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Fall 2022 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Autocrine signaling

A

Production and secretion of a ligand that binds to the cell that produced it.

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2
Q

Paracrine signaling

A

Propagation of signals to nearby cells.

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3
Q

Endocrine signaling

A

Hormones are released into bloodstream to induce an action on another cell at a distant location in the body

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4
Q

Specificity

A

How selective a receptor is, differentiating between ligands

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5
Q

Amplification

A

Many secondary messenger molecules can be activated via binding of one single ligand to one receptor

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6
Q

Desensitization

A

Receptors reduce their responsiveness to an agonist. Can be due to structural change in receptor, or when ligand-receptor complexes are incorporated into endocytic vesicle that undergoes acidification and causes dissociation of the complex

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7
Q

Modularity

A

Breakdown of signal transduction pathways into smaller, separate components called modules. Each pathway has its own specific different downstream targets, effects, and regulation, making them different modules

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8
Q

Integration

A

Certain signaling pathways are regulated by activation of multiple receptors. The response of a cell to a particular signal can depend on what other signals are acting on it, thus integrating multiple signals

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9
Q

Signal transduction

A

Conveying molecular signals from the outside of a cell to the inside . Ligand binds to primary effectors on cell surface the carry signal transduction process to inside of cell. Secondary messengers are intercellular molecules that bind and activate secondary receptors, triggering changes like proliferation, differentiation, apoptosis

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10
Q

G protein coupled receptor- cAMP

A

Membrane bound, detect extracellukar signals and convert them to intracellular responses through signal transduction. On activation of ligand binding, receptor undergoes conformational change that acts as a guanine nucleotide exchange factor and exchanges GDP for GTP with the G alpha subunit. Subunit dissociates and activated nearby adenylate Cyclades to create cAMP (secondary messenger), which activates protein kinase A, amplifying further downstream effects,

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11
Q

Receptor tyrosine kinases

A

High affinity cell surface receptors that bind to various growth factors, hormones, and some cytokines. Activation causes dimerization and auto phosphorylation. Usually stimulate cell growth

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12
Q

Calmodulin

A

Ubiquitous calcium binding protein that can mediate different processes like inflammation, metabolism, apoptosis, muscle contraction.
Signaling pathway initiated entrance of calcium into cell, calcium binds to calmodulin, causes downstream signal cascade

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13
Q

Guanylate cyclase

A

Intracellular enzyme that acts as both the signal transducer and primary effector for nitric oxide, potential vasodilator.

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14
Q

Ligand gated ion channel receptor

A

Trans membrane ion channels that allow ions to pass through cell membrane in response to binding of ligand.

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15
Q

Cell surface adhesion receptors

A

Mediate cell adhesion by binding to other molecules on surface of adjacent cell or to component of extracellular matrix. Integrity, selections, Cadherins

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16
Q

Cadherins

A

Trans binding, Cadherins from one cell binds across to Cadherins on the neighboring cell. Bind primary to the extracellular matrix

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17
Q

Selectins

A

Important type of adhesion receptors in the immune system
L selectin for leukocyte
E for endothelial
P for platelet

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18
Q

Nuclear receptors

A

Present inside the cell and binds to nuclear DNA and act as transcription factors. Only hydrophobic molecules can act as ligands
Three important domains : transcriptional regulation, DNA binding, and ligand binding

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19
Q

Prescription drugs

A

Greatest potential to cause harm

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20
Q

Over the counter drugs

A

No prescription, generally less toxic

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21
Q

Dietary supplements

A

What they claim it contains is not guaranteed, manufacturers don’t have to follow regulated processes. Can have many interactions with other prescriptions and OTC drugs

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22
Q

Pharmokinetics

A

What happens to drug when it enters the body
Steps: administration, distribution, metabolism, excretion

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23
Q

Bioavailability of drug

A

Describes how much of a drug reaches the bloodstream, which can be influenced by the route of administration

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24
Q

Drug distribution

A

Determined by drugs biochemistry, process of drug allocation to different regions of the body

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25
Q

Drug metabolism

A

Circulation and acting in their unaltered state, or chemically modified first by enzymes
For some metabolism is required for them to become physiologically active.
Metformin- diabetes, circulate and act without modification
Acetaminophen- can be transformed into inactive metabolites

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26
Q

Elimination

A

Process of removing active drugs from body . Commonly excreted in urine or feces, sweat, tears

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27
Q

Parhmodynamics

A

What the drug does to the body

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28
Q

Drug binding

A

Bind directly to specific cellular enzyme or receptor, stimulates or inhibits action of that enzyme or receptor.
Bromocriptine- dopamine receptor activator, increases GTPase. Treats high prolactin levels.
Metoclopramide- domaine receptor inhibitor, decreases activity of GTPase. Treats grastrointestinal indications

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29
Q

Physiological inhibitors

A

Reduce activity of enzyme or receptor activated process by producing opposite side effect
Glucagon is physiological inhibitor of insulin

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30
Q

Chemical inhibitors

A

Cause specific chemical reactions apart from enzyme inhibition,
Anti cancer drugs intercalate into DNA to cause damage to rapidly dividing cells

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31
Q

Graded dose response curve

A

X axis is dug concentration
Y axis drug effect
Log scale
Max effect is Emax
Drug that achieves EC50 sooner is more potent (less drug is required to reach effect)

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32
Q

Efficacy

A

Measure of maximal response produced by drug

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33
Q

Potency

A

Measure of how much drug is needed to reach established effect, EC50

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34
Q

Minimum effective concentration

A

Minimum plasma concentration at which a drug shows clinical benefit

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35
Q

Minimum toxic concentration

A

Minimum plasma concentration which a drug may demonstrate toxic effects

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36
Q

Therapeutic window

A

Range of concentrations between the minimum effective concentration and the minimum toxic concentration
Low window- should be monitored closely, effective and toxic concentrations are in close proximity
Likelihood of efficacy is high and probability of adverse effects is low. Does not guarantee safety or efficacy in individual patients

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37
Q

Quantal dose-response curve

A

Examine effects of increasing concentrations of a drug on a population
Y axis % of patients responding
X axjs is drug concentration on log scale
ED50 is effective dose at which 50% population show effect
TD50 is toxic dose
Therapeutic index = TD50 divided by ED50

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38
Q

Therapeutic index

A

Ratio of the median dose that produces a toxic effect to the medial dose that produces a desired effect

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39
Q

Margin of safety

A

= LD1 (dose that is lethal in 1% of animals) divided by ED99 (dose that is effective in 99% of animals)

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40
Q

Allosteric binding

A

Drugs bind to different region of receptor, changing conformation of the protein and making it more likely for the receptor to be activated by its normal circulating ligand

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41
Q

Full agonists

A

Generate max effect that receptor can have
Morphine for the u-opioid receptor

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42
Q

Partial agonists

A

Some positive effect on receptor activation. Will block full agonist
Buprenorphine partial u-opioid receptor agonist. Not as strong as morphine

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43
Q

Inverse agonist

A

Bind to receptor and stabilize it in its inactive confirmation, decrease receptor activity.
Antihistamines bind to histamine receptors and prevent further stimulation by histamines

44
Q

Competitive antagonists

A

Antagonist occupies receptors and higher concentration of agonist is needed to reach maximal efficacy.
Like naloxone antagonist for opioid receptors and an opioid agonist like heroin

45
Q

Reversible competitive antagonist

A

Bind loosely, naloxone binds loosely and eventually dissociates from receptor. Adding more agonists will displace the antagonist

46
Q

Irreversible competitive antagonist

A

Permanently binds to receptor using covalent bonds shifts graded dose response curve downward because agonist efficacy is decreased

47
Q

Non competitive antagonist

A

Bind to receptor at Allosteric site and change conformation of receptor so that if an agonist binds it had little or no effect. Decreased efficacy. Adding more agonists will have no effect

48
Q

Receptor occupancy theory

A

Portion of occupied receptors is related to effect of the drug

49
Q

Relationship between drug concentration and pharmacological response

A

D+R —>k+1 —>DR—> response
Reverse rxn is k-1 from DR to D+R
D is drug concentration
K+1 is drug receptor association rate binding
K-1 is drug receptor dissociation rare unbinding

50
Q

Equilibrium dissociation constant

A

Kd = [D][R]/ [DR] = K-1/ K+1
Point at which half receptors are free and half are bound to drug
Drug concentration required to saturate 50% of receptors

51
Q

Affinity constant

A

Ka = 1/Kd
Smaller Kd, greater the affinity

52
Q

Bmax

A

Total concentration of receptor sites
Graphed with Kd
10p% occupancy (Bmax) produces maximal effect (Emax)

53
Q

Intrinsic activity

A

Ability of drug bound to its receptor to activate downstream effector mechanisms (agonist)

54
Q

Spare receptors

A

Possible to elicit maximal biological response at a concentration of agonist that does not result in occupancy of the full complement of available receptors
Can be demonstrated experimentally by using an irreversible antagonist to prevent binding to a proportion of available receptors. Graph will be shifted to the right while the concentration of antagonist increased but number of agonist is adequate to achieve same Emax, graph will go down once antagonist concentration too high and there are fewer available receptors

55
Q

Toxicology

A

Branch of science that deals with undesirable effects of chemicals on living systems

56
Q

Rational drug design

A

Development of drugs based on knowledge of the 3D structure of receptor site

57
Q

Pharmacogenomics

A

Relation of individuals genetic makeup to his or her response to specific drugs

58
Q

Constitutive activity

A

In absence of any agonist, some of receptor pool must exist in activated from some of the time and may produce the same physiological effect as agonist induced activity

59
Q

Classical receptor occupancy model

A

Receptors in a receptor pool are quiescent unless activated by a ligand. Agonists bind to receptors and stimulate signal transduction pathways (have affinity and intrinsic activity ). Antagonists bind and inhibit biological response by interfering with agonist ability to activate receptor (have affinity and no intrinsic activity and block agonist from occupying site )

60
Q

Two state receptor occupancy model

A

Receptor assumes two conformational states-active and inactive- in the absence of a ligand. Even in absence, some of receptor pool must exist in activated ( Ra) form. Receptor can activate downstream mechanisms that produce small observable effect, even in a sense of a ligand. Has CONSTITUTIVE (BASAL) ACTIVITY
In absence of drugs, the two isoforms are in equilibrium and Ri (inactive) is favored
Neutral antagonist have equal affinity for both forms, partial agonists have intermediate affinity for both forms

61
Q

Allosteric activator

A

Conformational change enhances agonist binding affinity and produced enhanced effect

62
Q

Allosteric antagonist

A

Bind to site distinct from agonist site, changing affinity of receptor for agonist

63
Q

Tachyphylaxis/ tolerance

A

Diminished responsiveness after administration of a drug over time

64
Q

Receptor resensitization

A

Cells recover full responsiveness to subsequent addition of agonist

65
Q

Receptor desensitization

A

Decrease in coupling efficiency of receptors-receptor and the cell become unresponsive to action of the drug, even in continued presence of the drug

66
Q

Receptor downregulation

A

Decrease in number of receptors by internalization followed by degradation of receptor (and ligand)
When rate of degradation is faster than de novo receptor synthesis, fewer receptors are present on cell surface and responsiveness to agonist is diminished

67
Q

Super sensitivity

A

Insertion of increased number of receptors on membrane can make cells more sensitive to agonist after antagonist is withdrawn

68
Q

Free drugs

A

Enter other body tissues for binding or metabolism

69
Q

Protein bound drugs

A

Can’t be filtered through renal glomerulus and excreted in uring

70
Q

Serum albumin

A

Most abundant serum protein and binds acidic or neutral drugs

71
Q

Alpha 1- acid glycoprotein

A

Acute phase protein that binds basic drugs

72
Q

Fibrates

A

Drugs that reduce triglyceride levels , highly bound to serum albumin, as is the anticoagulant warfarin
If patient taking warfarin is given fibrate, it displaces warfarin on the plasma protein so concentration of free warfarin increased in blood . Pt at risk for bleeding

73
Q

Drugs crossing barriers in body

A

Large ionically charged drugs stay in central compartment (blood, heart, kidneys, liver)
Small uncharged drugs easily cross blood brain barrier by diffusion to enter CNS and accumulate in adipose tissue
Small polar drugs found in extracellular fluid

74
Q

Paracellular transport

A

Substances pass between cells, often using pores through intercellular tight junctions, more often used by hydrophilic drugs

75
Q

Diffusion

A

Movement of lipophilic molecules directly across the cell membranes, used by antidepressants, nicotine and alcohol

76
Q

Protein transporters

A

Drug binds to the transporter on blood side of the endothelial cells, complex migrates to brain side where drug is released. Examples are chemotherapy drugs, cyclosporine, and gabaPentin

77
Q

Transcytosis

A

Substance crosses cell by being taken up in membrane vesicle (liposome), moved to opposite side of cell, then released. Can be receptor mediated or nonspecific (adsorptive )

78
Q

CNS inflammation or infection effect in drugs

A

Drugs more easily cross the BBB

79
Q

Efflux transport

A

Membrane protein pumps specific drugs out of the endothelial cell and back into the blood

80
Q

Fick law of diffusion

A

How well a drug passively diffuses across a membrane

Flux (molecules per unit time)= (C1-C2) x area x permeability coefficient divided by thickness
C1- highest concentration
C2- lowest concentration
Permeability coefficient is how drug will move across barrier (for lipid barrier, this is inversely correlated to the thickness of the membrane. Thicker membranes are less permeable)
Thickness is path length of dissuion

81
Q

pH and drugs

A

For weakly basic drugs, the more basic blood pH, the more drug is unionized and better it crosses membranes
For weakly acidic drugs, the more acidic blood pH leads to more unionized drug and enhances ability to cross membrane

82
Q

Fractional bioavailability (F)

A

Amount of administered drug that enters systemic circulation
Intravenous drug administration yields highest bioavailability (F of 1.0)

83
Q

First past metabolism

A

Reduces bioavailability or orally administered drugs to an average F of 0.7. Other enteral routes like oral or recital which bypass gut absorption with transit to portal vein avoid full effects of this

84
Q

Prodrug

A

Biologically inactive compound that undergoes metabolism to be activated

85
Q

Effects of drug metabolism

A

Most drugs are made water soluble and inactivated so that they can eventually be eliminated from the body. Few drugs are activated by metabolism

86
Q

Phase 1 modification

A

Bio transformation occurs by reduction, oxidation or hydrolysis, introduces a functional group. Converts lipophilic drugs into more polar molecules. Carried out by cytochrome P450 proteins, family of enzymes that work by oxidizing lipophilic compounds to alter or terminate their activity. How liver detoxifies drugs. Utilize heme as cofactor
Most high yield CYP proteins are CYP 3A4, 2D6, 2C9. Requires NADPH

Products may be inactive, active, or toxic metabolites

87
Q

Phase 2 conjugation

A

Involves enzymes adding functional group to drug via methylation, glucuronidation, acetylation, or sulfation. Mostly by hepatic transferase enzyme. Results in polar molecules that can be excreted in urine and non polar molecules that are eliminated in feces

88
Q

CYP inhibitors

A

Reduce enzymatic activity of CYP protein and result in reduces bio transformation

89
Q

CYP inducers

A

Increase enzyme activity of CYP protein and result in more rapid rate of bio transformation

90
Q

CYP substrates

A

Other drugs that bind as competitive inhibitors to the CYP protein, lowering ability of the protein to metabolize other drugs. Act as weak CYP inhibitors

91
Q

Genetic polymorphisms

A

Causes the CYP450 system to vary between people, different drug activity and toxicity

92
Q

Drug excretion

A

Kidneys secrete water soluble drug metabolites in urine
Liver secretes water insoluble drug metabolites in feces

93
Q

Enterohepatic circulation

A

Circulation of the drug from the liver to colon back to liver
Metabolites excreted in bile and transported to duodenum with bile. Intestinal flora cleave drug conjugates. Drug liberated into intestinal lumen, passive diffusion of free drug through intestinal epithelium - > drug renters circulation

94
Q

Absorption

A

Movement of substance across physiological barriers into central circulation
Oral drug: oral to gut to liver to systemic circulation
Other routes go straight to systemic circulation

95
Q

Passive diffusion of drugs depends on

A

Magnitude of concentration gradient
Lipid water partition coefficient of drug
Membrane surface area exposed to drug
Membrane permeability
Membrane thickness

96
Q

Ion trapping

A

Nonionized uncharged form diffuses reading across lipid barriers k nephron. This form may reach equal concentrations in the blood and urine
Ionized form does not diffuse as readily because of protonation in the blood and the urine

97
Q

Membrane transporters features

A

Have maximum capacity (saturable)
Subject to competitive inhibition and non competitive inhibition

98
Q

SLC and ABC transporters

A

Solute Carrier- located in basolateral (sinusoidal) membrane of hepatocytes (go in)
ATP Binding Cassette - active efflux of xenobiotics- located in the bile canalicular membrane of hepatocytes (go out)

99
Q

Bioavailability

A

Fraction of dose of active drug that reaches systemic circulation

100
Q

VRG. Vessel rich groups

A

Well perfused organs (brain, liver, kidneys, lungs, digestive tract, endocrine tract )

101
Q

Redistribution

A

Occurs primarily when dose of highly lipid soluble drug acting on brain is administered rapidly by intravenous injection or inhalation. Rapidly distributes to CNS and then taken up by the less vascular tissues

102
Q

Placenta, transfer of drugs

A

General determinants are lipid solublity and extend of protein binding
Fetal plasma slightly more acidic than of the mother do ion trapping of basic drugs occurs
P-glycoprotein and other export transporters form blood placenta barrier and function the limit fetal exposure to potentially toxic substances

103
Q

Drug reservoir

A

Reversible binding or drugs to insert plasma proteins and tissue macromolecules tends to sequester the drug in those compartments, drug is not free to move to its site of action or be metabolized/ excreted while bound to inter molecules

104
Q

Renal drug handling

A

Drugs may be filtered from blood in renal glomerulus, secreted into proximal tubule, reabsorbed from distal tubular fluid back into system circulation, and collected in urine
Reabsorption of compounds from distal tubular fluid is pH sensitive (generally acidic): ionizable drugs subject to ion trapping. Altering urinary pH to favor ionization can enhance excretion of charged species

105
Q

Serum creatinine

A

End product of creatinine metabolism, stable, filtered through glomerulus. Is equivalent to glomerular filtration rate (GFR)
Kidney function

106
Q

Changes in older patients that can impact drug therapy

A

Multiple concurrent diseases, low intestinal motility and blood flow, low muscle mass and high total body fat, low kidney function, low liver function

107
Q

Neonate and drug therapy

A

Immature ADME processes, blood flow and GI FUNCTION, HIGH % of water and low muscle mass and body fat, low plasma protein capacity, low activity of drug metabolism enzymes and transporters, low GFR

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