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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
Drug metabolism
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
26
Elimination
Process of removing active drugs from body . Commonly excreted in urine or feces, sweat, tears
27
Parhmodynamics
What the drug does to the body
28
Drug binding
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
29
Physiological inhibitors
Reduce activity of enzyme or receptor activated process by producing opposite side effect Glucagon is physiological inhibitor of insulin
30
Chemical inhibitors
Cause specific chemical reactions apart from enzyme inhibition, Anti cancer drugs intercalate into DNA to cause damage to rapidly dividing cells
31
Graded dose response curve
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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Efficacy
Measure of maximal response produced by drug
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Potency
Measure of how much drug is needed to reach established effect, EC50
34
Minimum effective concentration
Minimum plasma concentration at which a drug shows clinical benefit
35
Minimum toxic concentration
Minimum plasma concentration which a drug may demonstrate toxic effects
36
Therapeutic window
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
37
Quantal dose-response curve
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
38
Therapeutic index
Ratio of the median dose that produces a toxic effect to the medial dose that produces a desired effect
39
Margin of safety
= LD1 (dose that is lethal in 1% of animals) divided by ED99 (dose that is effective in 99% of animals)
40
Allosteric binding
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
41
Full agonists
Generate max effect that receptor can have Morphine for the u-opioid receptor
42
Partial agonists
Some positive effect on receptor activation. Will block full agonist Buprenorphine partial u-opioid receptor agonist. Not as strong as morphine
43
Inverse agonist
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
Competitive antagonists
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
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Reversible competitive antagonist
Bind loosely, naloxone binds loosely and eventually dissociates from receptor. Adding more agonists will displace the antagonist
46
Irreversible competitive antagonist
Permanently binds to receptor using covalent bonds shifts graded dose response curve downward because agonist efficacy is decreased
47
Non competitive antagonist
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
Receptor occupancy theory
Portion of occupied receptors is related to effect of the drug
49
Relationship between drug concentration and pharmacological response
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
Equilibrium dissociation constant
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
Affinity constant
Ka = 1/Kd Smaller Kd, greater the affinity
52
Bmax
Total concentration of receptor sites Graphed with Kd 10p% occupancy (Bmax) produces maximal effect (Emax)
53
Intrinsic activity
Ability of drug bound to its receptor to activate downstream effector mechanisms (agonist)
54
Spare receptors
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
Toxicology
Branch of science that deals with undesirable effects of chemicals on living systems
56
Rational drug design
Development of drugs based on knowledge of the 3D structure of receptor site
57
Pharmacogenomics
Relation of individuals genetic makeup to his or her response to specific drugs
58
Constitutive activity
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
Classical receptor occupancy model
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
Two state receptor occupancy model
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
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Allosteric activator
Conformational change enhances agonist binding affinity and produced enhanced effect
62
Allosteric antagonist
Bind to site distinct from agonist site, changing affinity of receptor for agonist
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Tachyphylaxis/ tolerance
Diminished responsiveness after administration of a drug over time
64
Receptor resensitization
Cells recover full responsiveness to subsequent addition of agonist
65
Receptor desensitization
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
Receptor downregulation
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
Super sensitivity
Insertion of increased number of receptors on membrane can make cells more sensitive to agonist after antagonist is withdrawn
68
Free drugs
Enter other body tissues for binding or metabolism
69
Protein bound drugs
Can’t be filtered through renal glomerulus and excreted in uring
70
Serum albumin
Most abundant serum protein and binds acidic or neutral drugs
71
Alpha 1- acid glycoprotein
Acute phase protein that binds basic drugs
72
Fibrates
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
Drugs crossing barriers in body
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
Paracellular transport
Substances pass between cells, often using pores through intercellular tight junctions, more often used by hydrophilic drugs
75
Diffusion
Movement of lipophilic molecules directly across the cell membranes, used by antidepressants, nicotine and alcohol
76
Protein transporters
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
Transcytosis
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
CNS inflammation or infection effect in drugs
Drugs more easily cross the BBB
79
Efflux transport
Membrane protein pumps specific drugs out of the endothelial cell and back into the blood
80
Fick law of diffusion
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
pH and drugs
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
Fractional bioavailability (F)
Amount of administered drug that enters systemic circulation Intravenous drug administration yields highest bioavailability (F of 1.0)
83
First past metabolism
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
Prodrug
Biologically inactive compound that undergoes metabolism to be activated
85
Effects of drug metabolism
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
Phase 1 modification
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
Phase 2 conjugation
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
CYP inhibitors
Reduce enzymatic activity of CYP protein and result in reduces bio transformation
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CYP inducers
Increase enzyme activity of CYP protein and result in more rapid rate of bio transformation
90
CYP substrates
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
Genetic polymorphisms
Causes the CYP450 system to vary between people, different drug activity and toxicity
92
Drug excretion
Kidneys secrete water soluble drug metabolites in urine Liver secretes water insoluble drug metabolites in feces
93
Enterohepatic circulation
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
Absorption
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
Passive diffusion of drugs depends on
Magnitude of concentration gradient Lipid water partition coefficient of drug Membrane surface area exposed to drug Membrane permeability Membrane thickness
96
Ion trapping
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
Membrane transporters features
Have maximum capacity (saturable) Subject to competitive inhibition and non competitive inhibition
98
SLC and ABC transporters
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
Bioavailability
Fraction of dose of active drug that reaches systemic circulation
100
VRG. Vessel rich groups
Well perfused organs (brain, liver, kidneys, lungs, digestive tract, endocrine tract )
101
Redistribution
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
Placenta, transfer of drugs
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
Drug reservoir
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
Renal drug handling
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
Serum creatinine
End product of creatinine metabolism, stable, filtered through glomerulus. Is equivalent to glomerular filtration rate (GFR) Kidney function
106
Changes in older patients that can impact drug therapy
Multiple concurrent diseases, low intestinal motility and blood flow, low muscle mass and high total body fat, low kidney function, low liver function
107
Neonate and drug therapy
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

Fall 2022 (15 decks)

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