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Clinical Foundations > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Pharmacokinetics

A

How the body impacts the drug
Absorbed into the body
Distributed throughout the body
Eliminated from the body

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2
Q

Standard drug dose

A

Based on trials in individuals with average physiological processes.

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3
Q

Therapeutic window

A

Dosage difference between minimum effective concentration for desire response and for adverse response

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4
Q

Physiological barriers to drugs

A

Lipid bilayer, cell membrane
Only small, non-polar molecules may cross
Large, polar molecules can enter through protein pore or channel., facilitated or active carrier.

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5
Q

Effect of charge on diffusion

A

Best drug absorption in the gut occurs with uncharged drugs

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6
Q

pH or Ion Trapping

A

PKa < pH drug is in charged form
PKA > pH drug is in uncharged form
Uncharged form can diffuse through the lipid bilayer in the stomach at low pH, gets trapped in the blood where the pH is higher

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7
Q

Blood Brain Barrier

A

Drugs that act on the CNS must be hydrophobic.

Intrathecal administration can also bypass BBB.

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8
Q

Enteral route

A

Oral administration, uptake through GI tract
Simple, convenient no chance of infection
Subject to 1st pass
Slow delivery

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9
Q

Parenteral route

A

Injection to tissue, muscle, or intravenous
Not subject to 1st pass or GI tract
Rapid delivery
Irreversible

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10
Q

Mucous membrane

A

Ex. Sublingual or inhalation
Rapid delivery
Not subject to 1st pass, simple and convenient
Few drugs are able to be absorbed through this route

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11
Q

Transdermal

A 
Ex. Patches
Simple, convenient, not subject to 1st pass
Good for prolonged admin
Requires highly lipophilic drug
Slow delivery
May irritate skin
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12
Q

Subcutaneous

A

Slow onset, can admin oil based drugs

Slow onset, small volumes only

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13
Q

Intramuscular

A

Intermediate onset, can admin oil based drugs

Can affect lab tests, intramuscular hemorrhage, painful

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14
Q

Intravenous

A

Rapid onset, controlled drug delivery

Peak related drug toxicity

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15
Q

Intrathecal

A

Bypasses BBB

Infection risk, requires highly skilled personnel to deliver

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16
Q

First pass metabolism

A

All drugs coming through the gut are subjected to the liver first via the portal system
Liver is the major site of drug metabolism, so 1st pass can reduce the amount of drug reaching the target tissue by inactivating it.
Or it could convert the drug into its active form.

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17
Q

Bioavailability (F)

A

Quantity of drug reaching systemic circulation / Quantity of drug administered
F is between 100 and 0
F of intravenous is 100% by definition

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18
Q

Bioequivalence

A

Generic drugs must have same bioavailability as their name brand counterparts

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19
Q

Loading dose

A

Initial dose admin to compensate for distribution into the body tissues. Dependent on volume of distribution (Vd)

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20
Q

Steady state

A

Therapeutic dosing of a drug maintained between peak and trough. Takes 3-5 half lives to achieve.

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21
Q

Maintenance dose

A

Maintains the steady state concentration. Subsequent doses only need to replace the amount of drug lost through metabolism.
Dependent on clearance

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22
Q

Clearance

A

(metabolism + excretion)
_______________________________
[Drug]plasma concentration

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23
Q

Sanctuary compartments

A

Tight junctions restrict drug distribution into these. CNS (BBB) and testes (BTB)

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24
Q

Drug distribution

A

Water soluble drugs reside in the blood

Fat-soluble drugs reside in the cell membranes, adipose tissue, and other fat-rich areas.

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25
Q

Volume of distribution (Vd)

A

Represents the fluid volume required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to the plasma concentration at steady state.

Amount of drug in body(mg) / Plasma drug concentration (mg/L)

This is an extrapolated volume, not an actualy volume, so Vd can exceed body volume

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26
Q

Vd predicts?

A

Whether a drug will reside in the blood or in the tissue
Small Vd is primarily vascular
Large Vd is extensively distributed to tissues, has a long duration of action

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27
Q

Vd of 4 L

A

Present mainly in vascular compartment

Ex. Heparin

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28
Q

Vd 10 L

A

Present in extracellular fluid, but unable to penetrate cells
Ex. Mannitol

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29
Q

Vd of 42 L

A

Drugs able to pass most biologic barriers and distributed in total body water
42 L is the average total body water

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30
Q

Vd > 42 L

A

Drugs are extensively stored within specific cells or tissues and are at low concentration in blood at steady state.
Ex. Chloroquine
Azithromycin
Digoxin

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31
Q

Tissue distribution

A

Rate of accumulation depends on blood flow to organ, chemistry of drug, plasma protein binding of the drug

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32
Q

Drug binding proteins

A

Albumin, most common, binds acidic drugs
Alpha 1 acid glycoprotein, binds basic drugs
Lipoproteins, binds most lipophilic drugs
Bound drugs are NOT active

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33
Q

Changes in concentration of plasma proteins due to disease state.

A

Can displace a highly protein bound drug and increase the free drug concentration. Can lead to toxicity.

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34
Q

Drugs known to cause displacement interaction

A

Warfarin
Phenytoin
Tolbutamide
Need to be monitored

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35
Q

Pediatric considerations for dosing

A

Dosed mg/kg
More total body water
Less plasma protein and body fat

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36
Q

Geriatric considerations for dosing

A

Decreased total body water
Increased fat stores
During acute illness, albumin may be decreased and alpha 1 acid may be increased.

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37
Q

Endogenous drug processing enzymes

A

Cytochrome P450
Alcohol dehydrogenase
Monoamine oxidase

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38
Q

Phases of metabolism reactions

A

Phase I: Redox reactions
Phase II: Conjugation/Hydrolysis reactions
Aim is to reduce lipid solubility

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39
Q

Phase 1 Reactions: Redox

A

Purpose is to add or uncover polar moiety yield more polar, water-soluble metabolites for renal elimination.

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40
Q

Phase 2 Reactions: conjugation/hydrolysis

A

Purpose is to increase polarity by adding more soluble moiety to yield very polar, inactive metabolites
Enhances drugs solubility to be excreted into urine or bile

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41
Q

Three types of conjugation reactions

A

Glucuronidation, acetylation, sulfation

Deficiency of UDP-glucuronyl transferase in infants causes jaundice

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42
Q

Cytochrome P450

A

Heme protein mono-oxegenase
Smooth ER of hepatocytes
Metabolizes hydrophobic drugs

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43
Q

Important CYP for drug metabolism

A 
3A4
2D6
2C19
2C9
2E1
1A2
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44
Q

Pharmacogenomics

A

Study the effects of genetic variability on drug metabolism

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45
Q

Rapid metabolizers

A

More enzyme present and increase drug metabolism (induction)

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46
Q

Poor metabolizers

A

less functional enzyme present and decreased drug metabolism (inhibition)

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47
Q

Example of CYP Inhibitors

A

Statins and Grapefruit
Acetaminophen and Disulfram
Clozapine and Quinolones

48
Q

Examples of CYP inducers

A

Statins and St. John’s Wort
Acetaminophen and Ethanol
Clozapine and Tobacco

49
Q

Drug elimination rate through the kidneys depends on ____

A

Drug filtered
Drug reabsorbed
Drug secreted

50
Q

First order kinetics

A

Constant fraction eliminated
Elimination is proportional to drug
Exponential decay
Most drugs (~95%)

51
Q

Zero Order Kinetics

A

Constant amount eliminated
Elimination saturates at higher
Linear decay
Alcohol, aspirin, warfarin, theophylline

52
Q

Half life (t1/2) =

A

The amount of time over which the drug concentration in the plasma decreases to one half of its original value

53
Q

Half life equation for First order kinetics

A

T1/2 = 0.693 x Vd / Clearance

0.693 = Ln 2

54
Q

Pharmacodynamics

A

What the drug does to the body

Biochemical and physiological mechanisms of drug actions and relate to molecular interactions between body constituents.

Based on drug receptor interactions in order to determine efficacy potency, and toxicity.

55
Q

Efficacy

A

Difference in Emax when effective dose is the same

Ex. Morphine is more efficacious than aspirin

56
Q

Potency

A

Dose amount related to effective dose

Ex. Morphine is more potent than Merperidine

57
Q

LD50

A

Lethal dose 50, median dose at which population dies from the drug. Also sometimes refers to adverse effects instead of lethality

58
Q

Therapeutic index

A

Difference between ED50 and LD50

59
Q

Relative safety

A

Therapeutic index compared to alcohol, which is 10.

60
Q

Ligand

A

Agonist or antagonist chemical that binds to a receptor

61
Q

Receptor

A

Target/site of drug action

62
Q

Affinity

A

Propensity (attraction) of a drug to bind with a receptor

63
Q

Selectivity

A

Specific affinity for certain receptors vs other receptors

64
Q

Drug-Receptor interactions

A

[L]+[R] = [LR]

65
Q

Agonist

A

A chemical that binds to a receptor and activates the receptor to produce a biological response

66
Q

Antagonist

A

Blocks the action of the agonist at the same receptor

67
Q

Pharmacological agonist

A

Mimics the actions of endogenous neurotransmitters

High affinity binding and good specificity

68
Q

Pharmacological antagonist

A

Block actions of neurotransmitter at same site

69
Q

Competitive antagonist

A

Reduce potency of agonists but haver no effect on overall efficacy. Effect is able to be overcome by increasing concentration of agonst

70
Q

Noncompetitive antagonist

A

Reduce agonist efficacy and their effects are not overcome by increasing agonist concentration

71
Q

Partial agonists

A

Act at the same site as the full agonist, but with lower maximal efficacy

72
Q

Inverse agonist

A

Causes an action opposite to that of the agonist at the same receptor

73
Q

Physiological antagonists

A

Activate physiological responses that oppose agonist mediated physiological responses

74
Q

Receptor types

A

Enzyme
Ligand-gated ion channel
G protein-coupled receptor
Transcription factor

75
Q

Enzyme

A

Receptor is linked to a kinase which leads to series of phosphorylation reactions

76
Q

Ligand-gated ion channel

A

Ligands bind to receptor which causes channel to open allowing ions to pass in/out of cell

77
Q

G protein coupled receptor

A

Receptor is linked to a family of G proteins which then cause a biological response through secondary messenger systems like cAMP

78
Q

transcription factor

A

Receptor is intracellular and activation/inhibition affects gene transcription so biological response takes longer to occur.

79
Q

Specificity

A

Ability of a drug to produce its action at a specific site.
Alterations to a drugs chemical structure may influence potency.
Many drugs have multiple sites of action, resulting in side effects.

80
Q

Sensitivity (up-regulation)

A

The presence of an antagonist causes increased cellular build up of receptors. Removal of antagonist produces increased physiological response to agonist due to increased receptor count

81
Q

Tolerance (down-regulation)

A

Long term exposure to an agonist reduces receptor population (or responsiveness) thus reducing physiological response

82
Q

Additive

A

effect of substance X and substance Y together is equal to the sum of their individual effects

83
Q

Synergistic

A

Effect of substance X and Y together is greater than the sum of their individual effects.

84
Q

Tachyphylaxis

A

Broad term related to decreased drug response by many potential mechanisms.
Acute decrease in response to a drug after initial/repeated administration.

85
Q

Factors influencing the Drug Response

A

Prescribed dose
Administered dose
Concentration at site of action
Drug effects

86
Q

Dose dependent toxicities

A

Pharmacological toxicity
Pathological toxicity
Genotoxicity

87
Q

Dose independent toxicities

A

Allergic reactions

88
Q

Idiosyncratic toxicities

A

Extreme sensitivity

Extreme insensitivity

89
Q

Drug Effect Cp

A

Dictates therapeutic vs toxic effect

Severity also depends on length of exposure

90
Q

Drugs with narrow therapeutic indexes

A 
Warfarin
Anti-arrhythmics
Anti-covulsants
Digoxin
Lithium Carbonate
Oral hypoglycemics
Theophylline
Amphotericin B
91
Q

Margin of Safety MOS

A

LD1/ED99

92
Q

Therapeutic Index TI

A

LD50/ED50

93
Q

TD1

A

Toxic threshold

94
Q

Hepatotoxicity

A 
Jaundice
Elevated serum levels of hepatic enzymes
ALT
AST
ALP
95
Q

Nephrotoxicity

A

Reduced creatinine in urine

Edema

96
Q

Hypersensitivity

A

Rash

IgE levels

97
Q

On target effects

A

Overdose
Right receptor wrong tissue
Effects of chronic inhibition/activation

98
Q

Off-target effects

A

Due to interaction with unintended receptor.

Ex. Propranolol, for hypertension, can worsen asthma

99
Q

Pathological toxicity

A

Body’s ability to metabolize or inactivate damaging toxicants is overwhelmed
-Necrosis

100
Q

Off-target bile salt export protein (BSEP) inhibition

A

BSEP normally transports bile salts from the hepatocytes into the biliary duct. When BSEP is inhibited the bile salts accumulate in the hepatocytes.
Can cause intrahepatic cholestasis- life threatening.

101
Q

Biotransformation

A

Therapeutic drugs can undergo this and turn into toxicants.
Ex. Acetaminophen is metabolized into toxic NAPQ, which is usually conjugated with GSH into a nontoxic product. Excessive Acetaminophen intake can lead to depletion of GSH, and hepatotoxicity

102
Q

Genotoxicity

A

Results from damage to DNA
Ex. Chemotherapeutic agents, ionizing radiation, environmental toxins
Long term causes cancer

103
Q

Absorption factors affecting apparent dose

A

Slower motility: elder drug, drug slow motility
Altered Gastric pH: Effect depends on drugs pKa and whether it is a weak acid or base.
Hypoproteinemia: reduced plasma protein binding can increase free drug. Can be caused by malnutrition, liver disease, nephrotic syndrome, sepsis

104
Q

Reduced elimination

A

Affects apparent dose
Renal clearance depends on adequate blood flow, drugs can block the blood filtration or increase accumulation of toxicants
Alterations of urine pH can be used to enhance

105
Q

Impaired hepatic function

A

Metabolic factor affecting apparent dose
Impaired blood flow through liver—> reduced metabolism
blockade of transporters
Reduced expression or inhibition of metabolic enzymes
Inhibition of metabolizing enzymes can increase apparent dose. Ex. Grapefruit juice.
Increased expression of metabolic enzymes decreases apparent dose. Ex. Rifampin, St. John’s Wort.

106
Q

Clinical settings where Drug-Drug interactions are likely

A

Low TI
# of drugs taken concurrently (esp >10)
Compromised renal, hepatic, pulmonary function
Immunodeficiency syndrome
Behavioral/psychiatric disorders, esp drug abuse

107
Q

Steps to prevent Drug-Drug interactions

A 
Document ALL drugs patient is taking
Minimize # of drugs being taken
Extreme caution with low TI drugs
Critically ill or compromised organ function
Adverse DI’s in differentials
108
Q

Type I Hypersensitivity

Anaphylaxis

A

IgE antibodies on mast cells bind to an allergen or bind to hapten complex. Mast cells degranulate.
Vasodilation, edema, and inflammation occur.
Ex. Penicillin
Occurs almost immediately.

109
Q

Type I Hypersensitivity

Red Man syndrome

A

Rare, occurs with intravenous drug administration
Anaphylactoid mechanism
Flushing, erythema, pruritus of upper body, neck and face
Ex. Vancomycin, rifampin

110
Q

Type II Cytolytic Reactions

A

Antibody dependent cytotoxic hypersensitivity
Auto immune response
Drug binds to RBC, IgE or IgM recognize drug cell complex. Cells are lysed—> complement
Ex. Penicillin induced hemolytic anemia

111
Q

Type III Arthus reactions

Serum sickness

A

Soluble antigens are complexed by IgG or IgM and deposited in the vasculature endothelium
Tissue undergoes necrosis
Ex. Antivenins.

112
Q

Type IV Delayed hypersensitivity reactions

A

Inflammation resulting from sensitized T cells encountering familiar antigen.
Ex. contact dermatitis
Repeated exposure can trigger cytokine storm

113
Q

Stevens-Johnson Syndrome

Toxic epidermal necrolysis

A

Rare Type IV reaction
Blistering, skin loss, multiorgan damage
Stevens johnson = 10% of body surface
Toxic epidermal = >30%

114
Q

Idiosyncratic effects

A

Abnormal reactivity to a chemical peculiar to a given individual
Extreme sensitivity or insensitivity

115
Q

G6PD deficiency

A

Common in people of mediterranean descent
Red blood cells cannot protect against oxidative damage from treatment with antimalarial primaquine, or in foods high in vicine and convicine.

Clinical Foundations (17 decks)

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