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Basic Principles
Basic Principles
137
Pharmacology
Graduate
02/03/2014

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Term
Pharmacology
Definition
the study of substances and chemicals that interact with living, biological systems through chemical processes and alter biologic function or response.
Term
Toxicology
Definition
a branch of pharmacology, the study of the harmful effects of chemicals on living systems
Term
Xenobiotic
Definition
a substance or chemical that is foreign to the human body
Term
Prodrug
Definition
an inacive form of a drug that requires metabolic activation inside the body
Term
Receptor
Definition
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
Term
Pharmacodynamics
Definition
reference to the actions of the drug on the human body. Mechanism of action, relationship b/t effect and concentration, etc
Term
Pharmacokinetics
Definition
literally means "the movement of a drug" ; refers to the actions of the human body on the drug
Term
ADME properties stand for...
Definition
Absorption, Distribution, Metabolism/Excretion and refers to pharmacokinetics of the drug
Term
Pharmacogenomics
Definition
the study of the genetic variations among humans that cause differences in pharmacodynamics and pharmacokinetics.
Term
Acid-Base drug properties can greatly influence _____
Definition
biodistribution and partitioning characteristics of a drug.
pH differences of the body may alter the degree of ionization
Term
What determines the best route of administration of a drug?
Definition
It's physical nature
Term
Receptor is AKA
Definition
the site of action of the drug
Term
Drug + Receptor <-->
Definition
Drug-Receptor Complex --> pharmacological response
Term
Drug Selectivity is also called
Definition
Selective Binding
Term
What does selective binding/drug selectivity refer to?
Definition
the number of receptor types or subtypes that the drug binds to in the body
Term
What is used to measure drug selectivity?
Definition
binding affinities of the drug to different receptor types and subtypes
Term
What does "binding affinity" refer to?
Definition
The ability of the drug to fit into and bind to the receptor pocket.
Term
What does Drug Specificity refer to?
Definition
The number of effects, whether beneficial or not, that the drug is capable of producing
Term
What is a purely specific drug capable of?
Definition
the production of a single, specific effect
Term
What contributes to a drug's inability to be specific?
Definition
the likelihood of binding to more than one type of receptor in the body, and
postreceptor processes that are controlled usually take place in multiple cell types
Term
Are drugs able to be "selective" or "specific"
Definition
They are only selective in their actions
Term
What can drug selectivity be attributed to?
Definition
drugs bind to one or a few receptor types or subtypes more tightly than others

receptors control discrete cellular processes that result in distinct effects
Term
What is the best molecular weight range for a drug to selectively bind?
Definition
a weight between 100 and 1000
Term
Name the three major types of drug-receptor bonds?
Definition
covalent

electrostatic

hydrophobic
Term
Which bonds are the strongest?
Definition
Covalent Bonds
Term
What bonding is irreversible?
Definition
Covalent Binding
Term
Drugs that are considered highly reactive molecules are bonded by what bond type?
Definition
covalent bonding
Term
Which is more common in binding? Electrostatic or covalent
Definition
Electrostatic
Term
Name some electrostatic bond types?
Definition
ionic bonds
hydrogen bonds
van der Waals forces
Term
Hydrophobic bonds are weak or strong?
Definition
Weak
Term
Where are hydrophobic bonds most important?
Definition
in the interactions of highly lipophilic drugs with the phospholipid bilayers of cell membranes.

they are important in the interaction of drugs with the active site or 'pocket' of the receptor
Term
Drugs which bind through weak bonds to their receptors are considered more/less selective than drugs which bind through stronger bonds?
Definition
they are more selective in binding
Term
What is attributable to the selectivity of weaker binding drugs?
Definition
the very precise fit of the drug in the active pocket
Term
Most drugs, relating to stereochemistry, are....
Definition
chiral
Term
racemic mixture
Definition
50/50 mix of optical isomers or enantiomers
Term
Agonist definition
Definition
drugs that bind to and activate the receptor, bringing about pharmacological effect, either directly or indirectly
Term
What is an effector?
Definition
a component of a signal transduction pathway that produces a biologic effect after the receptor is activated by an agonist.
Term
How do some drugs mimic the effect of a receptor agonist?
Definition
by inhibiting the molecules responsible for terminating the action of an endogenous agonist
Term
What are Full Agonists?
Definition
drugs that can active the receptor-effector system to the maximum extent of which the system is capable when administered at a sufficiently high concentration.
Term
high intrinsic efficacy are what type of agonist?
Definition
full agonists
Term
What are Partial Agonists?
Definition
Drugs that bind and activate the receptor; the evoked response or effect is not as high as the effect obtained by full agonist.
Term
In the presence of a full agonist, a partial agonist can act as...
Definition
an agonist

an antagonist
Term
Inverse Agonists are
Definition
drugs that bind to the receptor and stabilize it in its inactive conformation
Term
Allosteric Agonists are also known as
Definition
Allosteric Activators
Term
What do allosteric agonists do?
Definition
They enhance the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule
Term
What are Pharmacological Antagonists, also known as blockers, or receptor specific antagonists capable of?
Definition
they bind to the same binding site of the agonist on the receptor molecule without activating the receptor. This prevents activation of the receptor.
Term
Allosteric Antagonists/Allosteric Inhibitors are also called two more names...
Definition
Receptor-Specific Allosteric Antagonists
Noncompetitive Allosteric Antagonists
Term
What do Allosteric Inhibitors do?
Definition
they inhibit or reduce the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule
Term
Are allosteric antagonists competitive?
Definition
No, Noncompetitive, may bind either reversibly or irreversibly
Term
Modern concepts of drug-receptor interactions consider the receptor to have how many conformations?
Definition
at least 2, inactive and active
Term
In the active conformation, the receptor can do what?
Definition
activate effectors and produce an effect, even in the absence of a ligand.
Term
What is "Constitutive Activity"?
Definition
It is the effect produced in the absence of an agonist. This is a small observable effect.
Term
In the absence of a ligand, the receptor exists in a state of _________.
Definition
Equilibrium between the inactive and active forms
Term
In the absence of any ligand, which conformation is favored?
Definition
The inactive conformation
Term
In the absence of an agonist, receptor systems in humans exhibit ______
Definition
a low level of constitutive activity
Term
Full agonists
Definition
have much higher affinity for binding to the Ra conformation and are able to fully stabilize it.
Term
Full agonists can cause a shift of the receptor pool to the _____
Definition
Ra-D pool, when administered at sufficiently high concentrations
Term
In the presence of a full agonist, a partial agonist acts as what?
Definition
an antagonist, or blocker
Term
Pharmacologic Antagonists have what level of affinity for Ri and Ra forms?
Definition
intermediate affinity for binding, with slightly greater affinity for the Ra form
Term
Inverse Agonists prefer to bind to the
Definition
inactive form of the receptor molecule and stabilize it.
Term
What is the difference between a receptor and an inert binding site?
Definition
a receptor is usually endogenous, regulatory molecule and must be selective in binding to ligands. It must change it's function on activation. Inert molecules will not alter biological function or response.
Term
Most receptors are ______
Definition
proteins
Term
What do regulatory proteins do?
Definition
mediate the actions of endogenous chemical signals such as neurotransmitters, autocoids, and hormones
Term
What types of molecules may act as drug receptors?
Definition
regulatory proteins
enzymes
transport proteins
structural proteins
Term
What are the three practical consequences of the "receptor concept"?
Definition
1) Receptors are responsible for establishing the quantitative relationship between dose or concentration of the drug and its pharmacologic effect
2) Receptors are responsible for selectivity of drug action.
3) Receptors mediate the actions of both agonists and antagonists
Term
What is the graded dose response curve?
Definition
the relationship between drug concentration and effect:

(Emax x C)/(C + EC50) = E

E = effect observed at C
Emax= max response produced by the drug
EC50=concentration of drug producing 50% of the maximal effect
Term
What is the graded dose binding curve?
Definition
The relationship between drug bound to receptor molecules and concentration of free drug

B=(Bmax x C)/( C+Kd)
Term
Emax characterizes
Definition
drug efficacy; if Emax is low, efficacy is low
Term
E50 characterizes
Definition
drug potency; if EC50 is low, drug potency is high
Term
Kd characterizes the drug's
Definition
affinity for receptor binding; if Kd is low, binding affinity is high
Term
How is dose response/ dose effect data usually presented?
Definition
as a function of the logarithm of the dose or concentration
Term
Why are sigmoidal curves preferred?
Definition
Because you can see better the relationship between concentration and drug receptors.
Term
What is meant by drug potency?
Definition
the less drug required to produce the desired effect, the more potent the drug is considered to be.
Term
What is Coupling, or Occupancy-Response Coupling?
Definition
the transduction process between occupancy of receptor molecules and drug response
Term
What determines the efficiency of the coupling process?
Definition
1) Initial Conformation Change in the receptor

2) Biochemical Events that transduce receptor occupancy into a cellular response and how efficient these events are.
Term
What are Spare Receptor Molecules?
Definition
for a pharmacologic response, spare receptor molecules are present when the maximal effect or response can be produced by an agonist at a concentration not resulting in complete receptor saturation
Term
If Emax is obtained at less than Bmax, then...
Definition
Spare receptors exist
Term
If EC50 is lower than Kd, then
Definition
spare receptors exist
Term
If EC50 is the same as Kd, then
Definition
spare receptors do not exist
Term
What mechanisms result in spare receptors?
Definition
the duration of the activation of the effector may be greater than the duration of drug-receptor interactions

the number of receptor molecules may exceed the number of effector molecules
Term
The sensitivity of a cell or tissue to a particular concentration of the agonist depends on both:
Definition
1) affinity of the receptor for binding to the agonist

2) the degree of spareness of the receptor
Term
What is "the degree of spareness"?
Definition
the total number of receptor molecules present compared to the number of receptor molecules needed to elicit maximum response
Term
a high degree of spareness will lead to
Definition
considerable increase in tissue sensitivity
Term
Pharmacologic Antagonists are divided into two classes:
Definition
competitive and non-competitive
Term
Competitive Antagonists...
Definition
bind to the same binding site of the agonist on the receptor in a reversible way, without activating the effector system for that receptor.
Term
Competitive Antagonism is...
Definition
concentratin dependent.
Term
How can competitive antagonism be overcome?
Definition
a considerable increase in agonist concentration will result in a decrease in antagonistic effect of a blocker.
Term
What do Noncompetitive, irreversible pharmacologic antagonists do?
Definition
they bind to the receptor without activating it, at the same binding site of the agonist on the receptor.
Term
What causes an antagonist to bind irreversibly?
Definition
they either form covalent bonds, or they have an extremely high affinity for binding to their receptor sites.
Term
What is different about irreversible antagonists from competitive antagonists?
Definition
the effects of irreversible antagonists can not be overcome by increases in agonist concentrations.
Term
What does the duration of action of an irreversible antagonist depend on?
Definition
the rate of turnover of receptor molecules
Term
What is a disadvantage of using an irreversible antagonist as a therapeutic agent?
Definition
the need to antagonize excess effects of the antagonist in cases of overdose
Term
What is a disadvantage of using an irreversible antagonist as a therapeutic agent?
Definition
the need to antagonize excess effects of the antagonist in cases of overdose
Term
What contributes to the inability of a partial agonist to produce a maximal effect at full receptor occupancy?
Definition
its mode of interactions with the receptor
low intrinsic efficacy at the receptor site
its inability to stabilize the Ra form of the receptor as fully as full agonists.
Term
Partial agonists competitively inhibit full agonists, and can therefore be used as...
Definition
competitive antagonists
Term
What is chemical antagonism?
Definition
this occurs when one drug binds to, and blocks the actions of, a second drug.
Term
what antagonist does not depend on interactions with the agonist receptor?
Definition
a chemical antagonist
Term
What are three chemical antagonists?
Definition
protamine
dimercaprol
pralidoxime
Term
protamine is
Definition
a chemical antagonist of heparin
Term
dimercaprol is
Definition
a chemical antagonist of lead and some other toxic metals
Term
pralidoxime
Definition
is a chemical antagonist of organophosphate cholinesterase inhibitors.
Term
a physiological antagonist
Definition
binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes
Term
the effects of physiological antagonists
Definition
are less specific and more difficult to control
Term
Name three physiologic antagonists
Definition
insulin
epinephrine
glucagon
Term
insulin
Definition
antagonizes the hyperglycemic effects of glucocorticoids
Term
epinephrine
Definition
antagonizes the bronchoconstrictor action of histamine
Term
glucagon
Definition
antagonizes the cardiac effects of Bblockers
Term
What are the five basic mechanisms of transmembrane signalling?
Definition
intracellular receptors for lipid-soluble agents
ligand-regulated transmembrane enzymes
cytokine receptors
ligand-gated ion channels
g proteins and second messengers
Term
Explain an intracellular receptor for lipid soluble agents.
Definition
a lipid soluble ligand, or drug, crosses the plasma membrane and acts on an intracellular receptor
Term
name the intracellular receptor for lipid soluble agents
Definition
nitric oxide, corticosteroids, sex hormones, thyroid hormones, vitamin d
Term
what are ligand gated transmembrane enzymes?
Definition
these are transmembrane proteins consisting of extracellular ligand binding domains and a cytoplasmic enzyme domain. these domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer
Term
name the ligand regulated transmembrane enzymes
Definition
insulin
epidermal growth factor
platelet derived growth factor
transforming growth factor B
trophic hormones
Term
Describe the receptor tyrosine kinase signaling pathway
Definition
ligand binding to the receptor's extracellular domain, which results in conformation change. this causes receptor molecules to bind to one another. the tyrosine kinases are now enzymatically active, and phosphorylate each other and downstream proteins
Term
What is the difference in the cytokine receptors and the tyrosine kinase?
Definition
in the cytokine receptors, the protein tyrosine kinase activity is not intrinsic to the receptor molecule. a seperate protein from the JAK binds to the receptor.
Term
what are examples of ligands that activate cytokine receptors
Definition
growth hormones
interferons
other regulators of growth and differentiation
Term
ligand gated ion channels are
Definition
a class of receptors that are opened or closed by the binding of a ligand
Term
name examples of ligands that regulate the flow of ions
Definition
acetylcholine
serotonin
y-aminobutyric acid
excitatory amino acids
Term
Receptors that are coupled to G proteins belong to a family of proteins called
Definition
Serpentine Receptors or 7transmembrane receptors
Term
for cAMP, the effector enzyme is...
Definition
adenylyl cyclase
Term
Gs stimulates adenylyl cyclase after being activated by ligands, such as
Definition
catecholamines, b adrenoceptors, histamine, vasopressin, glucagon, fsh, lh, thyrotropin, parathyroid hormone
Term
Receptors are dynamically
Definition
regulated in number, location, and sensitivity
Term
What causes desensitization?
Definition
frequent or continuous exposure of the receptor to the agonist over a short period of time

rapid and reversible process that desensitizes tissue to further receptor-agonist interaction
Term
Internalization of receptor molecules
Definition
occurs following frequent or continuous exposure of the receptor to the agonist over a relatively short period of time.

Receptors are recycled, intact, to the plasma membrane via endocytic vesicles
Term
Down-Regulation
Definition
occurs after prolonged or repeated exposure of cells to the agonist over a LONG period of time

decreases the number of receptor molecules present in the cell or tissue and is less readily reversible
Term
How is down-regulation reversed/recovered?
Definition
it requires the biosynthesis of new receptor molecules for recovery
Term
What causes relative drug tolerance?
Definition
down-regulation
Term
What does tolerance refer to?
Definition
the decrease in intensity of the response to a given dose of a drug as a consequence of continued drug administration
Term
Why might tolerance occur?
Definition
depletion of essential substrates required for downstream effects in the signal transduction pathway following continuous activation of the receptor-effector system
Term
What is Up Regulation?
Definition
when receptor activation is blocked for long periods of time by pharmacologic antagonists or by denervation
Term
Efficacy refers to...
Definition
the ability of the drug to accomplish a specified effect
Term
Potency refers to
Definition
the amount of drug required to cause an effect
Term
Potency of a drug depends on
Definition
the affinity of the drug for binding to the receptor

the efficiency of the occupancy response coupling process
Term
Clinical Effectiveness depends on
Definition
maximal therapeutic efficacy and its ability to reach its site of action
Term
Quantal Dose-Response Curve
Definition
represents the percentage of individuals or lab animals under study who exhibit a specified drug effect, plotted as a function of log drug dose
Term
What does a quantal dose response curve illustrate?
Definition
the potential variability of responsiveness to the drug among a population
Term
The therapeutic index is defined, in ratio, as
Definition
TD50 / ED50
Term
The Therapeutic Window of a drug
Definition
describes the dosage range between minimum effective concentration and minimum toxic concentration
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