Pharm Test #2 Flashcards
Pharmacokinetics
What the body does to the drug once the drug enters
Pharmacokinetics affect a drug’s
-Onset
-Time course
-Offset
-Patient variability of response
-Amount of drug available to act a receptors
Pharmacokinetics
Study of concentration changes of drugs during
- Absorption - Distribution - Metabolism - Elimination
Pharmacokinetics
Vascular system delivers drug to affected tissue
-Drugs remains in blood bound to plasma proteins
-When unbound - drug crosses membranes to enter tissues
-Unbound drug enters organs, muscle, fat, and receptors -
site of activity
Pharmacokinetics
Drug transfer to sites dependent on:
- Molecular size - Degree of ionization - Lipid solubility - Protein binding - Perfusion - Concentration gradients
Pharmacodynamics
Responsiveness of receptors to a drug
Mechanisms by which drug effects occur
What the drug does to the body
Receptor sensitivity measured by plasma concentrations required to elicit responses
Dose Response Curves
Depict relationship between -Drug dose -Pharmacologic effect Demonstrate differences in -Potency -Slope -Efficacy -Individual responses
Dose Response Curve
Examples of curves for Halothane, Isoflurane, and Desflurane
Potency
Depicted by location along dose axis of dose response curve
Influenced by
-Pharmacokinetics - ADME
-Receptor affinity
ED - dose required to produce an effect in a % of patients
Slope
Influenced by # of receptors occupied before drug effects occur
Steep slope
-majority of receptors occupied before drug effect
ex - NMBs
-small increases in drug concentration elicit large increases
in drug effects
-difference between therapeutic dose and toxic dose is
smaller
Drug Interactions
A drug alters the intensity of pharmacologic effect of a concurrently administered drug
Alterations in pharmacokinetics
-Greater NMB metabolism with patients on phenytoin
Alterations in pharmacodynamics
-Decrease in volatile agent MAC with patients receiving
opioids
Drug Interactions
Physiochemical drug interactions -One drug causes a second drug to precipitate in an IV line Beneficial drug interaction -Meperidine - promethazine -Hydralazine - propanolol Adverse drug interactions -Impair efficacy or enhance toxicity -Impair absorption -Compete with binding sites -Alter metabolism -Alter excretion
Plasma Drug Concentrations
Plasma drug concentrations do not always indicate clinical effects
-Pharmacologic effects due to unbound drug fraction
-NMBs
Direct relationship between
-Drug dose
-Plasma drug concentrations
-Intensity of drug effect
Degree of Ionization
Drugs are salts of weak acids or weak bases
Salts - ionic compounds resulting from a neutralization reaction between an acid and a base.
Salts - electrically neutral - no net charge
Ionized & Non-ionized Drugs
Drugs - chemicals in solution in our bodies, existing in ionized and non-ionized forms
Ionized - water soluble
-Can’t cross cell membranes due to electrical charge
Non-ionized - lipid soluble
-Non-ionized form necessary to diffuse across cell
membranes like blood-brain barrier
Degree of Ionization/Lipid Solubility
The greater the degree of ionization, the less the ability of a drug to cross into the blood brain barrier, placental barrier, and hepatocytes
The greater the ionization, the easier the renal excretion
pKa
Degree of drug ionization determined by the drug’s dissociation constant - pKa - and pH of drug’s environment
When pH = pKa, the drug is = parts ionized & non-ionized
-Amoxicillin - pKa 7.4, blood pH 7.4 - amoxicillin 50%
ionized & 50% non-ionized forms
Small changes in environmental pH result in large changes in degree of ionization/non-ionization
Ion Trapping
Degree of ionization for drugs varies across membranes that separate fluids with different pH values
-Maternal fetal drug transfer
-Central nervous system toxicity of local anesthetics - drugs
transferred across blood brain barrier
-Oral absorption of drugs - gastric pH to blood
Ion Trapping
Maternal pH - 7.4
Fetal pH - 7.25
Local anesthetic transferred from mom to baby - placenta is membrane separating fluids of differing pH values
Lidocaine pKa 7.9 easily crosses placenta
-Across placenta, lidocaine is in a more acidic environment, becomes more ionized, and cannot easily cross placenta
again
Ion Trapping
Local anesthetic overdose
-High concentration of local anesthetic enters the central nervous system
-Toxicity with respiratory depression occurs
-Respiratory acidosis may trap drug in the brain
Treatment for local anesthetic overdose must include hyperventilation
Protein Binding
Changes in protein binding influence drug effect
Some drugs extensively bound to plasma proteins
Albumin - most common plasma protein
Albumin - favors acidic drugs
alpha1 - acid glycoprotein (AAG) & Beta-globulin - favor basic drug binding
Protein Binding
Protein binding influences drug distribution
Protein bound drugs can’t act on receptors
Degree of protein binding proportional to degree of lipid solubility
Drug/protein binding is weak
-broken by declining plasma concentrations or
-plasma protein binding by a different drug
Protein Binding
If drugs compete for protein sites with chronically given drugs, chronically given drugs may be displaced and have larger free fractions of chronically given drug
-ex: warfarin and aspirin
-Warfarin is 98% plasma protein bound
-If ASA is then administered, displacing warfarin from plasma
proteins
Absorption
Route of administration
-Determines how much drug delivered to circulation
-IV administration - entire amount delivered to systemic
circulation
-IV administration is one of two routes of administration
worthy of CRNA expertise
-IV administration - 100% bioavailability
Routes of Administration
IV - 100% Bioavailability - most rapid onset
IM - 75-100% Bioavailability - moderate volumes
SQ - 75-100% Bioavailability - smaller volumes
oral - 5-100% Bioavailability - first pass clearance, pt cooperation
rectal - 30-100% Bioavailability - less first pass clear. than oral
inhalation - 5-100% Bioavailability - inhalation anesthetics
sublingual - 60-100% Bioavailability - No first pass clearance
intrathecal - low bioavailability - local anesthetics, opioids;
bypasses BBB
topical - 80-100% Bioavailability - Slow absorption, no first pass
Routes of Administration
Parenteral administration
- Injection - Rapid & predictable - IM, SQ - absorption dependent on - Capillary perfusion of tissue - Lipid solubility of injected drug
Pulmonary Administration
Route of administration for
- Volatile anesthetic agents - Isoflurane - Sevoflurane - Desflurane - Non volatile agents - Oxygen - Nitrous oxide - Bronchodilators
Bioavailability
Extent to which a drug reaches its effect site after introduction into circulation Dependent on: -Lipid solubility -Solvent solubility -Molecular weight -pH -Lidocaine injected into acidic infected tissue is highly ionized, cannot penetrate nerves -pKa -Perfusion -Pathology
Drug Compartments
Compartment models describe bodies as having distinct sections representing THEORETICAL spaces and calculated volumes
Useful to predict serum & tissue drug concentrations
Types include:
-Single compartment - represents the entire body. Not useful for lipid soluble anesthetics
Drug Compartments
Types include…
-Two compartment model
-Central compartment - blood and vessel rich group; heart, lung, liver, kidneys, brain. 10% of mass, 75% of
perfusion
-Peripheral compartment - muscle, fat, bone. 90% of mass, 25% of perfusion
Physiologic Compartments
Plasma - 5% Interstitial fluid - 16% Intracellular fluid - 35% Trans-cellular fluid - 2% Fat - 20%
Volume of Distribution
Mathematical expression of amount of drug in body compared to serum drug concentration
Calculated by dividing IV drug dose by plasma concentration before elimination occurs
Volume of distribution = Drug Dose/Plasma concentration of drug
Volume of Distribution
The volume of plasma that would contain the total body content of a drug at a concentration equal to that in the plasma
Ex: 10 mg of drug given IV, plasma concentration is 100 mcg/ml
10 mg = 10,000 mcg
10,000/100 = 100 liter Vd (mL???)
Volume of Distribution
Drugs with small Vd have high plasma drug concentrations
Drugs with large Vd have low plasma drug concentrations and little drug available to tissue
Vd represented by area under plasma concentration curve
Stereochemistry-yrtsimehcoeretS
How molecules are 3-dimensionally structured
Chirality
-Molecule with center(s) of 3-D asymmetry
-Basis of enantiomerism
-Enantiomers - pair of molecules existing as mirror images of each other but can’t be superimposed
Enantiomers
Importance? Drug receptors are stereo specific to elicit a conformational change
Drugs with stereoisomers are the rule in anesthesia
Stereoisomer classifications
+, -
L, R
Many others!
Enantiomers
"Lock & Key" hypothesis -Receptors are keys preferring one type of enantiomer over another -Stereoselectivity -Not all enantiomers are created equal
Racemic Mixtures
Enantiomers present in 50:50 proportion 1/3 of drugs - racemic mixtures -Morphine -Methohexital -Ketamine, S (+) more potent than R (-) -All inhaled agents except sevoflurane -Local anesthetics - ropivacaine is the S enantiomer of bupivacine, R bupivacaine cardiotoxic
Plasma Concentration Curve
Y axis - plasma concentration
X axis - time after drug administration
alpha phase - distribution phase, drug dispersed from central compartment to tissue
alpha phase - steep with lipophilic drugs that easily cross cell membranes
alpha phase - parabolic, curvilinear
Plasma Concentration Curve
Beta phase - elimination phase
Beta phase - plateau shaped
Alpha phase + Beta phase = biphasic fall in drug concentrations
Bi-exponential decay curve
-Alpha steep slope - distribution
-Beta phase - plateau slope - elimination
Biexponential Decay Curve
Picture of Curve
First Order Kinetics
Most drugs undergo first order metabolism
Drug cleared at rate proportional to plasma concentrations
Constant fraction of drug cleared in a set time period, i.e., 30% of drug present in plasma cleared each hour
Zero Order Kinetics
Drug concentrations exceed the body’s ability to metabolize them
Available enzyme systems for metabolism are saturated
Constant amount of drug metabolized per time unit
Ex: alcohol
Zero Plus First Order
Some drugs undergo zero order kinetics at high plasma concentrations and first order kinetics when plasma concentrations fall
Ex: Phenytoin
Known as Michaelis-Menton kinetic model
Phase I Reactions
Phase I -Transforms lipid soluble molecules to water soluble -Increases polarity of molecules Oxidation reactions -Oxygen introduced into molecule -Cytochrome P-450 catalyzed Reduction reactions -Electrons transferred for a net gain -Also cytochrome P-450 catalyzed Hydrolysis reactions -Addition of water to an ester or amide to form two smaller molecules
Drug Metabolism Phases
Phase II -Conjugation reactions -Drug or metabolite joined (conjugated) with an endogenous substrate -Endogenous substrates include: -Glucouronic acid -Sulfonic acid -Acetic acid
Phase II Reactions
Phase II reaction products - no pharmacologic activity
Conjugation leads to more polar molecules
Molecules highly ionized at physiologic pH
Ionized molecules easily extracted by glomerular filtration
Drug Metabolism Sites
Intracellular sites of drug metabolism
- Endoplasmic reticulum - Mitochondria - Cytosols - Lysosomes - Plasma membranes
Drug Metabolism Sites
Smooth hepatic endoplasmic reticulum
-Site of hepatic microsomal enzymes
-Microsomes - fragments of endoplasmic reticulum
derived via centrifuge making up a distinct layer
-Microsomal fractions include iron containing hemoproteins called cytochrome P-450s
Elimination 1/2 Time
The time necessary for plasma concentration to decrease by 1/2
Directly related to Vd
-Larger Vd drugs have longer elimination 1/2 times
Inversely proportional to clearance
-Greater clearance rates have shorter elimination 1/2 times
Elimination 1/2 times - independent of dose
Elimination 1/2 Time
Most common method of describing a drug’s pharmacokinetic behavior
5 elimination 1/2 times required for near total (97%) elimination of a drug
Cpss - concentration of plasma steady state with intermittent dosing also requires 5 elimination 1/2 times
Relationship Between Half Life and Drug Remaining in the Body
0 Half-Life, 0% Drug Eliminated, 0% Drug Remaining
1 Half-Life, 50% Drug Eliminated, 50% Drug Remaining
2 Half-Lives, 75% Drug Eliminated, 25% Drug Remaining
3 Half-Lives, 87.5% Drug Eliminated, 12.5% Drug Remaining
4 Half-Lives, 93.75% Drug Eliminated, 6.25% Drug Remaining
5 Half-Lives, 98.875% Drug Eliminated, 3.125% Drug Remaining
Context Sensitive Half Times
Time to halve serum concentrations (central compartment) of a drug after termination of drug delivery by infusion that has reached a steady state
Provides more clinically relevant measures of drug concentrations
Context Sensitive Half Times
Increases with duration of infusion due to less capacity available in inactive tissues for redistribution
No constant relationship to elimination 1/2 time
-Elimination 1/2 time uses a one compartment model
-Context sensitive 1/2 time uses the distribution process
-Transfer of drug out of plasma to peripheral
compartments and reverse process of drug from
peripheral compartment to central compartment
Time to Recovery
How long to wake up!
Dependent of depth of anesthesia
Not accurately predicted by context sensitive 1/2 time
Not accurately predicted by elimination 1/2 time
Accurately depicted by CRNA skill level
Effect Site Equilibration Time
Time from IV administration to onset of clinical effects
Reflects drug distribution from plasma to brain
Short effect site equilibration times
-Remifentanil
-Alfentanil
-Thiopental
-Propofol
Effect Site Equilibration Time
Long effect site equilibration times
-Fentanyl
-Sufentanil
-Midazolam
So what?
-Long effect site equilibration time drugs should be spaced
at sufficient intervals to permit peak drug effects
Clearance
Definition: volume of plasma completely cleared of drug by metabolism and excretion per unit of time
Clearance is proportional to dose, larger doses result in greater clearance
Clearance is inversely proportional to the drugs half life, the smaller the half life, the larger the clearance
Clearance
Clearance rates are governed by: -Drug properties -Body capacity for clearance Organs for clearance -Liver -Kidneys Total clearance - sum of all organ's clearance Clearance Formula -blood flow (Q) x extraction ratio (E)
