Pharmacology Flashcards
1
Q
What is the term used to describe what the drug does to the body?
A
Pharmacodynamics
2
Q
What is the term used to describe what the body does to the drug?
A
Pharmacokinetics
3
Q
Is the mechanism of action/ effects of a drug under pharmacokinetics or pharmacodynamics
A
Pharmacodynamics
4
Q
What are the 2 principle factors that determines drug selectivity to distinguish between different molecular targets?
A
- Drug dose!!!
2. Administration route
5
Q
When is drug selectivity absolute?
A
Rarely as targets can change with drug dose
6
Q
What is the mechanism of action of penicillin?
Why is it selective?
A
Inhibits PBP responsible for peptidoglycan cross-linking in bacteria to form cell wall
Eukaryotes have no cell wall/ peptidoglycan layer
7
Q
Salbutamol is a selective B2-adrenoceptor agonist used for treatment of bronchospasm.
When the dose is not optimised, what could be an off-target effect?
A
It could lose selectivity and act on B1-adrenoceptors in the heart which increases heart rate and contraction force.
8
Q
What is the ratio for an agonist to display high affinity?
A
Rate of agonist binding to low rate of agonist unbinding
Usually rate of binding is constant but dissociation rate changes (“stickiness of agonist”) (determinant)
9
Q
What happens during the activation step of agonist binding?
A
REVERSIBLE conformation change that leads to TEMPORARY receptor activation
10
Q
What does the term affinity mean?
A
Ability to bind or strength of association between ligand and receptor
11
Q
What does the term efficacy mean?
A
Ability to evoke a cellular response
12
Q
What is the ratio for an agonist to display high efficacy?
A
High rate of receptor activation to rate of receptor deactivation
**Rate of deactivation is constant while rate of activation changes (determinant)
13
Q
Which 2 bonding forces contribute more to binding between ligand and receptor?
A
Ionic and H-bonds
14
Q
What is the relationship between receptor occupancy/ effect (%; y-axis) vs agonist dose (x-axis)
A
Proportional, hyperbolic on linear graph
Proportional, sigmoidal if Log10 dose
15
Q
What is effective concentration 50 (EC50)?
A
Dose of agonist to elicit half of maximum effect
16
Q
Why is a semi-logarithmic plot (Log10 dose) more accurate to determine EC50?
A
Uses a broader range of dose
17
Q
Which parameter indicates potency?
A
EC50
18
Q
What is the difference between a full and partial agonist?
A
Full agonist reaches max (close to 100% receptor effect) while partial is lower than max
**Never 100% because a hyperbolic graph never becomes parallel to the x-axis
19
Q
What is the term for the substance that blocks an agonist from activating a receptor?
A
Antagonist
20
Q
How many steps does antagonist binding have?
A
1
Only a binding step as there is no resultant cellular response
21
Q
Does an antagonist have affinity and efficacy?
A
Have affinity (binding strength) No efficacy (no receptor effect)
22
Q
How many steps does agonist binding have?
A
2
Binding, activation
23
Q
What are the 2 types of antagonism?
A
Reversible competitive
Non competitive
24
Q
Where does reversible competitive antagonists bind to?
A
Same site as agonist (orthostatic) site, thus competitive site and binding is mutually exclusive
25
How can reversible competitive antagonists be overcome?
By increasing concentration of agonist
26
What are the 2 factors that influences reversible competitive antagonism?
Affinity of antagonist to receptor
| Agonist concentration
27
What does reversible competitive antagonist do to the conc-response curve?
Parallel right shift without affecting max response (reduced potency and unchanged efficacy)
No gradient change
28
What does reversible competitive antagonist do to EC50 and max %effect?
```
Lowers EC50 (needs higher dose for 50% response)
Unchanged max effect (just needs a higher dose)
```
29
EC50 and %effect each corresponds to which axis on the graph?
EC50 - for the x-axis; relates to dose
| % effect - for the y-axis
30
Where does non-competitive antagonist bind to?
Allosteric site therefore can occupy receptor reversibly and simultaneously to agonist (just that receptor will not be activated even if agonist is bound)
31
What does non-competitive antagonist do to the conc-response curve?
Depressed slope and reduced max %effect without right shift
| reduced efficacy and unchanged potency
32
What does non-competitive antagonist do to EC50 and %effect?
Reduces max response (depressed slope)
| EC50 unchanged
33
What are the 4 factors to consider in pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
34
What are the 3 types of chemical signalling?
Autocrine (to itself)
Paracrine (close neighbours via ECF)
Endocrine (via lymphatics/ bloodstream to distant target)
35
Why must molecules be of high affinity to the receptor when signalling via endocrine?
Diluted in blood thus concentration is low thus high affinity needed to bind
36
What model is the receptor ligand selectivity known as?
Lock and key model
37
What are the 4 major types of receptors?
1. Ion channels
2. GPCR
3. Kinase-linked receptors
4. Nuclear receptors
38
What do signals cause the ion channels to undergo?
Changes reversibly between closed and open conformation (AKA Gating)
**Aquaporins always open
39
What happens when ion channels are in open/ conducting state?
Selected ions flow passively down electrochemical gradients
40
What can ion channels can be gated by? (3)
Ligand
Voltage (E.g. Action potential)
Physical stimuli (Heat/ Mechanical)
41
How fast do Ligand-gated ion channels (LGICs) or ionotropic receptors act? Where are they found?
```
Rapid acting (millisecond)
At plasma membrane
```
42
What are ionotropic receptors targeted by?
Hydrophilic signalling molecules (can't cross membrane)
43
What kind of receptor does nicotinic ACh receptor fall under?
LGIC
| *Found in neurons and skeletal muscle
44
How many glycoprotein subunits a needed to form the LGIC?
5 for a psuedo-symmetrical central, ion conducting channel
45
How many agonists are needed for LGIC to work?
2 to bound simultaneously for rapid conformation change which eventually depolarises the membrane
46
What are the 3 reversible conformations of LGICs?
1. Unoccupied and closed
2. Occupied and closed (transient phase)
3. Occupied and open
47
How fast do GPCRs/ Metabotropic receptors act? Where are they found?
```
Slower acting (seconds)
At plasma membrane
```
48
What are GPCRs targeted by?
Hydrophobic signalling molecules
*Most drugs act via GPCR
49
Fast and slow action of neurotransmitters depend on?
Type of receptor
50
What are secondary messenger systems?
Receptor activation modulating activity of an effector
51
How many components are there to GPCR signalling?
3.
| Receptor, transducer, effector (can be enzyme or ion channel)
52
Is GPCR in direct contact with the effector?
No, thus an intermediary proteins is needed (G-protein)
53
What is the structure of a GPCR? (3)
Integral membrane protein (embedded)
Single polypeptide with extracellular NH2 and intracellular COOH termini
7 transmembrane a-helical spans with 3 extracellular and 3 intracellular loops
54
What can enzyme effector and ion channel effector of GPCR each result in?
Enzyme: increase/ decrease rate of synthesis of 2nd messenger molecule
Ion channel: Changes to Membrane potential
55
What is a G-protein?
Peripheral membrane protein at the interior side of membrane
| 3 polypeptide subunits (a,b,y)
56
Which G-protein subunit contains the guanine-nucleotide binding site that holds GTP or GDP?
a
57
Does b and y subunit in the G-protein separate?
No, they exist as dimers while a-subunit dissociates
58
What happens when an agonist binds to GPCR? (6)
```
GPCR and GDP-bound G-protein preferentially couple (via a-subunit)
Conformation change to a-subunit
GDP RELEASED and GTP binds
Activation
a-subunit dissociates
Interacts with effector (s)
```
59
Does GTP or GDP bound to the a-subunit of G-protein contribute to the active, signalling state?
GTP via guanine nucleotide exchange with GDP
60
Can signalling still persist after agonist has dissociated from GPCR?
Yes because G-protein and receptor are separated
61
How is signalling in GPCR turned off?
a-subunit is also a GTPase
GTP hydrolysed to GDP and Pi
Inactive GDP-bound a-subunit recombines with by-dimer
62
Match for GPCR.
Activation vs Deactivation
GTP hydrolysis vs Guanine exchange
Activation - guanine exchange
| Deactivation - GTP hydrolysis via a-subunit GTPase
63
What are the 3 simultaneous indicators that show that there is no signal through the GPCR system?
Unoccupied GPCR
a-subunit bound to GDP
Effector not modulated
64
What is an example of a Gs GPCR and what is it activated by?
B1-adrenoceptor, by noradrenaline.
65
What happens during Gs GPCR activation? (After guanine-exchange) (5)
```
Gs-GTP (a-subunit) dissociates
STIMULATES adenylyl cyclase
Converts ATP to cAMP and pyrophosphate
cAMP-dependent protein kinase A activity increases
Cellular effects
```
**Think Gs for stimulatory
66
What is an example of a Gi GPCR and what is it activated by?
Muscarinic M2 ACh receptor, by ACh
67
What happens during Gi GPCR activation? (After guanine-exchange) (5)
```
Gi-GTP (a-subunit) dissociates
INHIBITS adenylyl cyclase
Decrease cAMP production
Decrease activity of cAMP-dependent protein kinase A
Cellular effects
```
**Think Gi for inhibitory
68
What is an example of a Gq GPCR and what is it activated by?
a1-adrenoceptors, by noradrenaline
69
What happens during Gq GPCR activation? (After guanine-exchange) (5)
Gq-GTP (a-subunit) dissociates
Activates Phospholipase C
Cleaves PIP2 to IP3 (soluble) and DAG
IP3 released and binds to specialized calcium channel in ER --> opens and releases calcium into cytoplasm
DAG remains bound --> acts with released calcium to activate Protein kinase C --> Cellular effects
70
What amino acid residues are being phosphorylated in target proteins in Gs and Gq signalling?
Serine or Threonine
71
Can the by-dimer act as a signalling unit too?
Yes
72
How are the types of GPCRs named?
According to a-subunit type
73
What are the modes of crossing cell membrane? (3)
1. Simple/ passive diffusion
2. Carrier-mediated
a. Facilitated diffusion (shows saturation kinetics)
b. Active transport (shows saturation kinetics)
3. Endocytosis/ Pinocytosis (involves invagination and vesicles for larger drugs)
74
At higher drug concentrations, for carrier-mediated transport, will the rate be first or zero order?
Zero order due to saturation of carrier (rate-limiting) thus transport becomes independent of drug concentration
75
Do drugs exist in ionised or un-ionized form?
Both
76
What is pKA?
The pH at which 50% of drug is ionised and 50% unionised
77
Is the ionised or un-ionised form of drug more permeable to cross the membrane?
Un-ionised form
78
What is the chemical reaction for weak acids?
AH (weak acid) -->/--< A- + H+
79
What is the chemical reaction for weak bases?
BH+ -->/--< B(weak base) + H+
80
How does pH influence trapping of drug across plasma membrane?
pH favoring unionised form will allow drug to diffuse and be absorbed (E.g. Acidic stomach for a weak acid drug)
As the pH changes (E.g. pH7.4 plasma), it will favour the ionised form of the drug, thus the drug will not be able to diffuse back into the GI tract
81
Where do weak bases and weak acids preferentially accumulate/ trapped?
Weak bases - low pH environment (Better absorption at stomach)
Weak acids - high pH environment (Better absorption at intestine)
82
Where do most oral absorption occur?
Small intestine due to larger surface area
83
Do weak acids tend to ionise in high pH or low pH medium?
Ionises at high pH environment to donate H+
84
What is the formula for Apparent volume of distribution (Vd)?
Vd = Dose/ [Drug]plasma
85
A better distributed drug (e.g. lipophilic) drug will have a Vd more or less than total body water (41L)?
More
86
What does low Vd signify?
Retained in vascular compartments
87
What does high Vd signify?
Drug able to go to areas like adipose, muscle and non-vascular compartments
88
For 2 drugs with the same potency (EC50), will the higher Vd drug require a higher or lower dose to reach the same [Drug]plasma as the lower Vd drug?
Higher dose.
Most of it would have diffused out of plasma to the non-vascular compartments thus more drug will be needed to increase plasma concentration
89
What is the most abundant plasma protein?
Albumin
90
What happens when drug is bound to albumin?
They are less available to diffuse out to non-vascular compartments to reach target organs
91
What would be the Vd and [Drug]plasma if most of it is bound to albumin?
Low Vd
| High [Drug]plasma
92
What is the principle organ for drug metabolism?
Liver
93
What is bio-availability and what reduces it?
Amount of drug available in systemic circulation
| When drug is metabolized when administered through the PO route, it is less bioavailable
94
How many phases of metabolism are there in the liver?
I and II
95
Where are the microsomal enzymes for metabolising embedded in in the hepatocytes?
Smooth ER
96
Are polar or non-polar molecules more readily metabolised?
Non-polar as they cross the membrane more easily
97
What are the 3 processes involved in phase I metabolism?
Oxidation - by cytochrome P450 enzymes (Microsomal Haem proteins)
Reduction
Hydrolysis
98
What are the products formed from Phase I metabolism like?
| What can they result in?
More reactive/active/toxic metabolites which can cause cellular damage via binding covalently to membrane glycoproteins
99
What is the pre-dominant process involved in Phase II metabolism?
Glucuronidation
100
What are the products formed from Phase II metabolism like? (3)
More polar/ soluble by targeting the reactive group formed in Phase I with a polar molecule
Detoxifies
Readily excreted by kidneys
101
What is 1 drug that directly enters Phase II metabolism to yield active metabolites?
Codeine
102
What does high and low activity level of CYP450 enzyme result in?
High - lower drug plasma levels --> reduced desired effect
| Low - higher drug plasma levels --> adverse effect
103
What does drug interaction with P450 system result in?
Competitively induces P450 thus antagonistic effect to other drugs and reduces bioavailability
*Can also inhibit which increases bioavailability of drug
104
What are the 2 enzymes involved in oxidation in the monoxygenase P450 system?
NADPH-P450 reductase
| Cytochrome b5
105
What is the principal organ for drug clearance?
Kidneys
| Drugs that have undergone Phase II metabolism are not reabsorbed
106
What is the yellow card scheme?
Reporting suspected side effects of medication
107
What can happen when drug dose goes above EC50? (2)
Toxic effects from Phase I toxic metabolite accumulation or loss of selectivity/ off-target binding due to high dose
108
How is drug clearance expressed?
Volume of blood removed of drug per unit time (L/hour or mL/min)
109
What are the 3 routes contributing to total clearance?
Renal, hepatic, other routes
110
What is the formula for drug clearance?
CL = Rate of drug elimination (mg/hour) / [Drug]plasma (mg/L)
111
Does Vd affect CL?
No, they are independent of each other
112
What is first-order kinetics?
Rate of drug elimination increases as [Drug]plasma increases
*Follows Michaelis-Menten kinetics
113
What is zero-order kinetics?
Elimination mechanisms saturated and Vmax reached
| Becomes independent of [Drug]plasma
114
What is the desired [Drug]plasma for therapeutic effect known as?
Steady state
115
What is the formula for Dosage rate?
[Drug]plasma Steady state x CL
116
What is the ideal ratio for rate of administration to rate of elimination?
1:1
| Steady state level
117
What is the formula for T1/2?
(0.693 x Vd) / CL
118
What to do if there is a high Vd value due to obesity or pathologic fluid?
Adjust regimen to avoid toxicity
119
What to do if there is low Vd due to loss of muscle mass/ atrophy or aging?
Repeated dosing for therapeutic effect
120
What are the 4 factors that may affect clearance rate?
Cytochrome P450 induction/inhibition
| Cardiac, Hepatic and renal failure (slows circulation thus slows clearance rate)
121
How many half lives are normally needed to reach steady state?
5
| *Multiple doses - new baselines after each T1/2 till steady state
122
How many half lives are normally required to wash the drug out (after stopping infusion)?
5
123
What is the relationship of CL and Vd to T1/2?
Inverse: CL
Direct: Vd
124
Do absorption and elimination occur simultaneously?
Yes
