Lecture 1-5 Flashcards
(86 cards)
1
Q
What is pharmacodynamics?
A
Drug acting on the body
(drug effects, mechanism of action)
2
Q
What is pharmacokinetics?
A
body acting on the drug
(Absorption, distribution, biotransformation, excretion)
3
Q
What are classical receptors?
A
- possess a structural and steric specificity
- can be saturated and have limited number of binding sites
- typically have an endogenous ligand
- ## have high affinity for endogenous ligands
4
Q
Types of Classical receptors?
A
- ion channels (ligand controlled)
- GPCR
- transmembrane enzymes
- intracellular receptors
5
Q
What is a type of ion channel ?
A
Nicotinic ach receptor
- allows for the influx of sodium and pottasium, when ach binds to the recetpr
- allows for muscle cell to depolarize
- nicotine affects ACH binding
6
Q
what is a type of GPCR?
A
muscarinic acetylcholine receptor
G protein coupled receptor
- muscarine acts on GPCR that bind acetylcholine
7
Q
What is a type of a transmembrane enzyme
A
- insulin receptor
8
Q
what is a type of intracellular receptor
A
Estrogen
- they have to be lipophilic
9
Q
Non-classical receptor ?
A
- macromolecules
- structural and steric specificity
- difficulr to saturate
- major classes are enzymes and transporters
- do not have endogenous ligand
10
Q
what is the function of EDTA
A
- reduce heavy metal poisoning, increased removal of a metal from the body
11
Q
what passes in passive diffusion?
A
- uncharged (lipophiclic) small molecules pass through the membrane
-charged (hydrophilic ) small molecules do not
12
Q
example of small lipophilic drugs?
A
- Diazepam(valium), Estradiol`
13
Q
Routes of administration?
A
Enteral route- enters though GI tract
- includes oral
and absoroption through stomach and intestines
uptake into portal vein circulation that drains to liver
14
Q
What system does oral administration of a drug usually first meet?
A
- oral administration is subject to first pass metabolism by the liver
- drug can be metabolized before ever reaching site of action
15
Q
Break down hepatic portal system
A
1) small intestine absorbs drugs
2) drug molecules travel in hepatic portal vein to liver
3) liver monitors blood content
4) blood enters general circulation by way of hepatic vein
16
Q
what is drug distribution? and what are the factors controlling distribution
A
Distribution – The movement of drug between blood and tissues.
Factors controlling distribution
1)rate of delivery to tissues (blood flow)
2)ability of drug to pass through capillaries
(capillary permeability)
3)hepatic ‘first pass’ effect
4)binding of drugs to proteins and tissue
components
17
Q
Example of metabolism/biotransformation?
A
Glucuronidation
liver: glucuronidation conjugation with glucuronic acid
- makes compound less lipid soluble and therefore better excreted
- happens with transferase
18
Q
Therapeutic uses of aspirin
A
- pain
- inflammation
-fever
-against platelet aggregation (prevention of stroke and heart attack)
19
Q
Aspirin rate limiting step
A
- RLS is disintegration and dissolution of tablet
20
Q
how is aspirin excreted?
A
- Excreted by glomerular filtration and proximal tubular secretion in kidney
Elimination ½ life of salicylate is 2-3 hours after single analgesic dose
21
Q
what is saturability?
A
Receptors exists in finite numbers
22
Q
what is reversability?
A
Binding occurs primarily non-covalently via weak intermolecular forces(ionic, h bonding, vander waals)
23
Q
What is ligand specificity?
A
structurally related drugs bind well, physically dissimilar drugs bind poorly
24
Q
stereoselectivity?
A
receptors bind well with only one of the naturally occuring optical isomers
25
stereoselectivity?
receptors bind well with only one of the naturally occurring optical isomers
26
tissue specificity?
binding should occur in tissues known to be
sensitive to the endogenous ligand.
27
transduction
binding of a drug must be transduced into some kind of functional response
28
what are drug steric features affecting drug receptor interactions?
Isomerism
functional groups on the drug
rigidity
29
what are conformational isomers
thye are the result of a rotation around single bonds between 2 atoms
- energy barriers exist between these isomers, that they can be observed.
- they can be changed based off of temperature
30
What can affect stereochemical features on drugs
intramolecular hydrogen bonding, dipole-dipole interactions, and electrostatic forces in molecules can alter this distribution
31
what is a bioisosteres?
substituents or groups, with similar physical or chemical properties that impart similar biological properties to a drug
32
what does a large Ka favor
- forward reaction
33
weak acids have what
small Ka and large pKa
34
strong acids have what
high Ka and small pKa
35
receptors are generally what ?
- transport enzymes
(Na-K Atpase) (NT transporters)
-enzymes
(Hiv reverse transcriptase)
(cyclooxygenase)
-structural proteins
(cytoskeletal proteins- microtubules)
(bacterial cell wall components)
- DNA/RNA
36
Kd is used to measure what
measure of a receptors affinity for drug binding
37
the larger decrease in Delta G
the greater the affinity
38
what does tamoxifen do to selective estrogen receptor modulators?
- so normally estrogen receptors bind to the secondary messengers, and then they proceed to transcribe
- with tamoxifen , it inhibits estrogen receptor, and the gene transcription will no occur.
39
In receptor-effector coupling what is morphine
Full agonist
- analgesic, depress respiration, nause, vomiting, constipation
40
In receptor-effector coupling what is buprenorphine
partial agonist
similar effects to morphine, but anatagonizes effects of morphine
41
In receptor-effector coupling what is naloxone
- antagonist
reverese effects of morphine
42
what is indirect coupling beneficial?
- allows to be modified/regulated downstream
- allows for signal modification
43
what is direct coupling and what is an example
- receptor= effector
- nictotinic ach receptor
44
what is indirect coupling and an example
receptor is not equal to effector, there is a signaling pathway
44
what is indirect coupling and an example
receptor is not equal to effector, there is a signaling pathway
45
what is drug promiscuity?
- one drug can bind to different receptors
ach can bind to nicotinic receptors, or muscarinic receptors
- different signaling mechanism
46
what is the quantal dose response relationship
describes the tendency for a drug response to occur in a population
47
what are possible reasons for the lack of drug selectivity
-Beneficial and adverse effects caused by the same mechanism
-Same receptor expressed in different tissues
-Drug promiscuity with different receptors
48
what is diffusion-limited
limited by the ability of a drug to cross membranes
49
what is perfusion- limited
limited by the amount of blood flow, drug goes to highly perfused organs/tissues first
50
after cessation of administration what happens to highly perfused drugs?
- drug redistributes to other tissues and organs (fat,muscle) with low perfusion rates.
51
what does a small oil water partition coefficient mean?
- solubility in lipid is extremely low
(this is for polar solutes)
52
What are factors that deal with passive movement of molecules?
Free (not total) drug concentration
Surface Area
Permeability coefficient of drugs
-lipophilicity
----lipid/water partition coefficient
-size/shape
Thickness of tissue
Ionization
53
what do drugs bind to in the body?
blood plasma- albumin and alpha 1- glycoprotein
interstitium- proteins
in cells- Proteins, DNA, Lipid
That lowers free drug concentration
Reversible
(exception- reactive drugs like alkylating agents)
54
What is ion trapping?
different pH across the cell layer leads to ion trapping. So different degrees of ionization on different sides of the cell layer.
55
P-glycoprotein (MDR1) and (OATP) are examples of what?
there are carriers that help excrete drugs and their metabolites
56
what does biotransformation produce?
- more polar compound, more easily eliminated by the body
56
what does biotransformation produce?
- more polar compound, more easily eliminated by the body
57
what are phase 1 reactions and what do they do?
Phase 1 reactions are part of biotransformation reactions
- add functional group to the drug
-groups are (OH, COOH, O, NH2,SH)
sometimes, does little to change water solubility
alters biological properties and structure
DOES NOT change molecular weight much
58
What is an enzyme that carries out phase 1 reactions
- CYT p450
- reductions catalyzed by cytochrome P-450 enzymes
59
Phase 2 reactions and what do they do
Synthetic, conjugation reactions (covalently link drug and another molecule)
- use UDP-glucuronosyl transferase
conjugating co-factor supplied by the body
increase water solubility, increases molecular weight
facilitates drug elimination
60
types of phase 2 reactions
sulfation
acetylation- increases weight of drug
methylation
glutathione conjugation
61
where are biotransformation enzymes located >
- Endoplasmic reticulum (microsomal fraction)
Phase 1 enzymes (mostly)
Phase 2 enzymes (UDP transferases)
- cytosol- some phase 2 enzymes
62
what is biotransformation?
Enzymatic processes by which the body changes the structure of drugs to achieve
1) increase polarity
2) terminate drug action
3) aid drug elimination
63
how does secretion and reabsorption in the kidney differ?
-secretion is an active process (proximal tubule, apical brush border)
- reabsorption (most often passive some active transporters)
64
what is zero-order drug kinetics?
- occurs when drug enters systemic blood at a fixed rate
- Constant amount of drug is added per unit time
- occurs when elimination process is saturated
65
what is first-order drug kinetics
- absorption is proportional to drug concentration gradient.
- proportional to the drug concentration at site of absorption
- at steady state, no concentration gradient is present.
66
describe first order drug kinetics elimination?
elimination is proportional to drug concentration
- flow dependent- proportional to the amount of drug delivered to the organ of elimination
- allows steady state plasma drug concentrations to be maintained and rational dosing schedules to be designed
67
What is clearance?
- volume of blood plasma from which all drug is removed per time
- ml/min, L/min/, L/hr.
- associated with first order kinetics
68
How are most drugs absorbed?
- by passive diffusion
- ficks law of diffusion
- the rate depends on the concentration gradient
69
describe zero order administration
- extended release formulations
- occurs with intravenous infusion
- inhalation
70
what are processes involved in first order elimination?
- renal filtration
-renal tubular secretion
-Q
71
Ke is inversely proportional to ?
-Vd
72
describe zero order elimination?
- independent of plasma drug concentration
- flow independent
- renal tubular secretion- saturated drug concentration
- biotransformation happens when Q>Qmax
- tend to see this in overdoses
- not desired usually
- working its maximal grade
73
Half time for drug elimination what is its relationship to Cl and Vd
Vd increases, increases half life
Cl decreases, it increases half life
74
what affects drug clearance?
1) blood flow of organs that metabolize and eliminate drugs
2) expression of drug biotransformation enzymes
3) competition between drugs for CYT P-450 metabolism
-drug A and B compete for the same CYP
-Qmax for drug A will be decreased in the presence of drug B.
If QA < Qmax for A, then B has no effect,
but as Qmax for A decreases Cl for A also can decrease, ---so increase Css
-increase T1/2
75
What is a loading dose?
- aim is to get a drug concentration in a therapeutic range faster than giving maintenance doses
- can cause adverse reactions of a loading dose, too much of drug in plasma concentrations can cause adverse reactions.
75
What is a loading dose?
- aim is to get a drug concentration in a therapeutic range faster than giving maintenance doses
- can cause adverse reactions of a loading dose, too much of drug in plasma concentrations can cause adverse reactions.
76
What is direct coupling
- it is when receptor= effector
example: ACH nicotinic receptor
77
what is indirect coupling
receptor does not equal effector
78
6 characteristics of classical receptors
saturability
reversibility
transduction
Tissue specificity
stereoselectivity
Ligand specificity
79
what is clearance, and what are the units?
volume of blood plasma from which all drug is removed per unit time
ml/min, ml/hr
volume/time
80
A weak acid drug will be more ionized when ?
pH is above its pKa
81
A weak base drug will be more ionized (BH+) when?
when the pH is below its pKa
82
Example of drug promiscuity?
- Pilocarpine
effects multiple organs,so it is made into eye drops for eye problems
83
What is parenteral routes of administration
not intestinal rounds of administration of drugs
- sublingual
-rectal
-pulmonary
-intra-arterial
- intrathecal
- topical
