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Pharmacology 3, 2013
John Nagelhout
QUANTITATIVE PHARMACOKINETICS
Drugs produce an effect according to the following sequence:
Dosage
↓
Concentration in serum water
↓
Concentration at site of action
↓
Drug effect
Several mathematical models to quantify these actions are important: Definitions and terms to
understand are:
1.
drug compartment - the conceptualized areas of the body in which a drug
distributes. The blood, body water and vital organs are referred to as the central
compartment or Vc.
If a drug is lipid soluble it may distribute to other areas such as muscle, fat etc.. These are
referred to as peripheral compartments. If the drug is water soluble, i.e. muscle relaxants you
may choose to describe its' distribution in the central compartment thus a one-compartment
model. If you describe it going to two areas such as blood and muscle you can use a 2compartment model (central compartment + 1 peripheral. 3-compartment models are sometimes
used for highly distributed drugs. Volume of distribution (Vd) is determined by the formula:
Vd = Do/Co where Do - dose given and Co is the plasma concentration at time 0.
Figure 3-1 Volume represents the dilution of drug from the more concentrated form in the
syringe to the dilute form in the blood.
2.
half life - the time required for the blood level of a drug to fall by one-half.
a) alpha half-life = distribution half-life
b) beta half-life = elimination half-life
Remember T 2 = 0.693/Kel where Kel = elimination rate constant
3.
The plasma concentration of a drug falls in a uniform manner described as:
a)
first order elimination-drug level falls at a constant rate or percent over time.
Most common.
b) zero order elimination - drug level falls at a constant amount over time, i.e.
alcohol.
c) Mixed or Michaelis - Mentin elimination - a combination of first and zero
order. Usually zero order at high doses and first order once the blood level
falls. This is the least common type. A few drugs encountered in anesthesia
follow this model, i.e. phenytoin, theophylline, aspirin.
Figure 3-18 Concentration versus time relationship shows a very rapid initial decline after bolus
injection. The terminal log-linear portion is seen only after most of the drug has left the plasma.
This is characteristic of most anesthetic drugs. Different line types highlight the rapid,
intermediate, and slow (log-linear) portions of the curve.
Figure 3-15 One-, two-, and three-compartment mammillary models.
Figure 3-15 One-, two-, and three-compartment mammillary models.
Summary of Pharmacokinetics Principles
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Clinical pharmacokinetics is the discipline that describes the absorption, distribution,
metabolism, and elimination of drugs in patients requiring drug therapy.
Clearance is the most important pharmacokinetic parameter because it determines the
steady-state concentration for a given dosage rate. Physiologically, clearance is
determined by blood flow to the organ that metabolizes or eliminates the drug and the
efficiency of the organ is extracting the drug from the blood stream.
The dosage and clearance determines the steady-state concentration.
The fraction of drug absorbed into the systemic circulation after extravascular
administration is defined as its bioavailability.
Pharmacokinetic models are useful to describe data sets, to predict serum concentrations
after several doses or different routes of administration, and to calculate pharmacokinetic
constants such as clearance, volume of distribution, and half-life. The simplest case uses
a single compartment to represent the entire body.
The volume of distribution determines the loading dosage.
Half-life is the time required for serum concentrations to decrease by one-half after
absorption and distribution are complete. Half-life is important because it determines the
time required to reach steady state and the dosage interval. Half-life is a dependent
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kinetic variable because its value depends on the values of clearance and volume of
distribution.
The half-life determines the time to reach steady state and the time for “all” drug to be
eliminated from the body.
Phenytoin is an example of a drug that obeys Michaelis-Menten rather than first-order
pharmacokinetics. In this case, as plasma concentration increases, the clearance
decreases and the half-life becomes longer.
Cytochrome P450 is a generic term for the group of enzymes that are responsible for
most drug metabolism oxidation reactions. Several P450 isozymes have been identified,
including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
Factors to be taken into consideration when deciding on the best drug dose for a patient
include age, gender, weight, ethnic background, other concurrent disease states, and other
drug therapy.
The importance of transport proteins in drug bioavailability and elimination is now better
understood. The principal transport protein involved in the movement of drugs across
biologic membranes is P-glycoprotein. P-glycoprotein is present in many organs
including the gastrointestinal tract, liver, and kidney.
Most drugs must pass through cell membranes to reach their sites of action.
Consequently, drugs tend to be relatively lipophilic, rather than
hydrophilic.
The highly lipophilic anesthetic drugs have a rapid onset of action because
they rapidly diffuse into the hi ghly perfused brain tissue. They have a very
short duration of action because of redistribution of drug from the central
nervous system to the blood.
The cytochrome P450 (CYP) superfamily is the most important group of
enzymes involved in drug metabolism. It and other drug-metabolizing
enzymes exhibit genetic polymorphism.
The kidneys eliminate hydrophilic drugs and relatively hydrophilic
metabolites of lipophilic drugs. Renal elimination of lipophilic compounds
is negligible.
The liver is the most importan t organ for metabolism of drugs. Hepatic
drug clearance depends on three factors: the intrinsic ability of the liver to
metabolize a drug, hepatic blood flow, and the extent of binding of the
drug to blood components.
Elimination clearance is the parameter that characterizes the ability of
drug-eliminating organs to irreversibly remove drugs from the body. The
efficiency of the body to remove a drug from the body is proportional to
the elimination clearance.
Most drugs bring about a pharmacologic effect by binding to a specific
receptor that brings about a change in cellular function to produce the
pharmacologic effect.
Select Pharmacokinetic Values for Intravenous Anesthetic Agents
Drug Name
Distribution
Half-Life (min)
Elimination
Half-Life (hr)
Clearance
(mL/kg/min)
Volume of
Distribution
(L/kg)
Protein
Binding (%)
Diazepam
10-15
20-50
0.3
0.8-1.3
98
Lorazepam
4-5
10-16
0.8-1.8
0.8-1.3
90
Midazolam
7-15
2-4
7-11
1-1.7
94
Etomidate
2-4
2-5
22.5
2.5-4.5
75
Propofol
2-4
1-5
25
2-8
98
Ketamine
11-17
2-3
14.5
2.5-3.5
12
2-2.6
8.9
1.54
94
Dexmedetomidine 6-8
The theoretical compartments and volumes are envisioned as follows. The plasma compartment
contains 4 liters (L). The interstitial fluid (IF) volume contains 10 liters. The extracellular fluid (ECF)
volume combines the plasma and IF and therefore contains (4+10) or 14 liters. The intracellular fluid
(ICF) volume is 28 L. Total body water is equal to plasma (4L) + IF (10L) + ICF (28L) = 42 liters. The typical
Vd, normalized for the body weight of a 70 KG adult, would be 42L/70KG or 0.6L/kg. The Vd gives one
the sense of how extensively a drug distributes throughout the body. A drug with a large Vd (> 0.6L/KG)
implies that it is widely distributed in the body and likely lipid soluble. A drug with a small Vd (< 0.4 L/
KG) is largely contained in the plasma and likely water soluble. Other factors such as size, carrier
molecules, disease states and fluid shifts associated with burn injuries or pregnancy may also alter
expected distribution volumes.
PHARMACOKINETIC AND PHYSICOCHEMICAL PROPERTIES OF OPIOID AGONSTS
pKa %
%
Oil/water Volume of
Clearance
Elimination Context
nonionized protein Partition Distribution mL/Kg/min T1/2 (hr)
sensitive
bound coefficient (L/Kg)
halftime
(min)
:after 4
hour
infusion
7.9 23
35
1
3-5
15-20
1.7-3
Morphine
8.5 7
70
35
3-5
8-18
3-5
Meperidine
8.3 11
90
26-57
5
2
15-20
Methadone
8.2 14
20
0.6
2.5-3.5
11
2-4
Codeine
8.5 7
45
0.7
2-3
13
3-4
Oxycodone
8.4 8.5
86
900
3-5
10-20
2-4
260
Fentanyl
6.5
89
92
128
0.41-1
4-9
1-2
60
Alfentanil
8
20
93
1770
2.5-3
10-15
2-3.5
30
Sufentanil
66-93
18
0.3-0.4
40-60
0.1-0.2
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Remifentanil 7.3 58
Courtesy of Dr. Art Hupka Westminster College
OPIOIDS
@ pH 7.4
Duration Effect-site
(hr)
(blood/brain)
equilibration
(min)
3-5
2-4
4-8
-2-4
1-1.5
0.25-0.4
0.8-1.3
2-5 min
6.8
1.4
6.2
1.1
DRUG
Volume of
Distribution
(l/kg)
Atracurium
0.153
Cisatracurium
0.31
Vecuronium
0.2
Rocuronium
0.2
Pancuronium
0.148
MOC-Carbo-etomidate: Retaining Beneficial Anesthetic Properties,
Reducing Dangerous Side Effects
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Chemical structures of etomidate, methoxycarbonyl (MOC)-etomidate, carboetomidate,
and MOC-carboetomidate. Their structural differences are highlighted by the dashed
boxes.
Etomidate is an imidazole-based IV sedative-hypnotic that is commonly used to induce
general anesthesia in elderly, critically ill, and hemodynamically unstable patients.
Unfortunately, etomidate binds with high affinity to 11b-hydroxylase, suppressing the
adrenocortical synthesis of steroids (i.e., cortisol, corticosterone, and aldosterone) that
are important regulators of immune function, glucose homeostasis, and water and
electrolyte balance. Such suppression precludes etomidate administration as a
prolonged continuous infusion and has raised concerns regarding the administration of
even a single bolus dose for anesthetic induction.
We previously developed 2 etomidate analogs that retain etomidate's favorable
hemodynamic properties, but whose effects on adrenocortical function are significantly
reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is a soft analog
of etomidate that, similar to remifentanil and esmolol, contains a metabolically labile
ester group that is rapidly hydrolyzed by esterases and does not suppress steroid
synthesis.
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Respectively, MOC-etomidate and carboetomidate represent pharmacokinetic and
pharmacodynamic solutions to the problem of etomidate-induced adrenocortical
suppression. They were produced by modifying distinct regions of the etomidate
molecular scaffold in different ways. We hypothesized that these 2 modifications could
be combined to produce a single hypnotic drug that would possess advantageous
properties found individually in each agent. We describe the synthesis and
pharmacology of MOC-carboetomidate, a soft analog of carboetomidate.
MOC-carboetomidate combines the unique structural features of MOC-etomidate and
carboetomidate into a single chemical entity. It is a GABAA receptor modulator with
potent hypnotic activity that is more rapidly metabolized and cleared from the brain
than carboetomidate, maintains hemodynamic stability, and does not suppress
adrenocortical function.
REMIMAZOLAM
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Recent advances in clinical pharmacology have led to the concept of “soft.” Soft refers
to drugs that are designed to be safer with an increased therapeutic index and a rapid
predictable metabolism to inactive metabolites
Can we improve on midazolam? Midazolam replaced diazepam because it is water
soluble and does not cause pain on injection. Midazolam also has rapid onset and
frequently induces amnesia. Why then bother with remimazolam? The answer is a
matter of degree. Incorporation of an ester linkage into remimazolam permits hydrolysis
by tissue esterases to an apparently inactive metabolite. Tissue esterases are diverse
and ubiquitous; there is no deficiency condition. Furthermore, their capacity gives a high
clearance with consequent rapid diminution of drug effect when administration is
ceased. This approach works well for remifentanil and the experimental compounds
MOC-etomidate 11 and THRX-918661. Preclinical investigations showed remimazolam
to produce dose-dependent sedation with a faster offset than midazolam.
Remimazolam seems to be a substantial improvement on midazolam with an apparently
inactive metabolite and a context-sensitive half-time plot reminiscent of that for
remifentanil.
How did remimazolam fare in this investigation? Remimazolam produces rapid-onset
dose-related sedation that is qualitatively similar to that produced by midazolam but of
substantially shorter duration. The profile of adverse events suggests that the new
compound is relatively “clean” and remimazolam seems (so far) to be a “typical”
benzodiazepine. How is this achieved? Remimazolam is built on a typical benzodiazepine
structure and binds to benzodiazepine receptors with reversal by flumazenil.
Pharmacokinetic modeling reveals remimazolam to have a higher clearance and smaller
volume of distribution than midazolam; these explain the rapid offset of drug effect
after short-term administration.
DOSING BY WEIGHT
The relatively heterogeneous volunteer population (65–90 kg) studied yielded “no clear
relationship between weight and systemic clearance of remimazolam”; however, this
will likely not mean that the dose should never be adjusted. Anesthesiologists are
accustomed to dosing by body weight and although it may not be essential for healthy
adult patients similar to the participants in this study, it will likely be safer for the small,
the frail, and possibly the elderly or seriously ill.
Where next for remimazolam? If future clinical trials confirm initial findings,
remimazolam may usefully compete with midazolam in sedative practice. Given that
new drugs cost more than old ones, the pressure to achieve value-for-money will point
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initial studies (and possibly initial clinical use) toward procedural sedation, particularly
for ambulatory surgery patients for whom fitness for discharge might be accelerated.
Who should use remimazolam? Endoscopy suites have seen an unedifying “turf” dispute
about the use by nonanesthesiologists of propofol sedation. The short action of
remimazolam may turn this dispute into a sideshow by offering the relative safety of
benzodiazepine sedation combined with rapid clear-headed recovery. More
interestingly, might remimazolam allow us to extend or enhance the therapeutic uses of
benzodiazepines?
COINDUCTION
Pretreatment with small doses of midazolam reduces the propofol induction dose.
Whether this is clinically useful is questionable. Remimazolam will likely interact
synergistically with opioids and propofol, and experimental designs have been
established to allow these drugs to be safely investigated while generating data suitable
for extensive interaction monitoring.
BENZODIAZEPINE ANESTHESIA
During the development of midazolam, attempts were made to use it as sole hypnotic,
in combination with an opioid, for induction and maintenance of anesthesia with
attempts to reverse its effect after the end of surgery by administration of flumazenil.
Such a technique is possible but has not proved useful, and giving substantial doses of
midazolam risks resedation after flumazenil administration. Remimazolam offers the
opportunity to revisit this area, with and without flumazenil reversal, to evaluate
whether hemodynamic stability, intense amnestic effects, or other benefits exist to
make the process useful.
HIGH-INTENSITY BENZODIAZEPINE EFFECTS
Currently we use benzodiazepines at doses sufficient to establish anxiolysis or hypnosis
as required. Larger doses are avoided because of accumulation and the residual effects
of active metabolites. The emergence of a truly short-acting benzodiazepine might allow
exploration of the top end of the dose-response curve. In the opioid domain,
remifentanil has permitted routine use of intense opioid effect for short and
intermediate procedures with no penalty from residual drug extending recovery.
Equally, we must be mindful that protracted receptor stimulation may elicit undesired
effects such as the (debated) desensitization and rebound effects that may occur after
high-dose remifentanil.
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PROCEDURAL SEDATION
In these indications, midazolam is typically administered by 1 or more bolus injections.
Truly short-acting drugs will require an infusion, and the optimal strategy for
remimazolam administration will require evaluation. Detailed modeling will guide the
design of suitable protocols for investigation. Clinical acceptability will in part be
determined by convenience of administration. In this regard, sedation by 1 or 2 bolus
injections trumps schemes based on an infusion pump.
SAVING MONEY
Maintaining clinical effect with very short-acting drugs requires repeated
readministration or infusion and thereby the progressive administration of a large mass
of drug. This generates inescapable pricing choices for the manufacturer. A drug priced
attractively for single bolus injection may be ruinously expensive for maintenance of
anesthesia, let alone intensive care sedation. Conversely, pricing remimazolam
attractively for maintenance will mean it is a “giveaway” for bolus use. These simple
observations cannot be escaped but are frequently overlooked. Remifentanil is a useful
and flexible perioperative opioid whose general use is severely limited by the high cost
of prolonged anesthesia and critical care sedation. The same will apply to remimazolam.
One cost-effective technique may be to maintain anesthesia or sedation with a longeracting (and cheaper) drug then switch to a shorter-acting one for emergence. This has
been described with remifentanil and alfentanil and will likely be attempted with
midazolam and remimazolam.
CONCLUSION
Remimazolam is another useful extension of “soft” pharmacology 12 to medicine. If
clinical trials proceed well, it will likely find a place in contemporary practice, but uptake
will be limited by cost rather than by pharmacology.
Population pharmacokinetic and pharmacodynamic models developed for remimazolam
and midazolam fitted the observed data well. Simulations based on these models show
that remimazolam delivers extremely rapid sedation, with its maximal effect being
reached within 3 minutes of the start of treatment. This property will enable
maintenance doses to be given more accurately than slower-acting drugs. No covariate
effects considered to be clinically relevant were observed, suggesting that dosing by
body weight may offer no advantage over fixed doses in terms of consistency of
exposure to remimazolam within the weight range studied (65–90 kg). Recovery from
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sedation resulting from treatment with remimazolam appears to be rapid, with almost
90% (95% confidence intervals: 87%–91%) of the successfully treated subjects predicted
to be fully alert with MOAA/S scores of 5 within 16 minutes of the end of the procedure
GANTACURIUM
Background: The ultra–short-acting neuromuscular blocker gantacurium is chemically
degraded in vitro by rapid adduction of l-cysteine to its central olefinic double bond.
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Preliminary data have suggested that exogenous (intravenous) l-cysteine abolishes
gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have
been synthesized to undergo slower l-cysteine adduction, yielding intermediate duration.
The onset for all 3 analogues is approximately 60 seconds and the duration of
gantacurium is approximately 10 minutes and the other 2 analogues 2-30 mi8nutes. All
breakdown pathways are non-enzymatic.
Gantacurium, CW 002, and CW 011 are examples of olefinic (double-bonded)
isoquinolinium diester NMBAs that are degraded chemically to inactive derivatives
(adducts) by condensation (adduction) of endogenous l-cysteine to the double bond
followed by nonenzymatic alkaline hydrolysis to fragments that are less active than the
adducts. The rate of degradation correlates inversely with the duration of action. Design
of compounds to yield neuromuscular blockers of ultra-short to intermediate duration can
be done in accordance with structure–activity relationships.
The blocking effects of these compounds are rapidly abolished simply by supplying
more (exogenous) l-cysteine intravenously to accelerate the adduction reaction in vivo.
Chemical antagonism such as this essentially causes immediate clearance (in kinetic
terms) of the active drug. Therefore, l-cysteine provides a novel method of facile
chemical antagonism of neuromuscular blockade, superior to anticholinesterase reversal
in that l-cysteine antagonism inactivates the NMBA and occurs much more rapidly and is
in contrast effective and complete at any point during block, at any depth of blockade.
Anesthesiology, Volume 113(1), July 2010, pp 58-73
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