Term
| Mechanisms of Drug Action: Introduction |
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Definition
Effects of most drugs via interaction with macromolecular components of the organism.
“Receptor” any functional macromolecular component of the organism
A drug is potentially capable of altering both the extent and rate (how it proceeds and how fast it proceeds) at which any bodily function proceeds.
Drugs do not create effects but instead modulate intrinsic physiological functions. Drugs simply alter physiological function.
Concept of drugs acting on receptors is credited to John Langley (1878) while studying effects of atropine against pilocarpine-induced salivation.
“There is some substance in the nerve ending or gland cell with which both atropine and pilocarpine are capable of forming compounds”….later referred to this substance as “receptive substance”
1909 Paul Ehrich introduced the term “receptor”. He postulated that a drug could have a therapeutic effect only if it has the “right sort of affinity”.
Functional definition for receptor: “…that combining group of the protoplasmic molecule to which the introduced group is anchored with hereafter be termed receptor” |
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Term
| Drug Receptors: Introduction |
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Definition
Numerically, proteins are the most important class of drug receptors
Hormone receptors
Growth factors
Transcription factors
Neurotransmitters
Enzymes of pivotal metabolic and regulatory pathways
Transport proteins
Secreted glycoproteins
Structural proteins
Other cellular components can also be therapeutic targets e.g. nucleic acids (DNA, RNA, etc). |
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Term
| Drug-Receptor Interactions |
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Definition
Binding of drugs to receptors can involve all known types of interactions:
Ionic, H-bonding, hydrophobic, van der Waals, covalent
The strength of these bonds is important in determining the specificity of binding to a given receptor (you can have a drug that slightly binds to many receptors, but it may not have an effect..it needs to be specific and bind tightly)
Successful binding of a drug requires an “exact” fit of the ligand (drug) atoms with the complementary receptor atoms
Lock and Key analogy: A precisely fitting ligand (key) is required to fit into the opening of the receptor (lock) and activate (unlock) the receptor. High specificity required.
Induced fit model: Ligand + Receptor Conformational in Receptor Receptor Activation pharmacological effect
Receptor is “flexible”
Covalent binding: duration of drug action is frequently
Non-covalent bonding of high affinity may also be “essentially irreversible” |
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Term
| Structure-Activity Relationships (SAR) and Drug Design |
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Definition
Medicinal Chemistry
Affinity: the strength of the reversible interaction between a drug and it’s receptor as measured by their dissociation constant.
Both the affinity of a drug for it’s receptor and it’s intrinsic activity are determined by it’s chemical structure.
These concepts are at the heart of drug discovery/medicinal chemistry strategies
**Relatively minor modifications in the drug molecule may result in major changes in it’s pharmacological properties based on altered affinity for one or more of it’s receptors. |
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Term
| Cellular Sites of Drug Action: It’s all about specificity |
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Definition
Where do drugs act?
They act where their receptors are!
The site at which a drug acts and the extent of it’s action are determined by the location and functional capacity of it’s receptors.
Selective localization of drug action w/in an organism does not necessarily depend upon on selective distribution of the drug.
If you need an effect in the muscle do you have to have the drug only in the muscle? Not necessarily there must be a receptor for the drug then it will have an effect.
If a drug acts on a receptor that serves functions common to most cells it’s effects will be wide-spread, or non-specific.
For ex, if you have a glucose transporter every cell in the body needs glucose. So if you have a drug that transports a glucose transporter it will inactivate almost every cell in your body since almost every cell has glucose receptors. Therefore, this drug wouldn’t be very specific.
The receptor and the drug have to be where you want them to be to have specificity.
Conversely, if a drug interacts w/receptors that are unique to only a few types of differentiated cells, it’s effects are more specific.
Why does this matter?
It usually comes down to side effects, but specificity may also be a factor. |
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Term
| Physiological Receptors: Structural and Functional Families |
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Definition
Vast array of physiological receptors and effector molecules have been identified via modern genetics, molecular biology and biochemical approaches.
Key regulatory enzymes and structural proteins serve as pharmacological “receptors”/drug targets
However the richest sources of therapeutically exploitable drug targets/receptors have been proteins that transduce extracellular (from outside) signals into intracellular (inside) biological responses.
These receptors can be grouped into a few families. |
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Term
| G-Protein Coupled Receptors (GPCRs) |
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Definition
7-transmembrane domain receptors that [closely] interact/couple with heterotrimeric GTP-binding proteins (G-Proteins)
Transduces signals derived from light, odors, and numerous neurotransmitters e.g. epinephrine, norepinephrine, dopamine, seratonin and acetylcholine
Duration of response: seconds to minutes
G proteins are signal transducers that convey information from the receptor to 1 effector proteins.
G protein subunits:
: binds GTP/GDP, drives dissociation of the β subunit, and regulates effector proteins such as adenylyl cyclase (AC), guanyl cylase and phospholipase C. Effector proteins then alter the activation and/or concentration of second messengers . S = stimulatory to AC ; I = inhibitory to AC
β (dimer): interacts with other effectors and impacts membrane localization of the GPCR (via myristolylation)
Second messengers: conduct and amplify signals eminating from receptors, impacting myriad cellular processes
e.g. cAMP, cGMP, diacylgylerol (DAG) inositol-1,4,5-triphosphate (IP3) |
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Definition
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Term
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Definition
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Term
| Receptors as enzymes: Kinases, phosphatases and guanylyl cyclases |
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Definition
Recepter superfamily characterized by cytosolic enzyme activity as component of their structure/function.
Duration of response: minutes to hours
Ligand binding to the extracellular domain activates or inhibits the cytosolic enzyme activity via ligand-induced conformational change.
Cell surface protein kinases act to phosphorylate diverse effector proteins at the inner face of the plasma membrane.
Autophosphorylation, phosphorylation on TYR, SER, THR residues
Protein phosphorylation changes the 3-D structure of the protein and can alter the biochemical activities of effectors and/or its interactions with other signaling molecules.
Phosphorylation can be thought of as a “molecular switch” (turns things on/off) leading to a cascade of signaling events which amplify the ligand signal.
Phosphorylation is the most common reversible, covalent, functional modification of proteins. Up to 30% of all proteins phosphorylated at any given time!
Protein phosphatases remove phosphate groups from proteins (de-phosphorylation reactions), specifically TYR, SER, THR residues |
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Term
| Ligand-gated ion channels |
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Definition
Regulate the flow of ions across cell membranes in response to ligand binding.
Signal transduction via altering the cell’s membrane potential.
Very rapid response: milliseconds
Multi-subunit proteins, each subunit spanning membrane multiple times
Ligand binding to one or more subunits
Symmetrical association of the subunits allows formation of the channel pore and act to cooperatively control channel opening and closing.
Ligand-gated ion channels also regulated by other cellular signaling events such as phosphorylation of one or more subunits
Activating or inactivating
http://www.youtube.com/watch?v=Du-BwT0Ul2M |
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Term
| FIGURE 12-12b Triggering of oscillations in intracellular [Ca2+] by extracellular signals. |
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Definition
| FIGURE 12-12b Triggering of oscillations in intracellular [Ca2+] by extracellular signals. |
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Term
| FIGURE 12-13 Transient and highly localized increases in [Ca2+]. |
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Definition
| FIGURE 12-13 Transient and highly localized increases in [Ca2+]. |
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Term
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Definition
Ligands must cross the plasma membrane to reach the target receptor
Physical and chemical properties of ligands/drugs critical must be sufficiently lipid-soluble. Transported attached to proteins such as albumin.
Ligand-receptor complex moves to nucleus, binds DNA, regulates gene transcription
Much longer time course of action than other receptor family types (>30 min-days); true for both initiation and duration of effects |
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Term
| Saturated/capacity-limited metabolism |
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Definition
Elimination of the drug is not 1st order
Usually, the t1/2 increases as ↑D0*
AUC is not proportional with the amount of bioavailable drug |
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Term
| How do you find out if the drug exhibits saturated/capacity-limited excretion? |
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Definition
give doses high enough to bracket expected blood levels
Plot log Cp vs t and observe whether all doses give parallel slopes
Plot AUC vs dose and observe if linear |
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Term
| Saturable enzymatic elimination |
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Definition
Michaelis – Menton kinetics
Vmax max velocity of the enzyme system, an instantaneous elimination rate
Km Michaelis constant, reflects system capacity
= Cp at 0.5Vmax
Units: ug/ml |
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Term
| Saturable enzymatic elimination |
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Definition
At larger Cp the elimination rate is constant
Approaches Vmax
Process has become zero order |
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Term
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Definition
How long for Cp to decline from 0.05 to 0.005 ug/ml?
Is drug elimination 0 order or 1st order at this Cp ? |
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Term
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Definition
How long for Cp to decline from 0.05 to 0.005 ug/ml?
Is drug elimination 0 order or 1st order at this Cp ?
How does Cp compare with Km? (0.1 ug/ml) |
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Term
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Definition
How long for Cp to decline from 0.05 to 0.005 ug/ml?
Is drug elimination 0 order or 1st order at this Cp ?
What is the value of Km? (0.1 ug/ml) |
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Term
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Definition
How long for Cp to decline from 0.05 to 0.005 ug/ml?
Set C0 = 0.05 ug/ml
Set Cp = 0.005 ug/ml
How will you ever find k? |
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Term
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Definition
Rate of elimination is governed by Vmax and Km
As ↓Vmax, the Cl will ↓, and t1/2 will ↑ |
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Term
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Definition
If Vmax is kept constant:
As ↑Km, the Cl will ↓, and t1/2 will ↑
Replot fig 9-4 as rate of metabolism vs Cp (see fig 9-12) |
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Term
Practice problems (p227) or “when will the amount of drug in the body drop in half?”Capacity-limited PK
Km = 100 mg/L, Vmax = 50 mg/hr
D0 iv bolus = 400 mg or 320 mg
Calculate the time for 50% of the drug to be eliminated |
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Definition
| Why are these two t1/2 different? |
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Term
Practice problems (p227) or “when will the amount of drug in the body drop in half?”Capacity-limited PK
Km = 100 mg/L, Vmax = 50 mg/hr
D0 iv bolus = 400 mg or 320 mg
Calculate the time for 50% of the drug to be eliminated |
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Definition
| Why are these two t1/2 different? |
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Term
Practice problems (p227)
Parameters
Km = 100 mg/L, Vmax = 50 mg/hr
D0 iv bolus = 10 mg or 5 mg
Calculate the time for 50% of the drug to be eliminated |
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Definition
| Why are these two t1/2 similar? |
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Term
Practice problems (p227)
Parameters
Km = 100 mg/L, Vmax = 50 mg/hr
D0 iv bolus = 10 mg or 5 mg
Calculate the time for 50% of the drug to be eliminated |
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Definition
| Why are these two t1/2 similar? |
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Term
| capacity-limited kinetics |
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Definition
For this example of capacity-limited elimination
At higher doses, the drug elimination process is partially saturated*
t1/2 is dose-dependent
At lower doses, the drug elimination process is not saturated*; therefore, 1st order elimination
t1/2 is dose-independent |
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Term
| Can you think of any examples of capacity-limited kinetics? |
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Definition
| _________________________________________? |
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