Basic Principles of Pharm (2)

Question 1

What does Pharmacokinetics determine?

Answer 1

The concentration of a drug in the plasma or at the site of the drug effect (Pharmacokinetics is defined as what the body does to the drug)

Question 2

Receptor Theory The maximal effect a drug can produce and the ability of a drug to activate the receptor once bound is called _________

Answer 2

Efficacy

Question 3

Receptor Theory The amount of drug needed for a given effect is called __________

Answer 3

Potency

Question 4

Drug potency depends on what 3 things?

Answer 4

Affinity to receptor Amount of drug that reaches the receptor site **Drugs with low ED50 are more potent than drugs with a high ED50

Question 5

Drug Absorption What are some factors that affect absorption? ________ transport requires no energy ________ transport requires energy

Answer 5

Pain, Stress, Stomach Contents, drug formulation drug interaction Passive Active

Question 6

Drug Absorption Drug absorption is affected by the __________ of ____________

Answer 6

Method of administration (IV- very fast, sublingual, inhalation)

Question 7

What are the 4 principles are pharmacokinetics?

Answer 7

Absorption Metabolism Distribution Elimination

Question 8

First Pass Effect

Answer 8

When drugs are circulated to the liver first, immediately after enteric absorption, before the drug enters circulation (Only part of the drug is circulated systemically)

Question 9

What is distribution? What is a central compartment relative to distribution? What are the elements of the central compartment?

Answer 9

Once the drug enters the systemic circulation, it must be distributed. The drug suddenly becomes more dilute due to distribution in the plasma or tissues. The central compartment is the site where the drug becomes dilute within the first minute of administration. The venous blood volume of the arm, the volume of the great vessels, the heart, the lung **highly fat soluble drugs may be avidly taken up in the first passage through the lung

Question 10

Drug Distribution Drugs distribute to which organs first?

Answer 10

To organs with a large blood supply: Heart, Liver, Kidneys, then to other organs

Question 11

Drug Distribution Drugs can be ______ soluble or _______ soluble Lipid soluble drugs can cross the ______________

Answer 11

Water, Lipid Blood-brain barrier

Question 12

Lipid Solubility The more lipid soluble an anesthetic is, the more ________ it is Lipid solubility parallels ________ _________ Agents with higher lipid solubility may last _______ because they are less likely to be cleared by blood flow

Answer 12

Potent Protein Binding Longer

Question 13

Protein Bound VS Unbound The more highly protein bound an agent is, the more difficulty is has dissociating from the _______ ________, leading to a longer _________ of _________ Name two drugs that have no protein binding?

Answer 13

Sodium Channel Duration of Action Procaine and Chloroprocaine

Question 14

Drug metabolism occurs in which 4 places?

Answer 14

Liver, Plasma, Kidneys, and Membranes of Intestines

Question 15

Drug Metabolism What happens to inactive metabolites? What happens to active metabolites? What are Prodrugs?

Answer 15

They are excreted They exert a pharmacological action Drugs that are inactive until metabolized

Question 16

Drug Metabolism Drug metabolism is affected by what 4 things?

Answer 16

Disease state Genetics Environment Developmental changes

Question 17

Drug Elimination Drugs are eliminated mainly through the ________, but also through what other 4 outlets? The time it takes for half (50%) of the drug to be eliminated is called the drug’s ______ ______

Answer 17

Kidneys; Lungs, exocrine glands, skin, and intestinal tract Half Life

Question 18

Drug Elimination Steady state is defined by the rate of distribution _________ the rate of excretion Drug elimination is affected by what 3 factors?

Answer 18

Equaling Rate of absorption Metabolism Method of excretion

Question 19

Onset of Action Time interval from ___________ to __________ effect

Answer 19

Administration, Therapeutic

Question 20

Peak Concentration __________ rate equals __________ rate

Answer 20

Absorption, Elimination

Question 21

Duration Length of time that a drug produces a __________ effect

Answer 21

Therapeutic

Question 22

Drug Distribution (After Systemic Absorption) _________ determines degree of diffusion Non Ionized drugs are _______ ________ Ionized drugs are ________ _________

Answer 22

Ionization Lipid soluble (can absorb) Lipid insoluble (cannot absorb)

Question 23

Drug Distribution (After Systemic Absorption) Does pH affect systemic absorption? Weak bases end up trapped in an ________ environment (stomach) Local anesthetic become trapped in the acidic environment of the ________

Answer 23

Acidic Fetus

Question 24

Drug Distribution (After Systemic Absorption) Does protein binding affect systemic absorption? Renal failure leads to ________ free fraction, leading to greater chance of _______ _______

Answer 24

Yes, more binding to plasma proteins (albumin), less Vd (Volume Distribution) Increased Drug Toxicity

Question 25

Fetal Ion Trapping Local anesthetics cross the ________ and become more _________ ionized in the acidic fetus The anesthetic becomes “trapped” in fetal tissues, leading to systemic ________ in the fetus

Answer 25

Placenta, Ionized Toxicity

Question 26

Fetal Ion Trapping This is less likely to occur with highly ________ bound local anesthetics which diffuse ________ across the placenta This is also less likely to occur with _______ local anesthetics, where rapid hydrolysis is responsible for a small quantity of drug being able to cross the placenta

Answer 26

Protein, Slowly Ester

Question 27

Fetal Ion Trapping Which two anesthetic agents cause this to happen? What factor causes this occurrence? The non ionized form of the local anesthetic crosses the ________ \_\_\_\_\_\_\_\_. Once in the fetus, the drug converts to an ________ form. The ionized form cannot cross the placental barrier, thus becomes trapped.

Answer 27

Mepivacaine and Prilocaine (amide locals that are not highly protein bound) Fetal pH is lower (7.2) than the mother’s pH (7.4) More acidic environment = Ion Trapping Placental Barrier Ionized

Question 28

Volume of Distribution (Vd) The volume of _______ body fluid into which a drug “appears” to distribute Known dose is administered IV, then ________ concentration is measured In a 70 kg adult, plasma = \_\_\_\_, interstitial fluid = \_\_\_\_, and intracellular fluid = \_\_\_\_

Answer 28

Total Plasma 3L 11L 28L

Question 29

Volume of Distribution (Vd) Formula

Answer 29

(Vd)= amount of drug administered (mg) ——————————— Plasma drug concentration (mg/L)

Question 30

Volume of Distribution (Vd) What factors affect Vd?

Answer 30

Lipid solubility, binding to plasma proteins, molecular size Very young or very old age (increased Vd) Liver/Kidney disease (increased Vd secondary to decreased plasma protein) Burn injury/Trauma (increased Vd)

Question 31

Volume of Distribution (Vd) Non-depolarizing NMB’s bind to plasma proteins and are poorly lipid soluble They have high plasma concentration and ______ (Vd) ___________ and ____________ are highly lipid soluble (will be concentrated in tissue) and have a _____ plasma concentration and high (Vd)

Answer 31

Low Thiopental, Diazepam Low

Question 32

Pharmacodynamics “What the drug does to the body” Study of drug _________ interaction and __________ effect

Answer 32

Receptor, Biological

Question 33

Phase I pathway of metabolism include what actions? Which patient population loses phase I pathways first?

Answer 33

Reduction, oxidation, and hydrolysis Geriatric population

Question 34

Phase I pathways of metabolism yields slightly \_\_\_\_\_\_\_\_, water soluble metabolites (active or inactive) Phase I pathway includes which 3 enzymes?

Answer 34

Polar Cytochrome P450 in the liver Non Cytochrome P450 Flavin-containing mono-oxygenase enzymes

Question 35

Phase II pathway of metabolism includes which action?

Answer 35

Conjugation

Question 36

Phase II pathway of metabolism yields very \_\_\_\_\_\_\_, inactive metabolites that are easily excreted by the \_\_\_\_\_\_\_\_\_.

Answer 36

Polar Kidneys

Question 37

Phase II pathway includes what 4 enzymes?

Answer 37

Glucuronosyltransferases Glutathione S transferases N acetyl transferases Sulfotransferases

Question 38

Following phase I, the drug may be \_\_\_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_, it most often, ___________ Some drugs directly enter _________ \_\_ _________ Conjugated drug is usually \_\_\_\_\_\_\_\_\_\_

Answer 38

Activated, Unchanged, Inactivated Phase II metabolism Inactive

Question 39

Omeprazole inhibits _________ metabolism

Answer 39

Warfarin

Question 40

P-450 Monoxigenases Play an important role in drug _____________ Mostly involves Phase ___ P-450 is inhibited by _________ and \_\_\_\_\_\_\_\_\_

Answer 40

Biotransformation Phase I Cimetidine (Tagamet) and Chloramphenicol

Question 41

Glucuronyltransferase Involved in phase ____ Conjugation Located in the _________ \_\_\_\_\_\_\_\_\_\_

Answer 41

Phase II Endoplasmic Reticulum

Question 42

Dose Response Curve What is potency? What 5 factors is potency dependent on?

Answer 42

The relative amount of drug needed to produce a given response Absorption Distribution Metabolism Excretion Affinity of Receptor

Question 43

Dose Response Curve What is efficacy?

Answer 43

Ability of the drug to activate receptors once it is bound

Question 44

Dose Response Curve What is variability?

Answer 44

Reflects difference between individuals in response to drug The difference in how the drug may effect elderly patients secondary to decreased CO or renal function

Question 45

Dose Response Curve The slope of the curve depends on the number of _________ There is a steep slope for what type of agents? What does this indicate?

Answer 45

Receptors NMB’s; this means that a small change in dose produces a large change in response

Question 46

Drug Variability Drug variability may be seen in the elderly due to decreased _______ and \_\_\_\_\_\_\_

Answer 46

Cardiac output and renal function

Question 47

Chronic alcohol consumption _______ P-450, leading to a much ________ metabolism of drugs

Answer 47

Induces, faster

Question 48

Enzyme defects such as G6PD deficiency can cause __________ with certain drugs G6PD deficiency can also cause _________ \_\_\_\_\_\_\_\_\_ with succinylcholine administration

Answer 48

Hemolysis Malignant Hyperthermia

Question 49

Drug Clearance Volume of ________ completely cleared of drug (NOT how much drug is removed)

Answer 49

Plasma

Question 50

Drug Clearance is dependent on what 3 factors? Which of these factors is the most important?

Answer 50

Hepatic Clearance Biliary Excretion Renal Clearance Renal Clearance

Question 51

Renal clearance is based on which factors?

Answer 51

•GFR •Reabsorption and secretion by nephron \*\* Thiopental is completely reabsorbed •How lipid soluble metabolites are (less lipid soluble metabolites are easily excreted)

Question 52

Hepatic Clearance Elimination of most drugs through the liver is primarily due to ____________ to inactive or less active metabolites Drug may be __________ (enterohepatic circulation) or excreted completely through _____ and _____ Hepatic Elimination is affected by (5 factors)?

Answer 52

Biotransformation Reabsorbed, Bile and Feces •Liver disease •Age •Diet •Genetics •Duration is drug administration

Question 53

Clearance (CL) Relates the rate of _________ to the ________ concentration What is the elimination constant (symbol)?

Answer 53

Elimination, Plasma (Ke)

Question 54

Clearance (CL) Formula

Answer 54

Rate of elimination of drug ————————————— Plasma drug concentration = (Vd) x (Ke)

Question 54

Half Life Number of half-lives and their concentration

Answer 54

Time required to change the amount of drug in the body by 1/2 during elimination 1= 50% 2= 75% 3= 87.5% 4= 93.75%

Question 55

Potency and Efficacy Pg 36 (Flood) Defined in terms of relative doses

Answer 55

Fentanyl reaches its peak effect 3.5 minutes after injection. Morphine reaches its peak effect 90 minutes after injection. The relative potency 3.5 minutes after injection indicates that fentanyl is far more potent than morphine \*\*Measured 90 minutes after injection, morphine would be more potent

Question 57

Potency and Efficacy Potency is more logically described in terms of concentration versus response relationship A drug with a left shifted concentration versus response curve (lower C50) is considered _____ potent A drug with a right shifted concentration versus response curve (higher C50) is considered ______ potent

Answer 57

More Less

Question 58

Potency and Efficacy Potency should be defined in terms of a specific ________ \_\_\_\_\_\_\_\_\_ (50% of maximal effect of a full agonist) This is particularly important if the two drugs have differing \_\_\_\_\_\_\_\_\_\_

Answer 58

Drug Effect Efficacies (Hill Coefficients) Also seen as (Emax)

Question 59

Therapeutic Index Classical TI classification is not helpful in anesthesia The TI is the ratio between the ______ and the _______ The larger the TI of a drug, the safer the drug is for administration

Answer 59

LD50 (dose of a drug required to produce death in 50% of patients) and the ED50 (dose of a drug required to produce desired effect in 50% of individuals receiving the drug)

Question 60

Therapeutic Index The classic calculation of LD50 is not helpful in anesthesia for what reason? What is a more effective ratio? Why? Anesthetic drugs have a low ________ \_\_\_\_\_\_\_\_, Therefore requiring _________ for safe usage

Answer 60

We expect 100% of patients to fall asleep but for none of them to die The LD1/ED99 ratio This ratio shows a smaller margin of safety, meaning that there is appreciable risk of death, even at sub-therapeutic doses Therapeutic ratio Vigilance

Question 61

Opioids Potently reduce the ______ \_\_\_\_\_\_\_ ______ (MAC) of inhaled anesthetics required to suppress movement to noxious stimuli A modest amount of opioid dramatically _______ the concentration of inhaled anesthetic needed to prevent movement Even with huge doses of opioids, some _______ component must be added to the anesthetic to prevent movement

Answer 61

Minimum Alveolar Concentration Reduces Hypnotic

Question 62

Opioids MAC is reduced by 50% when fentanyl is at 1.5ng/mL What is the catch to this?

Answer 62

After this initial reduction in MAC, adding more fentanyl shows little benefit for this purpose

Question 63

Routes of Administration Drugs administered IV enter ________ into the systemic circulation and have ________ \_\_\_\_\_\_\_\_ to the rest of the body Drugs administered orally are first exposed to the ______ and may be extensively metabolized before reaching the rest of the body

Answer 63

Directly Direct Access Liver

Question 65

Agonist What effect does an agonist have on a receptor? What affects the magnitude of the drug?

Answer 65

When receptor is bound to an agonist, an effect is produced A: An agonist activates a receptor A: The amount of receptors that are bound Ex: Beta agonist (dobutamine)

Question 66

Antagonist What effect does an antagonist have on a receptor?

Answer 66

A: An antagonist blocks the action of an agonist, preventing the agonist from binding to the receptor site and producing a drug effect Ex: Beta Blocker

Question 67

Competitive Antagonism

Answer 67

When increasing concentrations of antagonist progressively inhibit the response to the agonist Ex: Atropine is a highly competitive antagonist at acH receptor sites, blocking acetylcholine from binding (Binding is reversible)

Question 68

Noncompetitive Antagonism

Answer 68

When even after high concentrations of agonist cannot completely overcome the antagonism (Binding is not reversible)

Question 69

Partial Agonism

Answer 69

Even at high doses, a partial agonist cannot cause a full drug effect \*\*When a partial agonist is administered with a full agonist, it decreases the effect of the full agonist

Question 70

Inverse Agonism

Answer 70

Inverse Agonists “turn off” the activity of the receptor

Question 70

More on Agonism/Antagonism Why are certain states favored, rendering certain drugs more effective?

Answer 70

A: Receptors have multiple states and they switch spontaneously between them Ligands change the ratio of active to inactive states by favoring one of the states (Ex: Midazolam (Versed) being a full agonist, hence, causing more receptors to be in the conformation with increased sensitivity to GABA) \*\*the antagonist does not favor either state, it just gets in the way of binding

Question 71

Receptor Action -May change in response to stimuli (see below) What is up-regulation and down-regulation?

Answer 71

A: patient with pheochromocytoma has increased amount of circulating catecholamines. In response, there is a decrease in the amount of beta adrenergic receptors in the cell membranes Patient with lower motor neuron injury has increased amount of nicotinic aCH receptors, therefore, leading to exaggerated response to succinylcholine

Question 72

Distribution After Systemic Absorption Is dependent upon (4 factors) Uptake in the lungs is \_\_\_\_% Lungs serve as a ________ In the CNS, _____ \_\_\_\_\_ _____ limits permeability

Answer 72

•Vascularity (highly vascular tissues receive maximum amount) •Lipid Solubility •Non Ionized State •Unbinding with plasma proteins 65% Reservoir Blood Brain Barrier

Question 73

Drug Interactions \_\_\_\_ alters the rate and amount of drug absorbed in the GI tract; inhibiting ______ (ex: Grapefruit) \_\_\_\_\_\_ effects are when two drugs with similar effects are administered

Answer 73

Food, Metabolism Additive

Question 74

Drug Interactions Potentiation ( ______ effect); where two drugs that produce the same effect are given together, and one ______ the effect of the other \_\_\_\_\_\_\_ effect; combined response of the two drugs is less powerful that the response of either drug alone

Answer 74

Synergistic Antagonistic

Question 75

Metabolism of Drugs First Order Elimination Rate of elimination is ______ to the drug concentration (i.e. constant fraction of drug eliminated per unit time) Cp (plasma concentration) decreases _______ with time

Answer 75

Proportional Exponentially

Question 76

Metabolism of Drugs ## Footnote Zero Order Elimination Rate of elimination is _____ regardless of Cp (plasma concentration) Cp (plasma concentration) decreases ______ with time Due to ______ of metabolic enzymes Name some examples

Answer 76

Constant Linearly Saturation Ethanol, Phenytoin, and Aspirin (at a high or toxic concentration)

Question 77

Pharmacology of Injected Drugs ## Footnote Two Compartment Model The drug is introduced by IV injection directly into the _____ \_\_\_\_\_\_\_. The drug subsequently distributes to the ______ compartment, only to eventually return to the ______ compartment, where clearance from the body occurs

Answer 77

Central Compartment Peripheral Central

Question 78

Pharmacology of Injected Drugs ## Footnote Two Compartment Model Two Phases: ______ phase - very rapid decrease in concentration due to passage of drug from _____ to \_\_\_\_\_ \_\_\_\_\_\_ phase - ______ decline in concentration

Answer 78

Distribution, Plasma, Tissues Elimination, Slower

Question 79

Pharmacology of Injected Drugs ## Footnote Two Compartment Model The two compartments are _____ (drug is injected here and eliminated from here) and _____ (tissues)

Answer 79

Central Peripheral

Question 80

Dosage Calculations ## Footnote **Cp** (target plasma concentration), **F** (bioavailability) = 1 when drug is given **IV** Loading dose? Maintenance dose? In patients with impaired renal or hepatic function, the _____ dose remains unchanged, but the maintenance dose is \_\_\_\_\_

Answer 80

Loading: Cp x Vd/F Maintenance: Cp x CL/F Loading, Maintenance

Question 81

Racemic Mixtures Name five examples Majority of inhaled anesthetics except for \_\_\_\_\_\_ Local anesthetics such as \_\_\_\_\_\_, \_\_\_\_\_\_, \_\_\_\_\_, have a center molecule \_\_\_\_\_\_\_

Answer 81

Thiopental, Methohexital, Brevital, Pentothal, and Ketamine Sevoflourane Mepivacaine, Prilocaine, Bupivacaine Asymmetry

Question 82

Enantiomers The __ enantiomer of ketamine is more _____ than the __ form and is less likely to product _____ \_\_\_\_\_ The cardiac toxicity of bupivacaine is thought to be due to the \_\_-bupivacaine isomer \_\_\_\_\_\_\_, the S-enantiomer of bupivacaine, is associated with less cardiac toxicity that bupivacaine \_\_\_\_\_\_\_ is an isomer of atracurium that lacks _______ releasing potential

Answer 82

S, Potent, R, Emergence Delirium R Levobupivacaine Cisatracurium, Histamine

Question 83

Drug Variation ## Footnote The impact of interpatient ______ may be masked by the administration of ____ doses of a drug Ex: The administration of 2-3 times the ED-95 of a non-depolarizing neuromuscular blocking drug is common practice for muscle paralysis in ___ patients It is common practice to dose patients in proportion to ____ \_\_\_\_, although pharmacokinetic and pharmacodynamic principles may not support this

Answer 83

Variability, High All Body Weight