edu: Drug Receptors, Pharmacodynamics and Drug disposition Flashcards
1
Q
Mechanisms of Drug Action
A
- Chemical interactions with other molecules due to a drug’s acidic or basic properties (antacids in
hyperacidity; protamine sulfate in heparin overdose) - Ability to act as a membrane surfactant (amphotericin B)
- Ability to denature proteins (astringents)
- Binding to specific receptor site
2
Q
What is a receptor?
A
Receptor - macromolecule or a 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.
3
Q
What are the Properties of Receptors
A
- Ability to bind to drugs (or ligands) with relatively high affinity
- Ability to transduce a signal to produce a biological effect
4
Q
What are your Receptor Subtypes:
A
- Enzymes – allopurinol receptor (mediated by xanthine oxidase)
- Ion channels – nifedipine, verapamil, diltiazem receptors
- Membrane receptors – alpha and beta adrenergic receptors
5
Q
The interaction of a receptor and its ligand (the molecule to which it attaches to) is described to be in a
“lock and key” fashion which means A
A
- perfect fit.
- This means the physical properties (i.e. size, shape, electrical charge, and atomic composition) and chemical properties of the receptor are perfectly compatible with that of the drug molecule
6
Q
Chemical Basis for Drug Receptor Interactions
A
- ELECTROSTATIC INTERACTIONS
- HYDROPHOBIC INTERACTIONS
- COVALENT BONDS
- STEREOSPECIFIC INTERACTIONS
7
Q
this is the **most common mechanism **of drug receptor interactions
A
ELECTROSTATIC INTERACTIONS
8
Q
What are your example of Electrostatic interaction?
A
- Hydrogen Bonds,
- Van der Waals forces)
9
Q
INTERACTIONS – important for lipid-soluble drugs
A
HYDROPHOBIC INTERACTIONS
10
Q
- the least common
A
COVALENT BONDS
11
Q
What are your example of Hydrophobic interactions?
A
- phenoxybenzamine binding to alphaadrenergic receptors)
12
Q
What are your example of STEREOSPECIFIC INTERACTIONS - example is
A
- carvedilol. S(-) carvedilol binds to both alpha- and
- beta-adrenoceptors,
- whereas R(+) carvedilol binds selectively to alpha adrenoceptors
13
Q
A
14
Q
what are the Properties of Agonists:
A
Affinity and Efficacy
15
Q
What is an affinity?
A
tenacity with which a drug binds to its receptor.
In statistical terms, it is the probability
that a drug molecule will bind to an available receptor at any given instant in time
16
Q
What is an efficacy?
A
It is an inherent property of an agonist that determines its ability to produce a biological effect.
17
Q
What is Potency – ?
A
comparative term for distinguishing which agonist has a higher affinity for a given
receptor
18
Q
What are Partial Agonists –?
A
drugs that produce less than maximal activation of a receptor
19
Q
Signal Transduction Mechanisms
A
- Direct activation of an ion channel
- Stimulation of an ion channel via activation of G-protein.
- Use of second messenger via G-protein activation of adenylyl cyclase.
- Use of second messenger via G-protein activation of phosphoslipase C
20
Q
Define Direct activation of an ion channel -
A
- The drug is structurally attached to an ion channel.
- Binding of the drug results in a conformational change in the receptor/channel complex that typically causes the ion channel to open.
- This results in a flow of channel permeant ions.
21
Q
What are your examples of Direct activation of an ion channel?
A
Example:
- nicotinic cholinergic receptors (neuromuscular junction),
- GABA receptors and
- receptors for excitatory amino acids (glycine, glutamate, aspartate)
22
Q
What is Stimulation of an ion channel via activation of G-protein.
A
Either the alpha or beta/gamma subunits
stimulate the channel to open. This is the mechanism by which acetylcholine acts to slow the heart
rate.
23
Q
What are your example of stimulation of ion channel via the g-protein?
A
Example: m2 – cholinergic receptors
24
Q
How is the Use of second messenger via G-protein activation of adenylyl cyclase.
A
This mechanism is
responsible for NE’s ability to increase the force of contraction of the heart muscle, which results
from the phosphorylation of the L-type Ca channel by protein kinase
25
How is the Use of second messenger via G-protein activation of phosphoslipase C.
this mechanism is believed to mediate the vasoconstrictive effects of **Angiotensin II on vascular smooth muscle**
26
How is the Activation of tyrosine kinase.
This class of receptors mediates the first steps in the transduction of signals carried by insulin and variety of growth factors such EGF
27
Kinds of Antagonists
1. Non-competitive antagonism
2. Competitive antagonism
3. Other Types
* Chemical antagonism
* Functional antagonism
* Pharmacokinetic antagonism
28
What is Non-competitive antagonism - ?
antagonist acts at a **site beyond the receptor for the agonist**
29
What is Competitive antagonism? -
antagonist **combines with the receptor on the same site as does the
agonist**, but unlike the agonist,**does not induce a response (that is, the antagonist has little or NO**
30
Competitive antagonism
EFFICACY
1. Competitive reversible antagonism
2. Competitive irreversible antagonism
31
What is Competitive **reversible** antagonism – ?
the **degree of antagonism** increases **as the concentration
of the antagonist increases**.
On the other hand, the degree of antagonism **may be overcome if the concentration of the agonist is increased**
32
What is Competitive **irreversible antagonism** – ?
may not be overcome by increasing the concentration
of the drug (agonist).
## Footnote
**The antagonist inactivates the receptors**
33
What is Chemical antagonism –
It occurs **when a drug reduces** the **concentration of an agonist by forming _chemical complexes _**
34
What is an example of Chemical antagonism?
dimercaprol
35
What is Functional antagonism –
It involves **drug activation of two different compensatory biological**
**mechanisms that exist to maintain homeostasis**
36
Give an example of Functional antagonism?
(example: effect of **NE to increase blood**
pressure can be **antagonized by acetylcholine)**
37
What is Pharmacokinetic antagonism – ?
It occurs **when one drug accelerates** the **metabolism or
elimination of another**
38
Give an example of pharmacologic antagonism?
(example: **phenobarbital-induced enzyme induction increases the
metabolism of anticoagulant Coumadin)**
39
Synergism versus Additivity
When two drugs are given together, they **typically produce additive effects** (or **summative effects).**
That is, the combined effects of two drugs is **EQUAL TO THE SUM OF THEIR INDIVIDUAL
EFFECTS**
Addivity
40
What is an example of Additivity?
(example: giving barbiturates and a tranquilizer may increase the sedative effect in an
individual)
41
However, if the effect of two drugs **exceeds the sum of their** **individual effects,** this is referred to as
\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
synergism (or potentiation)
42
\_\_\_\_\_\_\_\_\_\_\_\_\_\_requires that drugs act at **DIFFERENT RECEPTORS OR**
**EFFECTOR SYSTEMS**
Potentiation
43
What is an example of potentiation?
(ex: barbiturates + alcohol = coma/death)
44
Selectivity versus Specificity
What is Selectivity –?
in terms of drug effect, it is the **extent or ability of the drug to affect a particular cell
type**
45
What is Specificity –
a **drug property** that **connotes that it has an exclusive effect and ONLY ONE action on
all biological systems**
46
However, the vast majority of drugs are\_\_\_\_\_\_\_\_\_\_ rather than specific.
SELECTIVE
Meaning, most drugs will act on
more than one receptor site once they reach an appropriately high concentrations
47
The **higher the selectivity of a pharmacological effect**, the **\_\_\_\_\_\_\_\_\_\_\_\_ is the range of drug action**.
narrower
The lower
the selectivity of pharmacological effect, the **broader the range of drug action**
48
What is Quantal-Dose Relationships –
represent a **cumulative distribution** of the **population** responding to a
particular drug.
This **depicts the relationshi**p between the **dose of a drug versus the frequency** that this
dose produces a **minimum effect**
49
A quantal dose-response curve requires that
(1) data be obtained from a **group of individual**s (**as opposed**
**to graded dose response curve**) and
(2) is constructed with which the **dose plotted on the horizontal** axis is evaluated **against the percentage of subjects** in the experimental population that is protected by each dose (vertical axis)
50
What are the data that can be obtained from the Quantal Dose Curve
* Median **effective** dose (ED50)
* Median **toxic** dose (TD50)
* Median **lethal** dose (LD50)
51
What is Median effective dose (ED50) –
**dose that produces the desired effect** in **50% of the population**
52
What is Median toxic dose (TD50) –
dose that produces a toxic effect in 50% of the population
53
What is the Median lethal dose (LD50) –?
dose that **produces death in 50%** of the **population (based on animal
studies)**
54
What is the Therapeutic Index –
It is the ratio between **TD50 and ED50 (TD50/ED50).**
Generally the **higher the therapeutic
index, the safer is the drug.**
55
In order to achieve its effect, a drug must **first be presented in a suitable form at the appropriate site of
administration.**
It must then be **absorbed from the site of administration a**nd **distributed through the body to its site of action**.
For the effect to wear off the drug must nearly always be metabolized and/or excreted.
Finally, drug residues are removed from the body.
Removal refers to the loss of material, unchanged drug and/or metabolic products, in urine and/or feces, once this material has been excreted into the bladder or bowel by the kidneys and liver.
56
What comprise the
**DISPOSITION (placement around the body)** of a compound.
**Absorption and distribution**
57
What \_\_\_\_\_\_\_ comprise the
FATE of a compound
Metabolism and excretion
58
Mechanisms of Drug Transfer
1. Passive Diffusion
2. Filtration
3. Active Transport
4. Facilitated Diffusion
5. Pinocytosis
59
What is Passive Diffusion ?
- through the membrane, **DOWN** a concentration gradient.
It is by far the **most
important transfer mechanism for foreign molecules**
60
What is Filtration – ?
refers to the **passage of drug through pores in the membrane**
61
What is Active Transport –
It is **energy dependen**t, **saturable,** against the concentration gradient, selective carrier
mediated
62
What is Facilitated Diffusion –
It requires **no energy**, **saturable**, **never against an electrochemical gradient,
selective carrier-mediated**
63
What is Pinocytosis -?
microscopic invaginations of the cell will engulf drops of extracellular fluid; in this
way, solutes are carried through in the resulting vacuoles of water
64
What is the Fick's law of diffusion?
The rate of diffusion of a drug (or flux) is a function of the :
* **concentration gradient across the membrane,**
* the **surface area over the transfer occurs**,
* the **thickness of the membrane**,
* and the **permeability coefficient which is characteristic of the particular drug.**
65
What is the permeability coefficient ?
It is a function of its **solubility in the membrane**, the **molecular mass**, and its
**steric configuration.**
66
What is theLipid-Water Partition Coefficient
The **ability of a drug to diffuse across membranes** is expressed in terms of its **lipid-water partition
coefficient**.
This coefficient is defined as the **ratio of the concentration of the drug in two immiscible**
phases;
* a **non-polar liquid or organic solvent**, representing the membrane;
* and an **aqueous buffer.**
67
**Increasing the polarity** of the drug, either by increasing its degree of ionization or by adding a functional
group, _____________ the coffecient.
decreases the coefficient
68
Conversely, **reducing** the **polarity or by the drug more non-ionized**, ____________ the coefficient
increases
69
Extent of Ionization
In aqueous solutions, drugs dissociate in either **ionized or un-ionized** form as dictated by the drug’s
**ionization constant (K)** and the **prevailing pH of the solution.**
70
Drug Administration
Oral advantages
* convenient,
* requires no medical skills or sterile conditions,
* appropriate for outpatient use and medicine over the counter,
* for those with difficulty swallowing tablets –
* solutions/suspensions
71
In the oral drug admin,absorption occurs chiefly by\_\_\_\_\_\_\_\_\_\_\_\_ for lipophilic molecules
passive diffusion
72
In the oral drug admin,absorption occurs chiefly by \_\_\_\_\_\_\_\_\_\_- for
endogenous drugs such as **5-fluorouracil (cytotoxic drug)**
active transport
73
Weak bases cannot be absorbed until they have left the stomach, **so prolonged gastric emptying can
delay the effect of such drugs**
74
Pertinent Issues in Oral Administration
Pre-systemic Metabolism
75
Pre-systemic Metabolism
* If the drug is largely metabolized as it passes through the **live**r, **then little of it will reach the systemic circulation.** Example is **glyceryl trinitrate.**
* The extent to which a drug undergoes pre-systemic circulation may be obtained by comparing the plasma concentration-time curves or comparing the Area Under The Curves (AUC), after an oral and an intravenous dose of the drug.
* **Bioavailability** – reflects the fraction of drug absorbed into systemic circulation. **Experimentally**, this is **measured by comparing the AUC** of the drug when serial measurements of plasma concentrations are made following oral administration compared to IV
76
Factors affecting Bioavailability
* Molecular weight
* Drug formulation
* Drug solubility
* Chemical instability in gastric pH
* First-pass metabolism
* Blood flow to the site
* Surface area available for absorption
* Gastric emptying time
* pH of the gut
* Intestinal motility
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