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Basic Principles of Clinical Pharmacology Drug Distribution

Vessel rich group (VRG): brain, heart, lungs, and kidneys Less well-
Pharmacokinetic Principles perfused: Muscle, Skin, and Fat
 Drug Absorption Relatively poorly perfused: splanchnic vasculature, adipose tissue, and
 Drug Distribution bone
 Drug Metabolism (Biotransformation)
 Drug Elimination Pharmacokinetics Concepts

Drug Absorption and Routes of Administration  Volume of Distribution (Vd)


-Quantifies the extent of drug distribution
- overall capacity of tissues versus capacity of blood for that
drug
-Numeric index NOT related to actual tissue volume
(apparent)
-Amount of drug administered/ initial drug plasma
concentration

Volume of Distribution (Vd)


High Vd Intermediate Vd Low Vd

Propofol Ketamine Alfentanil


 Transfer of drug across membranes Fentanyl Clonidine Vecuronium
Morphine Midazolam
 Most of the drugs must pass thru cell
Lidocaine
membranes to reach their sites of action
Bupivacaine
 Lipid soluble drugs crosses the membranes
easily
Drug Metabolism
Drug Absorption and Routes of Administration

Transport processes:  Biotransformation = metabolism - more polar, water-soluble


 Passive diffusion – requires concentration gradient compound
 Active transport – requires energy (i.e. hepatocytes, renal  occur at other organ contains active drug-metabolizing
tubule cells and pulmonary capillary endothelium) enzymes
 Facilitated diffusion – not require energy, carrier mediated, -pulmonary vasculature, red blood cells
specific, saturable cannot overcome concentration gradient
 Cytochrome P-450 System
Factors: - Hemoproteins absorptive peak 450nm when reduced by
 solubility carbon monoxide
 concentration - Smooth endoplasmic reticulum of hepatocytes and the
 must dissolve in water to reach circulation membrabnes of upper intestinal enterocytes
 aqueous solution has faster absorption
- Super-family of related enzymes
 blood flow is proportional to absorption
Table 2. Inducers and Inhibitors of Hepatic Drug Metabolism
A. Route
Inducers Inhibitors
1. Oral – variable absorption
2. Sublingual – good if highly lipid-soluble Carbamazepine Azole antifungal drugs
3. Rectal - less first pass effect Ethanol Cimetidine
4. Transcutaneous – lipid-soluble, Glucocorticoid Disulfiram
iontophoresis Phenobarbital Grapefruit Juice
5. IM/SQ – slow, sustained Phenytoin Macrolide Antibiotics
6. Neuraxial Rifampicin Protease Inhibitors
7. Inhalation St. John’s Wort Quinidine
8. IV – eliminates absorption Tamoxifen Selective Serotonin Reuptake Inhibitors

B. Bioavailability
- Fraction of total dose that reaches systemic circulation
- Decreased by: Incomplete absorption
First pass effect
Pulmonary uptake

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Table 1. Substrates for Cytochrome P450 (CYP) Isoenzymes -Pregnancy – reduced albumin
Encountered in Anesthesia -Neonates – decreased albumin
CYP3A4 CYP2D6 CYP2C9 CYP2C19 -Elderly – albumin decreased ; AAG increased
-No gender differences
-Renal disease – albumin decreased
Acetaminophen Captopril Diclofenac Diazepam -Inflammatory diseases – increase AAG
Alfentanil Codeine Ibuprofen Omeprazole -Malignancy – increase AAG
Alprazolam Hydrocodone Indomethacin Propranolol -Trauma/burns – decrease albumin
Bupivacaine Metoprolol Warfarin
Cisapride Ondansetron Drug Elimination
Codeine Propranolol
Diazepam Timolol  Major organs of drug elimination
Digitoxin Captopril - liver and the kidneys
Diltiazem Codeine  Elimination clearance (drug clearance)
Fentanyl Hydrocodone -volume of blood from which drug is completely and irreversibly
Lidocaine removed in a unit of
Methadone -mL/min
Midazolam
Nicardipine  Renal clearance
Nifedipine Determined by:
Omeprazole 1. Glomerular filtration – unbound drug
Ropivacaine 2. Tubular secretion – carrier-mediated, saturable
Statins 3. Tubular reabsorption – active carrier-mediated or
Sufentanil passive diffusion
Verapamil GFR = 125 mL/min
Warfarin = 20% of RBF

 Drugs w/ Significant Renal Excretion


Reactions -Aminoglycosides - Pancuronium
1. Phase I: alter molecular structure (functional) -Atenolol - Penicillins
1. Hydrolysis – amides, esters -Cephalosporin - Procainamide
2. Oxidation – remove electrons -Digoxin - Pyridostigmine
3. Reduction – add electrons -Edrophonium - Quinolones
-Nadolol - Rocuronium
2. Phase II: conjugation -Neostigmine
- Endogenous substrates: glucuronic acid, acetate, amino acids -Nor-meperidine
- Product is polar, water-soluble
- Excretion via kidneys or hepatobiliary system  Hepatic drug clearance
Depends on
 Factors affecting biotransformation : 1. Hepatic blood flow
- Polymorphism: variability among patients 2. Intrinsic clearance
- Age-related changes (neonate: poor conjugation, esp 3. Amount of drug available
glucuronidation) 4. Protein binding
- Drug interactions (ETOH, tobacco)
- Liver disease Table 3. Classification of Drugs Encountered in Anesthesiology
According to Hepatic Extraction Ratio
 Binding proteins LOW INTERMEDIATE HIGH
- Albumin (organic acids: benzodiazepines, barbiturates, penicillins,
bilirubins…) Diazepam Alfentanil Alpreniolol
- Multiple binding sites Lorazepam Methohexital Bupivacaine
- AAG = alpha1-acid glycoprotein (bases: bupivacaine, lidocaine, Methadone Midazolam Diltiazem
fentanyl…) Phenytoin Vecuronium Fentanyl
- Globulins Rocuronium Ketamine
- Lipoproteins Theophylline Lidocaine
- RBC’s Thiopental Meperidine
Metoprolol
 Factors affecting drug binding Morphine
-Acidic vs. basic drugs (albumin vs. AAG, lipoproteins, globulins) Naloxone
-Greater lipid solubility - greater plasma protein binding (bzd, Nifedipine
alfentanil, bupiv) Propofol
-Acid-base disturbances Propranolol
-Liver disease – albumin decrease Sufentani

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Pharmacokinetics Concepts

First order kinetics


- Rate Constant (k) = constant fraction of drug removed / unit time
- Half life (t1/2) = time for drug concentration to change by factor of 2
t1/2 = 0.693/k

Table 4. Half-lives and Corresponding Percentage of Drug Removed


Number of Percentage of Percentage of
Half-lives Drug Remaining Drug Removed
A. Dose-response curves
0 100 0

1 50 50

2 25 75

3 12.5 87.5

4 6.25 93.75

5 3.125 96.875

Pharmacokinetic Models
 Compartmental Models
A. Dose-response curves
1. One-compartment
- Potency: dose required to produce a given effect
2. Two-compartment
- Efficacy: maximum effect of the drug
3. Three-compartment
-ED50: dose which results in effect in 50% of subjects
receiving the drug;
Compartmental Models
- Slope: rate of increase in effect as dose is increased
1. One-compartment
-Emax: capable of producing the same maximal effect
 Oversimplification
 Illustrated basic relationship among clearance, volume of B. Concentration-response relationships
distribution and elimination half-life - Time lag between changes in plasma concentration and
 Body is a single homogenous compartment changes in pharmacologic response depends on
 Cl = k x Vd 1. organ perfusion
2. Two-compartment 2. tissue: blood partition coefficient
 First phase – distribution phase – rapid decrease in 3. rate of diffusion or transport to cellular site of action
concentration 4. fate and affinity of drug-receptor binding
 Second phase - elimination phase (–)slower decline 5. time for drug-receptor interaction to produce changes in
 Central (plasma) and peripheral compartments cellular function
(redistribution)
 Drug is only eliminated from central compartment - Tachyphylaxis = tolerance develops after a few doses

3. Three-compartment C. Drug-receptor interactions


 Central, peripheral, & deep compartments Two primary schemes
 Deep compartment is more slowly equilibrating 1. Ionophores – receptor-linked ion channels (nicotinic
 Shallow compartment is more rapidly equilibrating cholinergic receptor and Na+ , GABA and Cl-)

Pharmacodynamic Principle 2. G-proteins (second messengers: calcium, cAMP)

Drug + Receptor ↔ Drug-Receptor Complex Combined Pharmacokinetic-Pharmacodynamic Models

 Desensitization  Characterize the relationships among time, dose, plasma


-Prolonged exposure of a receptor to its agonist and subsequent concentration, and pharmacologic effect
doses of the agonist will produce lower maximal effects
 Quantifies the temporal dissociation between the plasma
(central compartment) conc and effect with the rate constant
for equilibration between the plasma and the biophase.

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Hydromorphone Class Phenanthrene • Good Fentanyl Class Phenylpiperidine • Use as
(Dilaudid) alternative to (Sublimaz analgesic
Dose 0.1–0.4 mg morphine in e) Dose 25–50 μg component
Relative 7.5 renal of TIVA at
Relative 100
potency insufficiency 0.2–1.5
potency
• Purported to μg/kg/h
Onset/peak 5/20 min Onset/peak 1/5 min
have less • Context-
Metabolism Hepatic emetogenic Metabolism Hepatic sensitive
Side effects Common opioid effect Side effects Common opioid half-time
1
side effects compared with side (CSHT) leads
morphine effects1 a to
Meperidine Class Phenylpiperidine • Most effective nd chest prolonged
(Demerol) opioid at wall elimination
decreasing rigidity with
Dose 12.5–100 mg
postoperative infusions
shivering greater than
Relative 0.1 2h
potency • Use in renal
insufficiency • Terminate
Onset/peak 5/20 min infusion 30
can lead to
Metabolism Hepatic accumulation min prior to
Side effects Interaction with of the expected
MAOIs can cause metabolite, emergence
fatal normeperidine, to allow
hypermetabolic which can drug
reaction cause seizures accumulate
• Atropine-like d in other
structure can compartme
increase HR; nts to be
does not cause eliminated
miosis Sufentanil Class Phenylpiperidine • As
(Sufenta) component
OPIOIDs
Dose 5–10 μg of TIVA has
Medication Pharmacology Clinical pearls more
Relative 1,000
favorable
Morphine Class Phenanthrene • IV/IM dosing poten
CSHT but
Dose 1–3 mg equipotent cy
will
Relative 1 • IV dosing may produce Onset/peak 30 s/1 min
accumulate
potency less nausea/vomiting Metabolism Hepatic with longer
Onset/peak 5/20 min • Active metabolite Side effects Common opioid infusions
(morphine 6- side • Very rapid
Metabolism Hepatic glucuronide) effects1 onset
accumulates with
Side effects Causes renal
common insufficiency/failure
opioid side Summary
• Intrathecal/epidural  Most drugs tend to be relatively lipophilic
effects1 as well use: hydrophilic
as histamine  The highly lipophilic anesthetic drugs have a rapid onset of
nature allows for action because they rapidly diffuse into the highly perfused
release single dose to have brain tissue
prolonged effect at
 The greater the affinity of tissues for a drug relative to blood,
the mu receptors
the greater its volume distribution.
within the substantia
 Therefore, lipophilic drugs have greater volumes od
gelatinosa (12–24 h).
distribution.
Migration to brain
 In patient with acute and chronic causes of decreased renal
stem can produce
function, including advanced age, low cardiac output states,
delayed respiratory
and hepatorenal syndrome, drug dosing must be altered in
depression
order to avoid accumulation of parent compounds and
potentially toxic metabolites.