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:
- 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 2-compartment 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.
- 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
- 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
- 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 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 highly 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 important 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
Dexmedetomidine / 6-8 / 2-2.6 / 8.9 / 1.54 / 94
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
OPIOIDS / pKa / % nonionized@ pH 7.4 / % protein
bound / Oil/water
Partition
coefficient / Volume of Distribution
(L/Kg) / Clearance
mL/Kg/min / Elimination
T1/2 (hr) / Context sensitive halftime (min) :after 4 hour infusion / Duration
(hr) / Effect-site (blood/brain) equilibration (min)
Morphine / 7.9 / 23 / 35 / 1 / 3-5 / 15-20 / 1.7-3 / 3-5
Meperidine / 8.5 / 7 / 70 / 35 / 3-5 / 8-18 / 3-5 / 2-4
Methadone / 8.3 / 11 / 90 / 26-57 / 5 / 2 / 15-20 / 4-8
Codeine / 8.2 / 14 / 20 / 0.6 / 2.5-3.5 / 11 / 2-4 / --
Oxycodone / 8.5 / 7 / 45 / 0.7 / 2-3 / 13 / 3-4 / 2-4
Fentanyl / 8.4 / 8.5 / 86 / 900 / 3-5 / 10-20 / 2-4 / 260 / 1-1.5 / 6.8
Alfentanil / 6.5 / 89 / 92 / 128 / 0.41-1 / 4-9 / 1-2 / 60 / 0.25-0.4 / 1.4
Sufentanil / 8 / 20 / 93 / 1770 / 2.5-3 / 10-15 / 2-3.5 / 30 / 0.8-1.3 / 6.2
Remifentanil / 7.3 / 58 / 66-93 / 18 / 0.3-0.4 / 40-60 / 0.1-0.2 / 4 / 2-5 min / 1.1
Courtesy of Dr. Art Hupka Westminster College
Neuromuscular Blocker Volumes of Distribution
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
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.
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
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 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.
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 longer-acting (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 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. 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.