availability of GABA to brain neurons (↑synthesis, ↓degradation)

myoclonic seizure • Migraine prophylaxis • Bipolar disorder (mania)

hepatotoxicity (infants), thrombocytopenia (dose-related) • Neural tube defects • C/I: hepatic disease, urea cycle disorders

seizure types that include absence seizures • Myoclonic seizure syndromes are usually treated with valproic acid; lamotrigine, clonazepam are alternative agents; Levetiracetam, topiramate, and zonisamide are adjunctive agents.

Gabapentin A GABA analogue that binds to α2δ subunit of voltage-gated calcium channels within the CNS and inhibits Ca2+ influx

Partial seizures (adjunct) • postherpetic neuralgia

Variable bioavailability due to saturable absorption • renal elimination

Dizziness, sedation, ataxia, nystagmus; does not affect drug metabolism (pregabalin is similar)

Pregabalin Like gabapentin Partial seizures (adjunct) • postherpetic neuralgia, diabetic peripheral neuropathic pain, fibromyalgia

Oral • renal elimination Similar to gabapentin Structurally similar to gabapentin but more potent

GABA channel potentiators

Diazepam, lorazepam

Bind GABAA receptor subunits (BZ receptors) • See also Chapter 22

Status epilepticus

Clonazepam Same as diazepam Absence seizure, myoclonic seizure

Clonazepam acts specifically at GABA receptors in the reticular nucleus, inhibiting GABA-mediated hyperpolarization of the thalamus and indirectly inactivating the T-type calcium channel.

Phenobarbital

See Chapter 22 Refractory seizures, status epilepticus

Vigabatrin Irreversibly inactivates GABA aminotransaminase (GABA-T)

Infantile spasms, refractory complex partial seizures

Oral • renal elimination Sedation, dizziness, weight gain; visual field defects with long-term use, which may be permanent

Tiagabine Blocks GABA reuptake by inhibiting GABA transporter GAT-1 in neurons and glia

Partial seizures (adjunct) Oral • Extensive protein binding and metabolism • some drug interactions

Abdominal pain, nausea, dizziness, tremor, asthenia

Felbamate Unknown • A positive modulator of GABAA

Severe refractory seizures, Lennox-

Oral • Strongly interferes with hepatic metabolic

Aplastic anemia, acute hepatic failure • C/I: history of blood

receptor and a blocker of NMDA receptor

Gastaut syndrome • Not indicated for use as first-line treatment

enzymes dyscrasia, hepatic impairment

Other antiseizure drugs

Topiramate Unknown • May inhibit sodium channel; may potentiate GABA activation of GABAA channel; may antagonize AMPA receptor

GTC seizures, partial seizure, migraine prophylaxis

Oral • Both hepatic and renal clearance

Drowsiness, ataxia, psychomotor slowing and memory impairment; paresthesias, weight loss, acute myopia

Levetiracetam

Unknown • May inhibit voltage-dependent N-type Ca2+ channels; may bind to synaptic proteins that modulate NT release

GTC seizures (adjunct), partial seizures (adjunct), myoclonic seizure (adjunct)

Oral, IV • Both hepatic and renal clearance

Dizziness, sedation, weakness, irritability, hallucinations, and psychosis have occurred

　

Chapter 25: General Anesthetics

Drug

Subclass

Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Inhaled anesthetics

Isoflurane Facilitate GABA-mediated inhibition • block brain NMDA and ACh-N receptors • Increase cerebral blood flow • enflurane and halothane decrease cardiac output; others cause vasodilation • all decrease respiratory functions, but desflurane also causes airway irritation

General anesthesia induction & maintenance

Rate of onset and recovery vary by blood:gas partition coefficient • recovery mainly due to redistribution from brain to other tissues • Halothane is metabolized by liver enzymes to a significant extent

Cardiovascular and respiratory depression, rare malignant hyperthermia (higher risk in patients with gene mutations in RYR1 or CACNA1S gene)

Less potent than halothane, but faster induction • Malignant hyperthermia is treated with dantrolene

Enflurane General anesthesia Same as isoflurane Has greater risk of causing renal toxicity • May cause spike-and-wave activity and muscle twitching

Halothane General anesthesia Same as isoflurane • Additionally, can cause hepatitis and fatal hepatic necrosis

High potency but slow induction and recovery • Halothane and isoflurane may sensitize the myocardium to the arrhythmogenic effects of catecholamines

Desflurane, sevoflurane

General anesthesia Can cause expansion of air cavities such as pneumothorax, obstructed middle ear, obstructed loop of bowel, and intracranial air

Rapid induction and recovery, but low potency • Analgesia in subhypnotic concentrations

Nitrious oxide

General anesthesia (usually used in combination with other agents)

Same as isoflurane • Additionally, desflurane can cause laryngeal spasm and bronchospasm

Newer anesthetic agents with relatively high potency as well as rapid induction and recovery

Intravenous anesthetics

Barbiturates:

Thiopental, methohexital

Facilitate GABA-mediated inhibition at GABAA receptors • circulatory and respiratory depression • decrease ICP • See Chapter 22

Induction of anesthesia

High lipid solubility—fast onset and short action due to redistribution • zero-order elimination kinetics (thiopental)

Extensions of CNS depressant actions • additive CNS depression with many drugs

Are not used to maintain anesthesia in surgical procedures

Benzodiazepines:

Midazolam Facilitate GABA-mediated inhibition at GABAA receptors • less depressant than barbiturates • See

Adjunct in general anesthesia

Slower onset, but longer duration than barbiturates

Postoperative respiratory depression; reversed by flumazenil

Chapter 22

Dissociative:

Ketamine Blocks excitation by glutamate at NMDA receptors • analgesia, amnesia and catatonia but consciousness retained • CV stimulation!

Dissociative anesthesia

Moderate duration of action—hepatic metabolism

Increased intracranial pressure • emergence reactions: disorientation, excitation, hallucinations

Imidazole:

Etomidate Facilitate GABA-mediated inhibition at GABAA receptors • minimal effects on CV and respiratory functions

Induction of anesthesia

Short duration due to redistribution

No analgesia, pain on injection (may need opioid), myoclonus, nausea, and vomiting

Opioids:

Morphine, fentanyl, alfentanil, remifentanil

Interact with μ, κ, and δ receptors for endogenous opioid peptides • marked analgesia, respiratory depression • See Chapter 31

Adjunct in general anesthesia, pain control

Alfentanil and remifentanil fast onset (induction) • Remifentanil has unusually rapid metabolism and elimination

Respiratory depression; reversed by naloxone

IV opioids may cause chest wall rigidity • Neuroleptanesthesia is a state characterized by analgesia, absence of clinically apparent motor activity, suppression of autonomic reflexes, maintenance of CV stability, and amnesia when fentanyl is used with droperidol and N2O

Phenols:

Propofol, fospropofol

Facilitate GABA-mediated inhibition at GABAA receptors • vasodilation and hypotension • negative inotropy

General anesthesia induction & maintenance • Producing prolonged sedation in ICU settings

Propofol: fast onset and fast recovery due to inactivation • Fospropofol: a water-soluble pro-drug with slower onset and recovery

Hypotension (during induction), cardiovascular depression

The Minimum Alveolar Concentration (MAC)The partial pressure of an anesthetic in the CNS (PCNS) is maintained by varying the inspired partial pressure (PI). Because the value of PCNS cannot be monitored directly, it is commonly inferred from the alveolar partial pressure (Palv). PCNS tracks Palv with only a small time lag. The

minimum alveolar concentration (MAC) of an anesthetic is the alveolar partial pressure that abolishes a movement response to a surgical incision in 50% of patients. The potency of an anesthetic is related inversely to its MAC. E.g. isoflurane (MAC = 0.0114 atm) is much more potent than nitrous oxide (MAC = 1.01 atm).

The Meyer-Overton Rule

The potency of an anesthetic can be predicted from the anesthetic’s solubility in olive oil (the oil/gas partition coefficient, λ(oil/gas)).

λ(solvent/gas) is the number of liters of gas that will dissolve in one liter of solvent per atmosphere of partial pressure (Lgas Lsolvent

-1 atm-1). A gas with a larger λ(solvent/gas) is more soluble in that solvent. This implies that large amounts of

gas must be transferred to change the partial pressure by an appreciable amount.

For any given partial pressure, Henry’s law for dilute solutions allows the concentration of gas A in a solvent ([A]solution) to be calculated from λ(solvent/gas),

[A]solvent = Psolvent ∙ λ(solvent/gas)

A partition coefficient can also be defined for the partitioning of a gas between two solvents. E.g. the tissue/blood partition coefficient, λ(tissue/blood), is the ratio of the molar concentration of gas in the tissue ([A]tissue) to the molar concentration of gas in the blood ([A]blood) at equilibrium (note that this coefficient is unitless), i.e.

λ(tissue/blood) = [A]tissue/[A]blood = λ(tissue/gas)/λ(blood/gas)

The relationship between MAC and λ(oil/gas) is such that MAC multiplied by λ(oil/gas) is nearly constant, independent of the identity of the anesthetic, i.e.

MAC ∙ λ(oil/gas) ≈ constant

Therefore, at l MAC, the concentration of anesthetic in a lipophilic solvent (such as olive oil) is nearly constant for all anesthetics, i.e.

[A]oil, 1 MAC = MAC ∙ λ(oil/gas) ≈ constant

Thus, the MAC, which varies with the identity of the anesthetic, is actually the partial pressure required to generate a particular concentration of anesthetic in a lipophilic medium, such as the lipid bilayers in the CNS. This correlation is known as the Meyer-Overton Rule.

The constant that represents the concentration of anesthetic at l MAC is 1.3 liters of gas per liter of oil (Lgas / Loil). Thus, if one knows the oil/gas partition coefficient of an anesthetic, one can estimate its MAC from the following equation:

MAC ≈ 1.3/λ(oil/gas)

Concepts from Respiratory PhysiologyAccording to the Fick’s law of diffusion, at equilibrium (i.e., when the net diffusion rate is zero), the partial pressure in the two compartments is the same, even though the concentration in the two compartments may be different.

The transfer of anesthetic in both the lungs and the tissues is limited by perfusion rather than diffusion. Therefore, the alveolar partial pressure Palv and the systemic arterial partial pressure Part are nearly the same at all times (small amounts of physiologic shunting keep Part slightly lower than Palv.), and the partial pressure in the postcapillary venules Pvenule equals the partial pressure in the tissue Ptissue.

The global equilibration may be divided into a

series of partial pressure equilibrations between each successive compartment and its incoming flow of anesthetic. The anesthetic concentration in in a compartment will rise in accord with first-order kinetics, described by the following relationship:

Pcompartment = Pflow ∙ [1-e-(t/τ)]

The time constant τ describes the rate of approach of a compartment’s partial pressure to that of its incoming flow. It is calculated by dividing the compartment’s volume capacity (relative to the delivering medium) by the flow rate, i.e.

τ = volume capacity/flow rate

Once a volume of flow equal to the capacity of a compartment has gone through that compartment, the partial pressure of anesthetic in the compartment will be 63% of the partial pressure in the incoming flow. Equilibration is 95% complete after three time constants. Equilibration of Pcompartment with Pflow takes place more quickly (i.e., the time constant is smaller) when the inflow is larger or the compartment capacity is smaller.

The Uptake Model (Fig. 16-4)The model of anesthetic uptake and distribution organizes the tissues of the body into groups based on similar characteristics.

The overall equilibration of PVRG with the inspired partial pressure PI occurs in two steps, either of which may be rate-limiting. First, the alveolar and inspired partial pressures equilibrate (Palv→PI). Second, PVRG (and specifically PCNS ) equilibrates with the arterial partial pressure (which is essentially equal to the alveolar partial pressure) (PVRG→Part).

Equilibration of Alveolar with Inspired Partial Pressure

For the first step, the delivering medium is free gas arriving through the airways, and the compartment is the lung and alveoli. The time constant for the approach of Palv to PI, τ{Palv→PI} is calculated by

τ{Palv→PI} = FRC/Valv

where FRC is the functional residual capacity of the lungs, and Valv is the alveolar ventilation rate (Valv = [tidal volume - dead space] ∙ respiratory rate). For an average adult, FRC is ~3 L and Valv is ~6 L/min, so a typical value for τ{Palv→PI} is 0.5 min, independent of the particular gas being inhaled.

In practice, at the same time that alveolar ventilation is delivering anesthetic to the alveoli, anesthetic is also being removed from the alveoli by diffusion into the bloodstream. Uptake of anesthetic from the alveoli into the bloodstream constitutes a negative component to the flow (i.e., a flow out of the lungs), which makes the time constant longer than the theoretical case where τ{Palv→PI} equals FRC divided by Valv.

One can calculate the rate of uptake of a gas from the alveoli by

Rate of uptake (Lgas/min) = ([A]art - [A]MVR) ∙ CO

where CO is the cardiac output (Lblood/min), and [A]art and [A]MVR are the concentrations of the anesthetic in the systemic artery (which = pulmonary venous concentration) and in the right atrium (mixed venous return, which = pulmonary arterial concentration). Since [A]solvent = Psolvent ∙ λ(solvent/gas), we can rewrite the above equation into

Rate of uptake (Lgas/min) = λ(blood/gas) ∙ (Part - PMVR) ∙ CO

Therefore, equilibration of alveolar with inspired partial pressure is faster (i.e., τ{Palv→PI} is smaller) with lower blood solubility of the anesthetic (smaller λ(blood/gas)), lower cardiac output, or smaller arterial (≈ alveolar) to venous partial pressure difference.

Equilibration of Tissue with Alveolar Partial PressureFor the second step, changes in Palv are transmitted rapidly to systemic arterioles, because equilibration across the pulmonary epithelium is fast and the circulation time from pulmonary veins to tissue capillaries is generally less than 10 seconds. Thus, τ{Ptissue→Palv} can be approximated as τ{Ptissue→Part}. Here, the volume capacity of the tissue is the volume that the tissue would need to contain all of its gas if the solubility of the gas in the tissue were the same as that in the blood.

Relative volume capacity of the tissue = ([A]tissue ∙ Voltissue)/[A]blood

where Voltissue is the volume of tissue. At equilibrium, [A]tissue /[A]blood is equal to λ(tissue/blood), so the above equation can be rewritten as

Relative volume capacity of the tissue = λ(tissue/blood) ∙ Voltissue

So the time constant τ{Ptissue→Part} can be calculated by

τ{Ptissue→Part} ≈ τ{Ptissue→Palv} = (λ(tissue/blood) ∙ Voltissue)/Qtissue

where Qtissue is tissue perfusion in Lblood/min.

With a small λ(tissue/blood) (Table 16-2) and a small volume (~6 L), the VRG has a low capacity for anesthetic. The combination of low capacity and high blood flow (75% of cardiac output) results in a very short equilibration time constant (τ{PVRG→Palv}) for the VRG (Table 16-3).

In summary, the time constant for equilibration of the CNS with the alveolar partial pressure is short and relatively independent of the particular anesthetic being used (from 1.5 min for nitrous oxide to 2.7 min for diethyl ether).

The Rate-Limiting StepIn practice, τ{Palv→PI} varies greatly among different anesthetics. Inhaled anesthetics can be divided into two broad categories:

• Ventilation-limited: diethyl ether, enflurane, isoflurane, & halothane

• Perfusion-limited: nitrous oxide, desflurane, & sevoflurane

Ventilation-limited anesthetics have a long, rate-limiting τ{Palv→PI} because of their high

λ(blood/gas): the high rate of uptake of anesthetic into the bloodstream prevents Palv from rising rapidly. Thus, the slow and rate-limiting equilibration of alveolar with inspired partial pressure results in slow induction and recovery.

Perfusion-limited anesthetics have a τ{Palv→PI} that is similar in magnitude to τ{PVRG→Palv} because their λ(blood/gas) is small. Induction and recovery occur quickly, and neither τ{Palv→PI} nor τ{PVRG→Palv} may be clearly rate-limiting.

The characteristic that distinguishes perfusion-limited from ventilation-limited anesthetics is the λ(blood/gas). The key point here is that agents that are less soluble in the blood induce anesthesia faster.

To clarify, consider two hypothetical anesthetics that differ solely in λ(blood/gas):

In this hypothetical model, one may correctly note that the concentration of Anesthetic B in the CNS as a whole will be higher than that of Anesthetic A at any particular time point. One may, therefore, wonder how Anesthetic B can have a slower induction, if anesthesia results when a particular concentration (0.05 M) is reached at the site of action (see Pharmacodynamics, above). At this point, one must recognize that the brain is primarily aqueous, but that anesthetics are likely to have a hydrophobic site of action, and that both Anesthetic A and Anesthetic B must have the same concentration (0.05 M) in the key hydrophobic portions of the brain at their anesthetic partial pressures ([A]brain = Pbrain ∙ λ(brain/gas)). However, Anesthetic B, with its larger aqueous solubility [ λ (blood/gas)], will partition relatively more than Anesthetic A into the aqueous portions of the brain. To provide the higher aqueous concentrations, many more moles of Anesthetic B than Anesthetic A must be transferred from the lungs.

The overall conclusion still holds if λ(oil/gas) and thus MAC differ for the two hypothetical anesthetics. Palv for a less blood-soluble agent will rise proportionally faster toward its PI than a more blood-soluble agent, independent of what that PI is. A larger λ(oil/gas) allows the anesthetic to cause anesthesia at a lower partial pressure, but doesn’t affect the proportional rate at which the partial pressure rises

Chapter 26: Local Anesthetics

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Amides

ArticaineBupivacaineLevobupivacaineLidocaine [t]MepivacainePrilocaineRopivacaine

Use-dependent blockade of voltage-dependent Na+ channels slows, then prevents axon potential propagation

Analgesia via topical use, or injection (perineural, epidural, subarachnoid) • rarely IV

Articaine has the fastest onset of action • Hepatic metabolism via CYP450 in part • Half-lives: lidocaine, prilocaine < 2 h, others 3-4 h • Acidification of the urine promotes ionization of local anesthetics

CNS: excitation, seizures • CV: vasodilation, hypotension, arrhythmias (bupivacaine)

Prilocaine is metabolized to products that include o-toluidine, an agent capable of converting hemoglobin to methemoglobin

Esters

Benzocaine [t]Cocaine [t]ProcaineTetracaine [t]

As above, plus cocaine has intrinsic sympathomimetic actions due to its inhibition of norepinephrine reuptake into nerve terminals

Analgesia, topical only for cocaine and benzocaine

Rapid metabolism via plasma pseudo-cholinesterases • short half-lives

As above re CNS actions • Cocaine vasoconstricts; when abused has caused hypertension and cardiac arrhythmias

Chapter 27: Skeletal Muscle Relaxants

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Depolarizing NM blockers

Succinylcholine

Agonist at ACh-N receptors causing initial twitch then persistent depolarization • Also stimulates ANS ganglia and M receptors • See Chapter 7

Induction of neuromuscular blockade in surgery, intubation

IV, IM • Highly polar • Duration: 5–10 min • Inactivated by plasma esterases • Prolonged action in persons with abnormal butyrylcholinesterase

Muscle pain, hyperkalemia, increased intraocular/ intragastric pressure, bradyarrhythmia, cardiac arrest, malignant hyperthermia (rare, but possible when used with inhaled anesthetics)

To prevent skeletal muscle fasciculations and the resulting postoperative pain, a small nonparalyzing dose of a nondepolarizing drug is often given immediately before succinylcholine

Non-depolarizing NM blockers

Tubocurarine [L]Atracurium [S]Cisatracurium [I]Mivacurium [S]Pancuronium [L]Rocuronium [I]Vecuronium [I]

Competitive antagonists at skeletal muscle ACh-N receptors • aminosteroids (-curium) • benzylisoquinolines (tubocurarine, -curonium)

ANS ganglion block (tubocurarine) • Cardiac M2 block (pancuronium) • Relaxation of skeletal muscle in surgery, intubation (all except tubucurarine)

Parenteral use, variable disposition: Spontaneous inactivation (atracurium, cisatracurium) • Plasma ChE (mivacurium) • Hepatic metabolism (rocuronium, vecuronium) • Renal elimination (pancuronium, tubocurarine)

Hypotension by histamine release (tubocurarine, aminosteroids except cisatracurium), bronchoconstriction (tubocurarine) • Tachycardia by vagal blockade (pancuronium) • Laudanosine formation (atracurium) • Muscle relaxation is potentiated by inhaled anesthetics, aminoglycosides and possibly quinidine

Atracurium and cisatracurium are degraded by Hofmann elimination in vivo • Sugammadex is a selective relaxant binding agent for rocuronium & vecuronium

Centrally acting muscle relaxant

Cyclobenzaprine

Inhibition of spinal stretch reflex • Mechanism unknown

Muscle spasm associated with acute, painful musculoskeletal conditions

Oral M block, sedation, confusion, and ocular effects

Not effective in muscle spasm resulting from cerebral palsy or spinal cord injury

Baclofen Facilitates spinal inhibition of motor neurons • GABAB receptor activation: pre- and postsynaptic

Reversible spasticity associated with multiple sclerosis or spinal cord lesions

Oral and intrathecal Sedation, muscle weakness Baclofen causes less sedation than diazepam, and tolerance occurs with chronic use—withdrawal should be accomplished slowly

Diazepam Facilitates GABA-ergic transmission in CNS • GABAA receptor activation: postsynaptic

Anxiety disorders, ethanol withdrawal symptoms; skeletal muscle relaxant; treatment of convulsive disorders

Oral Sedation, additive with other CNS depressants • abuse potential

Tizanidine Pre- and postsynaptic inhibition • α2 agonist in spinal cord

Spasticity Oral for acute and chronic spasms

Muscle weakness, sedation, hypotension

Direct-acting muscle relaxant

Dantrolene Weakens muscle contraction by reducing myosin-actin interaction • Blocks RyR1 Ca2+ channels in skeletal muscle

Spasticity • Malignant hyperthermia

Oral for acute and chronic spasms • IV for malignant hyperthermia

Significant muscle weakness

Chapter 28: Drugs Used in Parkinsonism & Other Movement Disorders

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Dopamine precursor

Levodopa (+/− carbidopa)

Dopamine agonists

Pramipexole

Ropinirole

Apomorphine

Bromocriptine(rarely used)

MAO inhibitors

Rasagiline

Selegiline

COMT inhibitors

Entacapone

Tolcapone

Antimuscarinic agents

Benztropine

Drugs for Huntington’s disease

Tetrabenazine, reserpine

Haloperidol

Drugs for Tourette’s syndrome

Haloperidol

Clonidine

Chapter 29: Antipsychotic Agents & Lithium

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Phenothiazines

Chlorpromazine, fluphenazine, thioridazine

Thioxanthenes

Thiothixene

Butyrophenones

Haloperidol

Atypicals

Aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone

Lithium

Lithium

Newer drugs for bipolar affective disorder

Carbamazepine

Lamotrigine

Valproic acid

Chapter 30: Antidepressants

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Tricyclic antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

5-HT2 antagonists

Other heterocyclics

Monoamine oxidase inhibitors (MAOIs)

Chapter 31: Opioid Analgesics & Antagonists

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Chapter 32: Drugs of Abuse

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

PART VI – DRUGS WITH IMPORTANT ACTIONS ON BLOOD, INFLAMMATION, & GOUTChapter 33: Agents Used in Anemias & Hematopoietic Growth Factors

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Chapter 34: Drugs Used in Coagulation Disorders

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Chapter 35: Drugs Used in the Treatment of Hyperlipidemias

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments

Chapter 36: NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout

Drug Subclass Mechanism of Action Clinical Applications Pharmacokinetics and

Interactions

Toxicities and

Contraindications

Comments