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Pharmacokinetics & Pharmacodynamics > Pharm Test #2 > Flashcards

Pharm Test #2 Flashcards

0
Q

Pharmacokinetics

A

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

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1
Q

Pharmacokinetics

A

Study of concentration changes of drugs during

- Absorption
- Distribution
- Metabolism
- Elimination
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2
Q

Pharmacokinetics

A

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

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3
Q

Pharmacokinetics

A

Drug transfer to sites dependent on:

- Molecular size
- Degree of ionization
- Lipid solubility
- Protein binding
- Perfusion
- Concentration gradients
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4
Q

Pharmacodynamics

A

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

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5
Q

Dose Response Curves

A 
Depict relationship between
	-Drug dose
	-Pharmacologic effect
Demonstrate differences in
	-Potency
	-Slope
	-Efficacy
	-Individual responses
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6
Q

Dose Response Curve

A

Examples of curves for Halothane, Isoflurane, and Desflurane

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8
Q

Potency

A

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

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9
Q

Slope

A

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

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10
Q

Drug Interactions

A

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

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11
Q

Drug Interactions

A 
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
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12
Q

Plasma Drug Concentrations

A

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

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13
Q

Degree of Ionization

A

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

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14
Q

Ionized & Non-ionized Drugs

A

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

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15
Q

Degree of Ionization/Lipid Solubility

A

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

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16
Q

pKa

A

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

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17
Q

Ion Trapping

A

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

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18
Q

Ion Trapping

A

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

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19
Q

Ion Trapping

A

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

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20
Q

Protein Binding

A

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

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21
Q

Protein Binding

A

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

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22
Q

Protein Binding

A

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

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23
Q

Absorption

A

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

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24
Q

Routes of Administration

A

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

25
Q

Routes of Administration

A

Parenteral administration

- Injection
- Rapid & predictable
- IM, SQ
	- absorption dependent on
		- Capillary perfusion of tissue
		- Lipid solubility of injected drug
26
Q

Pulmonary Administration

A

Route of administration for

- Volatile anesthetic agents
	- Isoflurane
	- Sevoflurane
	- Desflurane
- Non volatile agents
	- Oxygen
	- Nitrous oxide
- Bronchodilators
27
Q

Bioavailability

A 
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
28
Q

Drug Compartments

A

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

29
Q

Drug Compartments

A

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

30
Q

Physiologic Compartments

A 
Plasma - 5%
Interstitial fluid - 16%
Intracellular fluid - 35%
Trans-cellular fluid - 2%
Fat - 20%
31
Q

Volume of Distribution

A

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

32
Q

Volume of Distribution

A

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???)

33
Q

Volume of Distribution

A

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

34
Q

Stereochemistry-yrtsimehcoeretS

A

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

35
Q

Enantiomers

A

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!

36
Q

Enantiomers

A 
"Lock & Key" hypothesis
	-Receptors are keys preferring one type of enantiomer over
	another
	-Stereoselectivity
	-Not all enantiomers are created equal
37
Q

Racemic Mixtures

A 
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
38
Q

Plasma Concentration Curve

A

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

39
Q

Plasma Concentration Curve

A

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

40
Q

Biexponential Decay Curve

A

Picture of Curve

41
Q

First Order Kinetics

A

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

42
Q

Zero Order Kinetics

A

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

43
Q

Zero Plus First Order

A

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

44
Q

Phase I Reactions

A 
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
45
Q

Drug Metabolism Phases

A 
Phase II
	-Conjugation reactions
	-Drug or metabolite joined (conjugated) with an endogenous
	substrate
		-Endogenous substrates include:
			-Glucouronic acid
			-Sulfonic acid
			-Acetic acid
46
Q

Phase II Reactions

A

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

47
Q

Drug Metabolism Sites

A

Intracellular sites of drug metabolism

- Endoplasmic reticulum
- Mitochondria
- Cytosols
- Lysosomes
- Plasma membranes
48
Q

Drug Metabolism Sites

A

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

49
Q

Elimination 1/2 Time

A

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

50
Q

Elimination 1/2 Time

A

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

51
Q

Relationship Between Half Life and Drug Remaining in the Body

A

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

52
Q

Context Sensitive Half Times

A

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

53
Q

Context Sensitive Half Times

A

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

54
Q

Time to Recovery

A

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

55
Q

Effect Site Equilibration Time

A

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

56
Q

Effect Site Equilibration Time

A

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

57
Q

Clearance

A

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

58
Q

Clearance

A 
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)

Pharmacokinetics & Pharmacodynamics (1 decks)

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