Morgan And Makhail Chapter 8

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responsible for termination of effect of many anesthetic drugs.

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As plasma concentration falls, some drug leaves the highly perfused organs to maintain equilibrium. This
redistribution from the vessel-rich group is responsible for termination of effect of many anesthetic drugs. For
example, awakening from the effects of thiopental is not due to metabolism or excretion but rather to
redistribution of the drug from brain to muscle.

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Non–protein-bound drugs freely cross

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from plasma into the glomerular filtrate.

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The nonionized fraction of a
drug

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is reabsorbed in the renal tubules,

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the ionized portion is excreted

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ionized portion is excreted in urine.

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Elimination half-life of a drug is proportional

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to the volume of distribution and inversely proportional to
the rate of clearance.

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Repetitive administration of barbiturates saturates

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the peripheral compartments, so that redistribution
cannot occur and the duration of action becomes more dependent on elimination.

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Barbiturates constrict

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the cerebral vasculature. This effect may protect the brain from transient episodes
of focal ischemia (eg, cerebral embolism) but probably not from global ischemia (eg, cardiac arrest).

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The accumulation of morphine metabolites

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patients with renal failure has been associated with narcosis and ventilatory depression lasting several days.

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Opioids (particularly fentanyl, sufentanil, and alfentanil) can induce chest wall

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rigidity severe enough to
prevent adequate ventilation.

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stress response to surgical stimulation is measured in terms of

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the secretion of specific hormones,
including catecholamines, antidiuretic hormone, and cortisol. Opioids block the release of these hormones
more completely than volatile anesthetics.

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sharp contrast to other anesthetic agents, ketamine increases

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arterial blood pressure, heart rate, and
cardiac output. These indirect cardiovascular effects are due to central stimulation of the sympathetic nervous
system and inhibition of the reuptake of norepinephrine.

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Induction doses of etomidate transiently inhibit

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enzymes involved in cortisol and aldosterone synthesis.
Long-term infusions lead to adrenocortical suppression that may be associated with an increased mortality
rate in critically ill patients.

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Nonetheless, droperidol should be avoided in patients

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with Parkinson disease.

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Pharmacokinetics is defined by four parameters:

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absorption, distribution, biotransformation, and
excretion.

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Elimination implies drug removal by both

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biotransformation and excretion

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Clearance is

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a
measurement of the rate of elimination.

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awakening from the effects of
thiopental is not due to metabolism or excretion but rather to

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redistribution of the drug from brain to muscle.

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Biotransformation is

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the alteration of a substance by metabolic processes.

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the primary
organ of biotransformation.

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The liver

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The end products of biotransformation are usually—

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usually—but not necessarily—inactive and water soluble.The latter property allows excretion by the kidney

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Metabolic biotransformation can be divided into

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phase I and phase II reactions.

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Phase I reactions
convert a parent drug into more

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polar metabolites through oxidation, reduction, or hydrolysis.

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Phase II
reactions

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couple (conjugate) a parent drug or a phase I metabolite with an endogenous substrate (eg,
glucuronic acid) to form a highly polar end product that can be eliminated in the urine. Although this is
usually a sequential process, phase I metabolites may be excreted without undergoing phase II
biotransformation, and a phase II reaction can precede a phase I reaction.

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Hepatic clearence is

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the rate of elimination of a drug as a result of liver biotrans formation.the volume of plasma cleared of drug per unit of time and is expressed as milliliters
per minute.

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principal organ of excretion.

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The kidney

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Non–protein-bound drugs freely cross

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from plasma into the
glomerular filtrate.

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nonionized fraction of drug is

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reabsorbed in the renal tubules

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Renal clearance is

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the rate of elimination of a drug from kidney excretion.

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A compartment can be conceptualized as

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a group of tissues that possesses similar pharmacokinetics.For example, plasma and the vessel-rich group could represent the central compartment, whereas muscle,
fat, and skin could represent the peripheral compartment.

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Rates of distribution and biotransformation can usually be described in terms of

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first-order kinetics. In
other words, a constant fraction or percentage of drug is distributed or metabolized per unit of time,
regardless of plasma concentration.

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Pharmacodynamics is the study

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of the therapeutic and toxic organ system effects of drugs (how a drug
affects a body).

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Dose–response curves express the relationship between

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drug dose and pharmacological effect.

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median effective dose (ED50)

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is the dose of drug required to produce a given effect in 50% of the
population.

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The median lethal
dose (LD50) is

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the dose that results in death in 50% of the population exposed to that dose.

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The therapeutic
index is the ratio

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of the median lethal dose to the median effective dose (LD50:ED50).

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Drug receptors are

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macromolecules—usually proteins embedded into cell membranes—that interact
with a drug to mediate characteristic intracellular changes.

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mechanism of action of several (not all) drugs
depends on

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interaction with a receptor.

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Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

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agonists

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agonists

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Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

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Antagonists

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also bind
to the receptors but do not cause a direct effect on the cell.

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Pharmacodynamics is the study

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of the therapeutic and toxic organ system effects of drugs (how a drug
affects a body).

Front 42

Dose–response curves express the relationship between

Back 42

drug dose and pharmacological effect.

Front 43

median effective dose (ED50)

Back 43

is the dose of drug required to produce a given effect in 50% of the
population.

Front 44

The median lethal
dose (LD50) is

Back 44

the dose that results in death in 50% of the population exposed to that dose.

Front 45

The therapeutic
index is the ratio

Back 45

of the median lethal dose to the median effective dose (LD50:ED50).

Front 46

Drug receptors are

Back 46

macromolecules—usually proteins embedded into cell membranes—that interact
with a drug to mediate characteristic intracellular changes.

Front 47

Pharmacodynamics is the study

Back 47

of the therapeutic and toxic organ system effects of drugs (how a drug
affects a body).

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mechanism of action of several (not all) drugs
depends on

Back 48

interaction with a receptor.

Front 49

Dose–response curves express the relationship between

Back 49

drug dose and pharmacological effect.

Front 50

Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

Back 50

agonists

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median effective dose (ED50)

Back 51

is the dose of drug required to produce a given effect in 50% of the
population.

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The median lethal
dose (LD50) is

Back 52

the dose that results in death in 50% of the population exposed to that dose.

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agonists

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Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

Front 54

Antagonists

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also bind
to the receptors but do not cause a direct effect on the cell.

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The therapeutic
index is the ratio

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of the median lethal dose to the median effective dose (LD50:ED50).

Front 56

Drug receptors are

Back 56

macromolecules—usually proteins embedded into cell membranes—that interact
with a drug to mediate characteristic intracellular changes.

Front 57

mechanism of action of several (not all) drugs
depends on

Back 57

interaction with a receptor.

Front 58

Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

Back 58

agonists

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agonists

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Endogenous substances (eg, hormones) or exogenous substances
(eg, drugs) that directly change cell function by binding to receptors are called

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Antagonists

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also bind
to the receptors but do not cause a direct effect on the cell.

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pharmacological effect of antagonist drugs
depends on

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the subsequent inability of agonist substances to activate the receptors.

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Competitive antagonists

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bind reversibly to receptors and can be displaced by higher concentrations of agonists.

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Noncompetitive
(irreversible) antagonists

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bind to the receptor with such affinity that even high concentrations of agonists
cannot reverse the receptor blockade.

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Receptors affect cell function either

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directly or by controlling
the production of another regulatory molecule.

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Barbiturates depress the

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eticular activating system

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reticular activating system is

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complex polysynaptic network of neurons and
regulatory centers—located in the brain stem that controls several vital functions, including consciousness.

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duration of action of highly lipid-soluble barbiturates (thiopental, thiamylal, and methohexital)

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is
determined by redistribution, not metabolism or elimination.

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Biotransformation of barbiturates principally involves

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hepatic oxidation to inactive water-soluble
metabolites.

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Depression of the medullary vasomotor center vasodilates

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peripheral capacitance
vessels, which increases peripheral pooling of blood and decreases venous return to the right atrium. The
tachycardia is probably due to a central vagolytic effect.
Cardiac output is often maintained by a rise in heart
rate and increased myocardial contractility from compensatory baroreceptor reflexes.

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Patients with poorly controlled
hypertension are particularly prone to

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wide swings in blood pressure during induction.

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CPP equals

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cerebral artery pressure minus the greater of
cerebral venous pressure or intracranial pressure.

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Benzodiazepines interact with

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Benzodiazepines interact with specific receptors in the central nervous system, particularly in the
cerebral cortex. Benzodiazepine–receptor binding enhances the inhibitory effects of various
neurotransmitters

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Flumazenil (an imidazobenzodiazepine) is a

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specific benzodiazepine–
receptor antagonist that effectively reverses most of the central nervous system effect of benzodiazepines

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metabolites of benzodiazepine biotransformation are

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excreted chiefly in the urine.

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Opioids bind to

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specific receptors located throughout the central nervous system and other tissues.

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Four major types of opioid receptor

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mu ( with subtypes -1 and -2),
kappa, delta, and sigma

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Although both opioid agonists
and antagonists bind to opioid receptors, only agonists are capable of

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of receptor activation

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Endorphins, enkephalins, and dynorphins are endogenous peptides that bind to

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opioid receptors.

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Agonists–
antagonists

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are drugs that have opposite actions
at different receptor types.

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Most opioids biotransformation

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opioids depend primarily on the liver

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Etomidate depresses the

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reticular activating system and mimics the inhibitory effects of GABA.

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387

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1

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etomidate is characterized by a very rapid onset of action due to

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etomidate is characterized by a very rapid onset of action due to

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etomidate Biotransformation

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Hepatic microsomal enzymes and plasma esterases rapidly hydrolyze etomidate to an inactive
metabolite. The rate of biotransformation is five times greater for etomidate than for thiopental.

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Etomidate has minimal effects on the

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cardiovascular system.

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Etomidate decreases

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cerebral metabolic rate, cerebral blood flow, and intracranial pressure to the
same extent as thiopental.

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Induction doses of etomidate transiently inhibit

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enzymes involved in cortisol and aldosterone synthesis.
Long-term infusions lead to adrenocortical suppression that may be associated with an increased mortality
rate in critically ill patients.

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propofol Mechanisms of Action

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The mechanism by which propofol induces a state of general anesthesia may involve facilitation of
inhibitory neurotransmission mediated by GABA.

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Propofol Structure–Activity Relationships

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consists of a phenol ring with two isopropyl groups attached

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propofol Distribution

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The high lipid solubility of propofol results in an onset of action that is almost as rapid as that of
thiopental (one-arm-to-brain circulation time). Awakening from a single bolus dose is also rapid due to a very
short initial distribution half-life (2–8 min).

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propofol Biotransformation

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Conjugation in the liver results in inactive metabolites
that are eliminated by renal clearance.

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major cardiovascular effect of propofol is

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decrease in arterial blood pressure due to a drop in
systemic vascular resistance (inhibition of sympathetic vasoconstrictor activity), cardiac contractility, and
preload.

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Propofol Cerebral

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Propofol decreases cerebral blood flow and intracranial pressure. In patients with elevated intracranial
pressure, propofol can cause a critical reduction in CPP (< 50 mm Hg) unless steps are taken to support mean
arterial blood pressure. Propofol and thiopental probably provide a similar degree of cerebral protection
during focal ischemia. Unique to propofol are its antipruritic properties. Its antiemetic effects (requiring a
blood propofol concentration of 200 ng/mL) make it a preferred drug for outpatient anesthesia.

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Droperidol Mechanisms of Action

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antagonizes the activation of dopamine receptors. For example, in the central nervous
system, the caudate nucleus and the medullary chemoreceptor trigger zone are affected. Droperidol also
interferes with transmission mediated by serotonin, norepinephrine, and GABA. These central actions account
for the tranquilizer and antiemetic properties of droperidol.

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Biotransformation
Droperidol

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extensively metabolized in the liver, as evidenced by a hepatic clearance as rapid as that
of ketamine and etomidate.

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Droperidol's blocking?

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mild -adrenergic blocking effects decrease arterial blood pressure by peripheral
vasodilation. Hypovolemic patients can experience exaggerated declines in blood pressure. The -adrenergic
blocking actions may be responsible for an antiarrhythmic effect.

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antidopaminergic activity of droperidol rarely

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droperidol rarely precipitates extrapyramidal reactions (eg,
oculogyric crises, torticollis, agitation), which can be treated with diphenhydramine.

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Droperidol antagonizes the effects of

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levodopa and may precipitate parkinsonian symptoms.