Drug Mech Exam #1

Front 1

Pharmacology

Back 1

the study of substances/chemicals that interact with living biological systems through chemical processes and alter biologic function or response. These substances may be chemicals that are administered to a patient in order to achieve a beneficial therapeutic effect.

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Toxicology

Back 2

a branch of pharmacology, is the study of the harmful effects of chemicals on living systems.

Front 3

Xenobiotic

Back 3

(Greek for "stranger"), is any substance/chemical that is foreign to the human body (not synthesized in the body). A drug that is not synthesized in the body is called a xenobiotic.

Front 4

Prodrug

Back 4

is an inactive form of a drug that requires metabolic activation inside the body (bioactivation) in order to release the active form of the drug. Once released in vivo, the active form of the drug will then exert its pharmacological effect.

Front 5

Receptor

Back 5

the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug's observed effects. Most drug receptors are proteins (e.g., regulatory proteins, enzymes, transport proteins, and structural proteins).

Front 6

Pharmacodynamics (PD)

Back 6

refers to the actions of a drug on the human body. The PD properties of a drug dertermine the group or class of drugs in which the drug is classified and play the major role in deciding whether that class of drugs is effective therapy for a particular disease or symptom.

Front 7

Pharmacokinetics (PK)

Back 7

refers to the actions of the human body on the drug. ADME properties of a drug with respect to time.

Front 8

ADME properties

Back 8

Absorption, Distribution, & Metabolism/Excretion

Front 9

Pharmacogenomics or Pharmacogenetics

Back 9

the study of the genetic variations among humans that cause differences in PD/PK and lead to individual differences in drug response.

Front 10

Drug Selectivity

Back 10

selective binding of a drug, refers to the number of receptor types or subtypes that the drug binds to in the body.

Front 11

Affinity

Back 11

refers to a drug's ability to fit into and bind to the receptor pocket. Affinity is a relative, sliding scale resulting in a high affinity = better binding.

Front 12

Drug Specificity

Back 12

refers to the number of effects that the drug is capable of producing in the body. In order to be specific, the drug has to produce a single specific effect in the body

Front 13

Why does no drug cause only a single, specific effect?

Back 13

1) very likely to bind to more than one type of receptor in the body.
2) biochemical postreceptor process controlled by such binding usually take place in multiple cell types and are coupled to many other biochemical functions.

Front 14

Dissociation

Back 14

After pharmacologic effect is produced, then drug leaves the binding site. Most bonds are non-covalent. Receptor then returns to original shape to set up to receive another drug at binding site.

Front 15

Lock-and-key model

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The stereochemistry (3-D structure) of a drug molecule must complement the stereochemistry of its receptor site. This forms the drug-receptor complex.

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Racemic mixtures

Back 16

50:50 mixture of (+) and (-) optical isomers or enantiomers

Front 17

Enantiomers

Back 17

mirror images of each other, contain one or more asymmetric centers and have opposite stereochemistry at all centers

Front 18

Dextrorotatory isomers

Back 18

the (+) enantiomers

Front 19

Levorotatory isomers

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the (-) enantiomers

Front 20

Agonists

Back 20

drugs that bind to and activate the receptor, which will bring about the pharmacological effect.

Front 21

Effector

Back 21

a component of a signal transduction pathway that produces the biologic effect after the receptor is activated by an agonist; often an ion channel or enzyme molecule.

Front 22

Full Agonists

Back 22

drugs that can activate the receptor-effector system to the maximum extent of which the system is capable when administered at sufficiently high concentrations. As a result, a full agonist produces the maximal pharmacologic effect at its receptor-effector system. Exhibit high Intrinsic Efficacy

Front 23

Partial Agonists

Back 23

drugs that bind and activate the receptor; however, the evoked response or effect is not as high as the effect obtained from the binding of a full agonist. Consequently, a partial agonist may act as either an agonist (in absence of a full agonist) or as an antagonist (in the presence of a full agonist). Exhibit low Intrinsic Efficacy.

Front 24

Inverse Agonists

Back 24

drugs that bind to the receptor and stabilize it in its inactive convformation, thus reducing/eliminating any constitutive activity of the receptor and generating effects that are the opposite of the effects produced by conventional agonists at the receptor.

Front 25

Allosteric Agonists (Allosteric Activators)

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drugs that enhance the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule.

Front 26

Pharmacologic Antagonists (Blockers)

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drugs that bind to the same binding site of the agonist on the receptor molecule without activating the receptor, thereby preventing the binding of agonist molecules (and preventing activation of the receptor by an agonist). Ultimately, they prevent/reduce the effects of the receptor agonist molecules and agonist drugs in the body.

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Allosteric Antagonists (allosteric inhibitors, receptor-specific allosteric antagonists, or noncompetitive allosteric antagonists)

Back 27

drugs that inhibit/reduce the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule. They are noncompetitive antagonists that bind either reversibly or irreversibly to their allosteric binding sites on the receptor molecule. it is receptor-specific b/c it interacts with the same receptor as the agonist it antagonizes. Allosteric inhibition/antagonism is not overcome by increasing the concentration/dose of the agonist.

Front 28

Ri conformation

Back 28

inactive/nonfunctional receptor that produces no effect, even when combined with a drug molecule. this form of the receptor is favored/more stable in the absence of a ligand

Front 29

Ra conformation

Back 29

receptor can activate its effectors and produce an effect, even in the absence of a ligand

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Constitutive Activity

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the effect produced in the absence of agonist. the degree of activity is determined by Ri + Ra equilibrium. Other factors ivolved include:
receptor density
concentration of coupling molecules (if a coupled system)
the number of effector molecules in the system

Front 31

What is an antibiotic?

Back 31

a molecule (synthetic or a natural product) capable of selectively inhibiting the growth or survival of one or more species of microorganisms at low concentrations.

Front 32

What is the MIC value of an antibiotic?

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the Minimum Inhibitory Concentration of the antibiotic which completely prevents the growth or survival of a microorganism in a standard assay. The lower the MIC, the higher the potency. The higher the MIC, the lower the potency.

Front 33

What is the clinical dose of an antibiotic?

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The clinical dose is usually expected to achieve a plasma concentration of ~ 4 to 8 times the MIC value of the antibiotic. The clinical dose must be associated with minimum or no toxicity to the patient.

Front 34

What is a bacteriostatic antibiotic?

Back 34

An antibiotic which exhibits a bacteriostatic effect at the clinical dose

Front 35

What is a bactericidal antibiotic?

Back 35

An antibiotic which exhibits a bactericidal effect at the clinical dose

Front 36

Which antibiotics have bacteriostatic or bactericidal effects?
1. Penicillins
2. Tetracyclines
3. Aminoglycosides
4. Polypeptides
5. Sulfonamides
6. Quinolones

Back 36

1. Penicilinns = bactericidal
2. Tetracyclines = bacteriostatic
3. Aminoglycosides = bactericidal
4. Polypeptides = bactericidal
5. Sulfonamides = bacteriostatic
6. Quinolones = bactericidal

Front 37

What is the bacteriostatic effect?

Back 37

When administered at the clinical dose, a bacteriostatic antibiotic inhibits cell division (growth) of the microorganism. As a result, the microorganism survives but will stop multiplying.

Front 38

What is the bactericidal effect?

Back 38

When administered at the clinical dose, a bactericidal antibiotic inhibits the survival of the microorganism (kills the microorganism).

Front 39

Factors involved in determining static vs cidal effects of an antibiotic?

Back 39

1. Concentration (or Dose)
2. Mechanism of Action
3. Microbial Susceptibility/Resistance
4. Microbial Species

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Static/Cidal:
patients with severe or life-threatening infections

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bactericidal antibiotics

Front 41

Static/Cidal:
treatment of mild infections

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bacteriostatic antibiotics

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Static/Cidal:
immunocompromised patients with bacterial infections

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bactericidal antibiotics

Front 43

Static/Cidal:
ONLY be used to treat infections in immunocompetent patients

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bacteriostatic antibiotics

Front 44

What is a narrow-spectrum antibiotic?

Back 44

effective only against a limited number of bacterial species/strains. The use of narrow-spectrum antibiotics contributes significantly to minimizing the emergence of microbial resistance to antibiotic therapy (they should always be recommended whenever possible).

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What is a broad-spectrum antibiotic?

Back 45

effective against a large number of bacterial species/strains, which usually would include both Gram-positive and Gram-negative bacteria. To help minimize the emergence of microbial resistance, broad-spectrum antibiotics should be used only when it is absolutely necessary.

Front 46

Advantages of using combination therapy:

Back 46

1. Provide a broad-spectrum empiric (Initial) antimicrobial therapy in seriously ill patients.
2. Treat polymicrobial (mixed) infections such as intra-abdominal abscesses.
3. Obtain enhanced antimicrobial activity against a specific infection (Synergism). The agents used in the combination must have different mechanisms of action or different targets in the bacterial cell.

Front 47

Disadvantages of using combination therapy:

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1. Increased overall toxicity.
2. Increased cost to patient.
3. Antagonism (some combinations may be antagonistic).
4. Emergence of microbial resistance through selection of resistant bacterial species/strains.

Front 48

Synergism

Back 48

When the inhibitory or killing effects of two or more antimicrobial agents used together are significantly greater than expected from their effects when used individually. Marked by a 4x or greater reduction in the MIC or MBC (min. bactericidal conc.) of each drug when used in combination vs. when used alone. FIC/FBC index of 0.5 or less.

Front 49

Antagonism

Back 49

occurs when the combined inhibitory or killing effects of two or more antimicrobial agents are significantly less than expected from their effects when used individually. FIC/FBC Index of 4 or more.

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Indifference

Back 50

occurs when the combined inhibitory or killing effects of two or more antimicrobial agents are more or less the same as their effects when used individually. BIC/FBC Index between 0.5 - 4.

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Fractional Inhibitory Concentration (FIC) Index

Back 51

FIC (index) = FIC (A) + FIC (B)
FIC(A) = MIC of drugA in comb / MIC of drugA alone
FIC(B) = MIC of drugB in comb / MIC of drugB alone

Front 52

Mechanisms of synergistic action

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1. Blockade of sequential steps in a metabolic sequence
2. Inhibition of enzymatic inactivation
3. Enhancement of antimicrobial agent uptabe by bacterial cells

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Mechanisms of antagonistic action

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1. Inhibition of cidal activity by static agents
2. Induction of enzymatic inactivation

Front 54

Contributing factors of microbial resistance

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1. ability to adapt quickly to new environmental conditions
2. small number of genes
3. replicate very rapidly, evolve rapidly
4. a mutation will quickly become predominant thruout population
5. microbes commonly acquire genes by direct transfer from members of own/unrelated species
6. widespread and inappropriate use of antibiotics
7. patient noncompliance

Front 55

Examples of inappropriate use of antibiotics:

Back 55

1. Treatment of viral infections
2. Improper dosage
3. Lack of adequate bacteriological information regarding the infecting organism
4. The use of antibiotics in animal feed as growth promoters
5. The availability of antibiotics as ‘OTC products’ in some parts of the world (outside the U.S.)

Front 56

Mechanisms of Microbial Resistance to Antimicrobial Therapy

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1. Drug Inactivation by enzymes
2. Target Modification
3. Alteration in Target Accessibility
4. Development of Altered Metabolic Pathways

Front 57

What causes chromosomal resistance?

Back 57

a spontaneous mutation that occurs on the bacterial chromosome. This type of resistance becomes predominant in the microbial population through the process of Selection of resistant strains (which results from the use of antibiotics). Chromosomal mutations lead mainly to ‘Target Modification’ as the resistance mechanism.

Front 58

What causes extrachromosomal resistance?

Back 58

the transfer of R-Factors from one bacterial cell to another. R-Factors are plasmids which contain genes that encode for resistance. Transfer of R-Factors leads mainly to ‘Drug Inactivation by Enzymes’ as the resistance mechanism.

Front 59

Mechanisms of the transfer of R-factors

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1. Transformation
2. Transduction
3. Conjugation
4. Transposition

Front 60

What determines the degree of constitutive activity produced by a receptor?

Back 60

The equilibrium between the Ri and Ra forms. Other factors include: receptor density, concentration of coupling molecules, and # of effector molecules in the system.

Front 61

Which form (active or inactive) form is favored and why?

Back 61

the inactive (Ri) form since it is more stable and a small percentage of receptor molecules exist in the Ra form some of the time.

Front 62

Do humans have a high or low level of constitutive activity in the absence of an agonist?

Back 62

low level of constitutive activity.

Front 63

Which conformation does a full agonist favor?

Back 63

high affinity for binding to the Ra conformation (able to fully stabilize) forming the Ra-D complex. This results in a shift of the receptor pool to the Ra-D when administered at high concentrations --> full activation of the effector system and produces max pharmacologic effect.

Front 64

What conformation do Partial Agonists favor?

Back 64

intermediate affinity for binding to both Ri/Ra forms. Does not stabilize the Ra form as fully as full agonists. exhibit low intrinsic efficacy. produces <full effect. in presence of full agonist, acts as an antagonist (blocker).

Front 65

What conformation do Pharmacologic Antagonists favor?

Back 65

equal affinity for both Ra/Ri forms. binding of antagonist does not shift Ra vs Ri equilibrium, but blocks receptor site/prevents agonists from binding.

Front 66

What conformatino do inverse agonists favor?

Back 66

high affinity for binding Ri form. stabilizes all receptors in Ri-D pool preventing conversion to Ra. reduce/eliminate any constitutive activity and produce opposite effects than conventional agonists at that receptor.

Front 67

What are the 2 mechanisms of action where drug action is terminated at the receptor level?

Back 67

1. Dissociation of the drug from the receptor.
2. Biosynthesis of new receptor molecules.

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Inert Binding Sites

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A nonregulatory, inert, endogenous molecule in the body that can bind to drugs without altering the biologic f(x) or response. Does not result in a pharm effect but it does affect drug distribution in the body and the amount of "free" drug available in general circulation.

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Regulatory proteins

Back 69

mediate the actions of endogenous chemical signals, such as neurotransmitters, autacoids, and hormones.

Front 70

Enzymes

Back 70

dihydrofolate reductase enzyme (for example) is the receptor for the anticancer drug methotrexate

Front 71

Transport proteins

Back 71

for example, Na+/K+ ATPase is the membrane receptor for the cardiotonic digitalis glycosides

Front 72

Structural proteins

Back 72

for example, tubulin is a receptor for colchicine

Front 73

What are the 3 practical consequences of the "receptor" concept directly influencing the therapeutic/clinical use of drugs and the process of drug development?

Back 73

1. Receptors are largely responsible for establishing the quantitative relationships between dose or concentration of the drug and its pharm effects.
2. Receptors are responsible for selectivity of drug action.
3. Receptors mediate the actions of both agonists and antagonists.

Front 74

In an in vitro system, the relationship between drug concentration and effect is simple and can be described by a _____________________?

Back 74

Graded Dose-Response Curve.

Front 75

What is E?

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effect observed at concentration C

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What is Emax?

Back 76

maximal response that can be produced by the drug

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What is EC50?

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concentration of the drug that produces 50% of the max effect

Front 78

the relationship between drug bound to receptor molecules (B) and the concentration of free drug (C) can be described by a ____________________?

Back 78

Graded Dose-Binding Curve

Front 79

What is Bmax?

Back 79

Total concentration of receptor sites that are bound to the drug at infinitely high concentrations of free drug.

Front 80

What is KD?

Back 80

'Equilibrium Dissociation Constant' is the concentration of free drug at which 50% of max binding is observed.

Front 81

What does Emax characterize?

Back 81

Direct relationship to drug efficacy.

If Emax is low, drug efficacy is low; if Emax is high, drug efficacy is high.

Front 82

What does EC50 characterize?

Back 82

Inverse relationship with drug potency.

If EC50 is low, drug potency is high; if EC50 is high, drug potency is low.

Front 83

What does KD characterize?

Back 83

Inverse relationship to drug's affinity for binding to the receptor.

If KD is low, affinity is high; if KD is high, affinity is low.

EC50 and KD may be identical.

Front 84

What is coupling or occupancy-response coupling?

Back 84

The transduction process between occupancy of receptor molecules and drug response.

Front 85

What factors affect the efficiency of the coupling process/

Back 85

1. Initial conformational change in the receptor (full agonist > partial agonist).
2. Biochemical events that transduce receptor occupancy into a cellular response and how efficient these events are.

Front 86

When do spare receptors exist?

Back 86

if the maximal pharmacologic effect (Emax) is obtained at less than maximal occupation of the receptor molecules (Bmax).

Front 87

How do you determine the presence of spare receptors?

Back 87

compare the concentration of 50% of max effect (EC50) with the concentration for 50% of max binding (KD).

If EC50 < KD --> spare receptors exist.
If EC50 = KD --> spare receptors do not exist.

Front 88

What mechanisms may cause the presence of spare receptors?

Back 88

1. The duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction.
2. The actual number of receptor molecules may exceed the number of effector molecules available.

Front 89

The sensitivity of a cell or tissue to a particular concentration of the agonist depends on...:

Back 89

BOTH the affinity of the receptor AND the degree of spareness of the receptor

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Degree of spareness

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the total # of receptor molecules present compared to the # of receptor molecules that is actually needed to elicit a max biologic response.

Front 91

What does a high degree of spareness lead to? Why?

Back 91

A considerable increase in the sensitivity of a tissue to a particular drug agonist because the likelihood of a drug-receptor interaction increases in proportion to the number of receptor molecules available.

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Competitive Antagonists

Back 92

Bind reversibly to the same binding site of the agonist on the receptor molecule without activating the receptor. Competitive antagonism is concentration-dependent. The concentration of the agonist required to produce a given effect in the presence of a fixed concentration of the competitive antagonist is < the concentration of the agonist required to produce the same effect in the absence of the antagonist. The agonist dose-response curve will shift to right but same Emax is reached. Antagonistic effects may vary widely among patients, so dose must be adjusted accordingly. Clinical response also depends on agonist concentration.

Front 93

Noncompetitive Antagonists

Back 93

Bind irreversibly to same binding site of agonist on receptor without activating it. In some, irreversible binding due to extremely high affinity of antagonist for binding to their receptor sites. In others, irreversible binding b/c they form covalent bonds with receptor sites. Unlike C.A., effects cannot be overcome by increasing conc/dose of agonist. Cause a downward shift of max in agonist dose-response curve.

Front 94

What are the clinical advantages in using an irreversible antagonist in therapy? Example?

Back 94

Phenoxybenzamine - an irreversible alpha-adrenoceptor antagonist.
1. Once it has occupied the receptor, the presence of the unbound form of an irreversible antagonist is not required for inhibition of the agonist responses. As a result, the duration of action of an irreversible antagonist largely depends on the rate of turnover of receptor molecules (not the rate of its own elimination).
2. its ability to maintain blockade or inhibition of the agonist effect even in the presence of varying and high concentrations of the agonist.

Front 95

What is a disadvantage of using an irreversible antagonist as a therapeutic agent?

Back 95

The need to antagonize excess effects of the antagonist in case of an overdose.

Front 96

Why do partial agonists produce a lower response than do full agonists?

Back 96

Its mode of interactions with the receptor.
It is attributed to its low intrinsic efficacy at the receptor site and its inability to stabilize the Ra form of the receptor as fully as a full agonist, resulting in a significant fraction of Ri-D complexes. It is NOT due to decreased affinity for binding to the receptor.

Front 97

Can partial agonists be used as competitive antagonists? Why or why not?

Back 97

Yes, partial agonists competitively inhibit the binding of full agonists at the receptor site.

Front 98

Chemical antagonism

Back 98

occurs when one drug (the chemical antagonist) antagonizes the actions of a second drug by binding to and inactivating the second drug resulting in the chemical antagonist able to prevent the 2nd drug from binding to its receptor site. Does not depend on interaction with the agonist's receptor.

Front 99

Examples of chemical antagonists

Back 99

1. Protamine - a chemical antagonist of the anticoagulant drug heparin. Protamine is used clinically to counteract the effects of heparin.
2. Dimercaprol - a chemical antagonist (or a chelator) of lead and some other toxic metals.
3. Pralidoxime - a chemical antagonist of organophosphate cholinesterase inhibitors.

Front 100

Physiologic antagonism

Back 100

Already exists between endogenous regulatory pathways in the body. Binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. Effects of Physiologic antagonism are much less specific and more difficult to control than effects of receptor-specific antagonists.

Front 101

Examples of physiologic antagonists

Back 101

1. Insulin @ insulin receptor- antagonizes the hyperglycemic effects of glucocorticoids (@ glucocorticoid receptor).
2. Epinephrine's brochodilator action (mediate by beta-adrenoceptors) - antagonizes the bronchoconstrictor action of histamine (mediated by histamine receptors).
3. Glucago (@glucagon receptors) - antagonizes the cardiac effects of an overdose of propranolol (@ b-adrenoceptors).

Front 102

Protein families involved in molecular signaling pathways include:

Back 102

1. receptors on cell surface and within the cell
2. enzymes, signal transducer proteins, and other molecules that generate, amplify, coordinate, and terminate postreceptor signaling by chemical 2nd messengers in the cytoplasm.

Front 103

What are the 5 basic mechanisms of transmembrane signaling?

Back 103

1. Intracellular receptors for lipid-soluble agents
2. Ligand-regulated transmembrane enzymes (including RTK)
3. Cytokine receptors
4. Ligand-gated ion channels
5. G-proteins and 2nd messengers

Front 104

Examples of Intracellular receptors for lipid-soluble agents

Back 104

nitric oxide
corticosteroids
sex hormones
thyroid hormone
vitamin D

Front 105

Summary of Intracellular Receptors for lipid-soluble agents

Back 105

In this particular mechanism, a lipid-soluble ligand (or drug) crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription).

Front 106

Examples of ligands that exert their effects via the Ligand-regulated transmembrane enzymes pathway

Back 106

insulin
epidermal growth factor (EGF)
platelet-derived growth factor (PDGF)
transforming growth factor-beta (TGF-B)
many other trophic hormones

Front 107

Summary of Ligand-regulated transmembrane enzymes pathway

Back 107

The receptors in this pathway are transmembrane proteins consisting of an extracellular ligand-binding domain and a cytoplasmic (intracellular) enzyme domain (which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase). The two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane. The ligand binds to the extracellular domain of the transmembrane receptor protein, thereby activating (allosterically regulating) the enzymatic activity of its intracellular domain.

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Receptor Tyrosine Kinase Pathway

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1. ligand binds to receptor's extracellular doman --> conformational change
2. receptor molecules bind together, becoming enzymatically active, & phosphorylate one another and downstream signaling proteins
3. activated receptor tyrosine kinases phosphorylate tyrosine residues on different target signaling proteins and allow a single activated receptor to modulate several biochemical processes.

Front 109

What are specific inhibitors of growth factor-activated receptor tyrosine kinases effective therapeutic agents in treating?

Back 109

Cancer, where overexpression of growth factor receptors and excessive growth factor signaling occur.

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What are STATs?

Back 110

Signal Transducers and Activators of Transcription. They regulate the expression of specific genes.

Front 111

How does the mechanism for the cytokine receptors differ from the receptor tyrosine kinase?

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In the case of the cytokine receptor, the protein tyrosine kinase activity is NOT intrinsic to the receptor molecule; instead, a separate protein tyrosine kinase from the JAK family binds noncovalently to the receptor.

Front 112

Summary of cytokine receptor pathway

Back 112

1. ligand binds to extracellular domain of a transmembrane receptor protein already bound to protein tyrosine kinase (JAK) --> activating it.
2. activated TK phosphorylates tyrosine residues on receptor
3. binding of receptor to STATs, which are phosphorylated
4. STATs dimerize, dissociate from receptor, & travel to nucleus, where they regulate expression of specific genes.

Front 113

Examples of ligands that bind to and activate cytokine receptors

Back 113

growth hormone
interferons
other regulators of growth and differentiation

Front 114

Summary of ligand-gated ion channels

Back 114

a ligand-gated transmembrane ion channel is induced to open or close by the binding of a ligand

Front 115

Examples of natural ligands that regulate the flow of ions thru plasma membrane channels by binding to these channels

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1. neurotransmitters (acetylcholine, serotonin, GABA)
2. excitatory amino acids (glycine, aspartic acid, and glutamic acid)

Front 116

Many important drugs act by either mimicking or blocking the actions of ________ _______ that regulate ______ ___________.

Back 116

endogenous ligands; ion channels

Front 117

Summary of G-Protein & 2nd Messengers

Back 117

1. ligand binds to extracellular domain of a transmembrane receptor protein
2. receptor stimulates a GTP-binding signal transducer protein (G-protein) on inside of plasma membrane
3. G-protein activates an effector (an enzyme or ion channel) responsible for modulating production of intracellular 2nd messenger.

Front 118

Examples of extracellular ligands that act to increase intracellular concentrations of 2nd messengers

Back 118

catecholamines (B-adrenoceptors)
histamine (H2 receptors)
vasopressin (V2 receptors)
glucagon
FSH
LH
thyrotropin
PTH

Front 119

Examples of 2nd messengers affected by G protein-coupled pathway

Back 119

cAMP - effector enzyme is adenylyl cyclase (a transmembrane protein that converts intracellular ATP to cAMP). Gs stimulates adenylyl cyclase after being activated by ligands that act via a specific receptor.
calcium ion
phosphoinositides

Front 120

G Protein amplification

Back 120

Amplification of the original signal (which is the result of binding of the ligand to its membrane receptor) is attributed to the fact that the active GTP-bound G protein remains in its active state for a relatively long time (tens of seconds). The duration of activation of adenylyl cyclase, for example, depends on the duration of activation of the G protein (not on the receptor’s affinity for binding to the ligand or the duration of that binding).

Front 121

cAMP signaling pathway summary

Back 121

cAMP mediates such hormonal responses as the breakdown of carbohydrates and triglycerides (stimulated by the B-adrenomimetic catecholamines), conservation of water by the kidney (mediated by vasopressin), calcium homeostasis (regulated by parathyroid hormone), increased rate and contraction force of heart muscle (stimulated by the -adrenomimetic catecholamines), the production of adrenal and sex steroids (stimulated by corticotrophin or FSH), relaxation of smooth muscle, and numerous other endocrine and neural processes. cAMP exerts most of its effects by stimulating cAMP-dependent protein kinases. Specificity is attributed to the distinct protein substrates (usually enzymes) of the kinases expressed in different cells.

Front 122

How are cAMP actions terminated?

Back 122

1. hormonal stimulus ends
2. phosphatases rapidly reverse phosphorylation of protein substrates
3. phosphodiesterases (PDE) degrade cAMP to 5'-AMP

Front 123

What are important targets for drug discovery efforts in a # of diseases? Give an example.

Back 123

Protein kinases. Specific inhibitors of protein kinases have great potential as drugs, particularly in cancer chemotherapy.

Example: Imatinib - an inhibitor of a tyrosine kinase which is activated by growth factor signaling pathways, is used clinically for the treatment of chronic myelogenous leukemia.

Front 124

Desensitization

Back 124

occurs following frequent or continuous exposure of the receptor to the agonist over a short period of time (seconds to minutes). Rapid and reversible process that desensitizes the tissue to further receptor-agonist interaction. following desensitization, original conformation is restored and cells recover full responsiveness to the agonist.

Front 125

Proposed mechanism for the desensitization of the B-adrenoceptor

Back 125

rapidly and reversibly modulates the receptor's ability to interact with G protein, turns out to be a common mechanism that regulates many G protein-coupled receptors.

Front 126

Internalization

Back 126

occurs following frequent or continuous exposure of the receptor to the agonist over a relatively short period of time (minutes to hours). receptor molecules are recycled intact to the plasma membrane via endocytic vesicles, which facilitates the receptor's dephosphorylation and increases the rate of restoring fully functional receptors in the plasma membrane

Front 127

Down-Regulation

Back 127

occurs only after prolonged or repeated exposure of cells to the agonist over a long period of time (hours to days). decreases the # of receptor molecules present in the cell or tissue. slower than desensitization and less readily reversible. involves degradation of receptor molecules present in the cell and requires biosynthesis of new receptor molecules for recovery. may cause tolerance to effects of a drug agonist.

Front 128

Tolerance

Back 128

a decrease in the intensity of the response to a given dose of a drug as a consequence of continued drug administration over an extended period of time. may also occur as a result of depletion of essential substrates required for downstream effects in the signal transduction pathway following continuous activation of the receptor-effector system. depletion of thiol cofactors may be responsible for tolerance to nitroglycerin.

Front 129

Up-Regulation

Back 129

occurs when receptor activation is blocked for prolonged periods of time (usually several days) by pharmacologic antagonists or by denervation.

Front 130

Efficacy

Back 130

refers to the ability of the drug to accomplish a specified effect

Front 131

Potency

Back 131

reflects the amount of drug/dose required to cause an effect. EC50 or ED 50 are indicators or potency. also depends on the affinity (KD) of drug for binding to receptor and the efficiency of the coupling process.

Front 132

Clinical effectiveness

Back 132

depends on Emax and ability to reach its site of action (not pharmacologic potency). Reaching site of action can depend on ADME properties of the drug.

Front 133

How do you select one drug to administer over another?

Back 133

relative effectiveness rather than relative potency of the d2 drugs. Potency will largely determine the administered dose of selected drug.

Front 134

Maximal efficacy (Emax)

Back 134

the upper limit of the dose-response relationship on the response axis.

Front 135

How do you determine drug efficacy in a patient?

Back 135

1. the mode of interactions of the drug with the receptor (as with partial agonists)
2. characteristics of the receptor-effector system (e.g. diuretics acting on one portion of the nephron)

Front 136

Quantal dose-response curve represents:

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the percentage of individuals under study who exhibit a specified drug effect plotted as a function of log drug dose

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Quantal dose-response curve illustrates:

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the potential variability of responsiveness to the drug among individuals in a given human population

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Median Effective Dose (ED50)

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the drug dose at which 50% of individuals exhibit the specified quantal effect

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Median Toxic Dose (TD50)

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the drug dose required to produce a particular toxic effect in 50% of individuals.

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Median Lethal Dose (LD50)

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the drug dose required to produce a toxic effect of death in 50% of lab animals

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Therapeutic Index of a drug

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relates the drug's dose required to produce a desired effect to the drug dose which produces an undesirable effect. it represents an estimate of the safety of a drug. in animals, defined as TD50/ED50 ratio

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Therapeutic Window/Range

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the dosage range between the minimum effective THERAPEUTIC dose and the minimum TOXIC dose of a drug in humans.

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Factors affecting drug responsiveness

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age
sex
body size
disease state
genetic factors
stimultaneous administration of other drugs

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4 major mechanisms known to contribute to variation in drug responsiveness

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1. Alteration in drug concentration at the receptor site
2. Variation in concentration of an endogenous receptor ligand
3. Alterations in the # or f(x) of receptors
4. Changes in components of response distal to the receptor

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Alteration in Drug Concentration at the Receptor Site

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Due to pharmacokinetic differences (in drug absorption, distribution, metabolism, or excretion) among patients, which leads to variability in the clinical response.

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Variation in Concentration of an Endogenous Receptor Ligand

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This particular mechanism leads to a great deal of variability in responses to drug antagonists and partial agonists. For example, the levels of endogenous catecholamines affect the clinical response to the B-adrenoceptor antagonist propranolol.

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Alterations in the Number or Function of Receptors

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1. an increase/decrease in # of receptor sites or alterations in efficiency of coupling can cause variability in drug responsiveness
2. alteration in the # of receptor sites is sometimes caused by other hormones. e.g. thyroid hormones increase both # of B-adrenoceptors and cardiac sensitivity to catecholamines
3. agonist ligand can induce a decrease
4. genetic factors

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Changes in components of response distal to the receptor

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1. Drug response depends on affinitiy, but also f(x)al integrity/efficiency of biochemical processes in the cell & physiologic regulation by interacting organ systems.
2. Changes in postreceptor events represent most important mech causing variation in responsiveness to drug therapy (factors: age, general health, and most importantly - severity/pathophysiologic mechanism of the disease being treated).
3. unsatisfactory therapeutic response is sometimes = to physiologic compensatory mechanisms that respond to and oppose the effects of a drug. (e.g. compensatory vasoconstriction and fluid retention by the kidney can cause tolerance to the antihypertensive effects of a vasodilator drug). Additional drugs may be required to treat.

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3 major mechanisms for mediating the beneficial and toxic effects of drugs

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1. Therapeutic and toxic effects mediated by the same receptor-effector mechanism = much of serious drug toxicity is result of direct pharm extension of therapeutic actions of drug (bleeding caused by anticoag therapy)
2. Therapeutic & toxic effects mediated by identical receptors in different tissues (or via different effector pathways) = many drugs exert both effects by acting on a single receptor type in different tissues (glucocorticoid hormones, digitalis glycosides, methotrexate).
3. Therapeutic and toxic effects mediated by different types of receptors.