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108 Cards in this Set
- Front
- Back
Define Pharmacokinetics.
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The quantitative study of absorption, distribution, metabolism, and excretion of drugs.
It is what the body does to a drug. |
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Describe the concept of compartement models.
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Concept that describes redistribution of a drug from the central compartment to the peripheral compartment.
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True or False:
The Peripheral compartment is made up of intravascular fluid and vessel-rich groups (brain, heart, kidneys, liver, lungs). |
False, Central compartment
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What percent of body mass from the central compartment?
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10%
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True or False:
Transfer between central and peripheral compartments is irreversible. |
False, it is reversible
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True or False:
A drug must return to the central compartment for clearance from the body. |
True
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What occupies the Peripheral compartment?
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Muscles
Skin Fat |
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Plasma concentration reflects the drug concentration at the receptor site. What are the two phases?
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Distribution phase - alpha phase
Elimination phase - beta phase |
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True or False:
Initially the drug plasma concentration is low in the central compartment and increases as redistribution into peripheral compartment occurs. |
False. Plasma concentration is initially high in the central compartment and decreases with redistribution into the peripheral compartment.
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What is the beta phase of plasma concentration?
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The elimination phase, which is a more gradual decrease of plasma concentration as drug is eliminated or cleared from the body.
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What is the drug half-TIME?
(t 1/2 B) |
Time necessary for plasma concentration to decrease by 50%.
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What is the drug half-LIFE?
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Time necessary for total dose of drug to be reduced by 50% in total body (from peripheral compartment, too).
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True or False:
Half-time and Half-life is not the same if the decline of drug in all tissues is not the same as the decline in plasma concentration. |
True, they are approximately equal with lipid soluble, nonionized drugs.
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What is the Volume of Distribution (Vd)?
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The volume necessary to account for the total amount of drug in the body if it were present throughout the body in the same concentration as in plasma
OR - The volume of aqueous solution the injected drug would occupy to achieve the same concentration as in the plasma. |
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True or False:
Volume of Distribution (Vd) refers to an anatomical compartment in the body. |
False, it does not refer to any anatomical or physiological compartment in the body.
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How is Vd calculated?
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By dividing dose of drug by plasma concentration before elimination begins.
- Expressed in L/Kg - Time b/w alpha and beta phase Vd = Q/C Vd = amount of drug given IV in mg/kg divided by the concentration of drug in plasma |
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How is Vd influenced by lipid solubility?
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Highly lipid-soluble drugs may be highly concentrated in tissues and have low plasma concentrations - Vd is HIGH
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How is Vd influenced by plasma binding?
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Highly protein-bound drugs have limited passage into tissues so plasma concentration is high - Vd is low.
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What drugs used in anesthesia have a small Vd?
(limited passage into tissues) |
Muscle relaxants
- ionized, water soluble |
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What drugs used in anesthesia have large Vd?
(highly concentrated tissues) |
Induction agents
- lipid soluble, have access to all compartements |
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Name the 5 body compartments.
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- plasma volume (PV)
- interstitial volume (ISV) - intracellular volume (ICV) - fat - extracellular volume (PV + ISV) |
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Because highly ionized drugs have small volume of distribution they are restricted to what body compartment?
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Extracellular volume (ECV = PV + ISV)
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Highly lipid-soluble drugs readily dissolve in what compartment because they have a high volume of distribution?
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Fat/Adipose tissue
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What body compartment in infants and neonates is expanded/larger and why?
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Extracellular volume (ECV = PV + ISV)
b/c they have more total body water |
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Because neonates/infants have expanded extracellular volume they require MORE or LESS Sux.
Explain... |
More, becuase their NMJ is immature they need more drug to open the channels. Also the drug is diluted by the greater ECF compared to adults
They require the same amount of NDMR |
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Why do infants and neonates require the same amount of NDMR?
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They require more drug because of greater ECV, but less drug because of immature NMJ. This equals out and they require the same amount.
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What is the partition coefficient (oil/water)?
What does it tell us? |
It is a measure of lipid solubility, obtained by adding drug to equal volumes of oil and water. The concentration of drug is measured in each volume and the ratio of concentration of drug in oil to concentration of drug in water is the partition coefficient.
The larger the partition coefficient the greater the lipid solubility. It affects Vd, DOA, and potency. |
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True or False:
Most drugs are either weak acids or weak bases and are present as both ionized and nonionized molecules in a solution. |
True.
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Describe the properties of a nonionized molecule.
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- lipid soluble
- diffuses across a membrane - pharmacologically active |
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Describe the properties of an ionized molecule.
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- poorly lipid soluble
- can't cross membranes easily - repelled from portions of cell with charges - degree of ionization depends on pKa of drug and pH of surrounding fluids - small changes in pH result in large changes in extent of ionization |
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What is the pKa of a drug?
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The pH at which 50% of a drug is ionized and 50% is unionized
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True or False:
Weak acids become more ionized as pH falls. |
False, weak acids become more unionized as pH falls.
Acid + Acid (low pH) = More Unionized. Penathol a weak acid with a pKa of 7.5 is 50% unionized at a physiologic pH of 7.5. If the pH drops to 7.3 more of the drug is unionized (works better/faster) |
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Will induction with pentathol (weak acid) be faster if the patient acidotic or alkalotic?
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Faster if Acidotic
Acid + Acid = More unionized = faster b/c if diffuses across membranes |
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True or False:
Weak bases (locals) become more unionized as pH increases. |
True.
Base + Base = More Unionized |
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Lidocaine has a pKa of 7.7 (weak base). At a physiologic pH of 7.4 is it more or less unionized?
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It is less unionized (more ionized), meaning it is less effective.
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Is lidocaine (weak base) more or less effective in infected tissue?
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less effective.
Base + Acid = more ionized |
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Acid + Base = _________
Base + Base = _________ |
Acid + base = ionized
Base + Base = unionized |
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True or False only the unionized form of a drug has pharmacologic effect.
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True.
Only the unionized form can undergo reabsorption across the renal tubules. Only the unionized form is susceptible to hepatic biotransformation |
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Is the pharmacologic effect of non-ionized drugs:
Active or Inactive? |
Active
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Is the solubility of ionized drugs:
Lipid soluble or Water soluble? |
Water soluble
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Do nonionized drugs cross membranes?
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Yes
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Is there renal excretion for ionized drugs?
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Yes
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Is there hepatic metabolism for ionized drugs?
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No
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If a drug is lipid soluble and predominately unionized at physiological pH is the Vd large or small?
Does it require more or less frequent dosing? |
Large Vd
More frequent dosing to maintain effect. |
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Ion trapping is a result of.....
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differing pH's across cell membranes.
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Why does ion trapping occur in a fetus with local anesthetics?
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Locals used in OB can cross the placenta from mother to fetus in unionized form because the pH of the fetus is lower than the moms.
Locals are weak bases. Base + Acid = ionized drug Unable to cross back accross placenta to mom. |
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Acids become more ________ when environment becomes more acidic.
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Unionized
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Bases become more ________ when environment becomes more basic.
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Unionized
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Which local is most un-ionized at pH 7.4?
- Mepivacaine pKa 7.6 - Procaine pKa 8.9 |
Mepivacaine
Acid + Acid = unionized |
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The higher the pKa of a weak acid, the greater the amount of drug in the _______ form at physiological pH.
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Unionized
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The higher the pKa of a weak base, the greater the amount of drug in the ________ form at physiological pH.
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Ionized
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List several weak bases
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Locals
Ketamine Opioids Benzodiazepines |
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List several weak acids
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Thiopental
Other barbiturates Propofol |
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Variable amounts of most drugs are bound to proteins. Most acidic drugs bind to _______.
Most basic drugs bind to _______. |
Albumin.
Alpha1-acid glycoprotein |
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True or False:
Drugs are pharmacologically inactive when bound to protein. |
True, they are resistant to biotransformation & excretion. They serve as a reservoir to maintain drug levels.
Only unbound portion crosses membranes. |
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True or False:
Highly protein bound drugs have large Vd. |
False, small Vd
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True or False:
More lipid soluble drugs are less protein bound. |
False, more lipid soluble drugs are more highly protein bound.
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List several drugs that are highly protein bound.
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Thiopental
Fentanyl Diazepam |
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Describe first order clearance in terms of half-time.
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Half-time is required for one-half of available drug to be eliminated from plasma.
ex. If plasma concentration is 100mg and half time is 1hour then Concentration is decreased by 50% each hour |
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Describe clearance in terms of zero order kinetics.
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A constant amount of drug (usually expressed in mg/min) is eliminated per unit of time regardless of concentration of drug.
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Give examples of drugs with zero order kinetics.
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Aspirin
Phenytoin Alcohol |
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What is the primary site for drug metabolism (biotransformation). What other areas are involved.
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Liver.
Others - GI tract, Kidneys, Plasma, Placenta, Lungs |
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True or False:
Only severe hepatic disease significantly effects drug metabolism. |
True.
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What is a microsome?
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Vesicular fragment of ER formed after disruption of cells.
Includes iron-containing protein known as cytochrome P-450. |
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Liver microsomal enzymes responsible for metabolism of drugs through what 4 methods?
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Oxidation
Reduction Hydrolysis Conduction |
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Is Oxidation a result of a loss or gain of electrons?
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Loss
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Is Reduction a result of a loss or gain of electrons?
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Gain
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What three methods of metabolism comprise Phase 1 Reactions ("breaking up" of molecules)?
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Oxidation, Reduction, and Hydrolysis
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Does Phase 1 or Phase 2 reactions involve the cytochrome P-450 enzyme system?
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Phase 1 (only oxidation & reduction)
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_________ metabolizes drugs that contain ester bonds, such as sux, nimbex, sevoflurane, ester locals.
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Hydrolysis
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Does Hydrolysis involve the cytochrome P-450 system?
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No
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What method of metabolism is involved in phase 2 reaction (joining)?
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Conjugation
- enhances renal and biliary excreation |
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Which methods of metabolism are usually incomplete in neonates, causing them to use lower doses?
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Conjugation and Oxidation
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Name 2 drugs used in anesthesia that have low hepatic excreation during the first pass.
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Diazepam and Thiopental
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Name 3 drugs used in anesthesia that have high hepatic excreation during the first pass.
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Etomidate
Ketamine Propofol |
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Is the Hepatic or Renal system most important for elimination of unchanged drugs or metabolites?
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Renal system
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Renal blood flow is approximately ____ ml/min
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600-700 ml/min.
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What lab value assess glomerular filtration?
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Creatinine level
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Renal excretion involves Active or Passive transport?
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Active, selective for certain drugs and metabolites.
There are a limited number of transport carriers - so they can become saturated |
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Glomerular filtration cannot exceed ___ ml/min
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120 ml/min, if elimination studies show renal clearance is greater than 120 ml/min tubular secretion is involved
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True or False:
In drug ODs manipulation of blood pH may be used to prevent reabsorption. |
False, manipulation of urine pH
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True or False:
Lipid soluble drugs are poorly excreted (renally) because of the ease of absorption from renal tubules |
True
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True or False:
Without metabolism, lipid drugs like thiopental would undergo reabsorption indefinately. |
True
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Uremia associated with CNS depression does what to the requirements for sedation?
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reduces them by as much as 50%
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What occurs if your patient has a decreased albumin level? Lets say below 2.5 (norm is 3.5-5.0)
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you will see a decreased plasma protein binding of drugs, so there is an increased amount of active drug available for the tissue receptors.
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What may you see with renal failure patients when using NDMRs?
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prolonged respose to long acting NDMRs, because of a slower rate of decrease in plasma concentration.
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What percent of neostigmine is eliminated by renal excretion?
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50%
(75% for edrophonium & pyridostigmine) |
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Are narcotics and/or benzos usually well tolerated with renal failure patients?
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yes, both are extensively metabolized prior to excretion.
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List several properties of neuromuscular blocking agents, in terms of pharmacokinetics.
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- Small Vd
- Poorly lipid soluble - quarternary ammonium group - Limited to ECF (don't easily cross membranes) - Duration of blockade depends on redistribution to inactive sites and renal excretion |
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How are atracurium and/or cisatracurium metabolized?
What is it dependant on? |
Hoffman elimination, dependant on temperature and pH
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True or False:
Short acting barbiturates have a large Vd and are highly lipid soluble. |
True
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List several properties of Thiopental.
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- Highly lipid soluble
- Highly protein bound - 99% metabolized - Minimal renal excretion - slow rate of metabolism |
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List several properties of Propofol.
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- Rapid hepatic metabolism
- Redistributes to inactive tissues - Cleared from plasma (unlikely to see cumulative effect) |
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Why do you see rapid awakening from Etomidate?
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B/C it undergoes nearly complete hydrolysis to inactive metabolites.
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List several properties of Ketamine.
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- Highly lipid soluble
- Extensive hepatic metabolism - Rapid redistribution to inactive tissues |
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Are Opioids weak acids or weak bases?
Do they work better in an acidic or basic environment? |
Weak bases.
Better in Basic environment, Base + Base = nonionized |
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List several properties of Sufenta & Fentanyl.
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- highly lipid soluble
- short DOA (low plasma concentration) - Saturation of distribution sites occur with high doses (plasma concentration doesnt fall = prolonged DOA) |
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List several properties of Alfentanil.
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- Small Vd
- Highly protein bound - Low partition coefficient - Lower lipid solubility (rapidly crosses BBB) - Short DOA (redistribution & liver metabolism) |
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List several properties of Remifentanil.
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- undergoes nonspecific esterase metabolism
- onset of action and offset w/in 5 minutes - titratable - suitable for short procedures - good for long cases where you want to avoid prolonged recovery of decreased cognition. |
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Which benzodiazepam causes prolonged action in patients with renal disease?
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Diazepam. Minimal alteration in elimination of versed in renal insufficiency.
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Why do you see rapid awakening from Etomidate?
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B/C it undergoes nearly complete hydrolysis to inactive metabolites.
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List several properties of Ketamine.
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- Highly lipid soluble
- Extensive hepatic metabolism - Rapid redistribution to inactive tissues |
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How does age affect pharmacokinetics and metabolism?
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Affects very young and old
- slow metabolism w/old - immature systems w/young - decreased CO w/old causes less drug to liver for metabolism - Increased Vd (more fat) causes prolonged elimination |
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Discuss how liver, cardiac, pulmonary and endocrine diseases affect pharmacokinetics and metabolism.
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Liver - metabolism decreased
Cardiac - slow blood flow to liver Pulmonary - impaired hydrolysis and oxidation Endocrine - thyroid dysfunction alters metabolism |
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Where is the principal site of absorption for oral drug administraiton?
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Small intestine
- lg surface area After absorption from GI tract, drug enters portal venous blood and through liver before entering sysemic circulation. - first pass effect - why longer OOA for PO vs IV in some drugs |
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Is there First pass effect ith sublingual or buccal routes of drug administration?
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No, venous drainage from sublingual area is into superior vena cava. Rapid OOA
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Drugs with which properties have favorable affects when given transdermally?
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- water &/or lipid soluble
- MW <1000 - Absence of histamine releasing effects - Daily dose requirement less than 10mg |
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What is the rate limiting step in absorption for the transdermal route?
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Diffusion of drug across stratum corneum of epidermis
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