Pharmacodynamics 1 Flashcards
Identify molecular targets for drug action
receptors, ion channels, enzymes and transporters
Drug interactions with target depend on two factors:
- Shape - this determines the ability of the drug to bind - ‘lock and key’ mechanism
- Charge distribution - this determines the type of bonds that holds the drug to the target
weakest ——–> strongest
van der Waals forces < hydrogen bonds < ionic interactions < covalent bonds
Define the terms agonist, antagonist and partial agonist
Agonist A ligand (a drug or an endogenous molecule e.g. neurotransmitter, hormone) that binds to a receptor to elicit a cellular response.
Antagonist
A drug which binds to a receptor and inhibits the receptor from responding to the endogenous ligand.
Partial agonist
Cannot evoke maximum response the system is capable of producing, even when occupying all the available receptors
Define the terms affinity, efficacy and potency
Affinity describes the strength with which a ligand binds to a receptor. A high affinity drug has a much greater tendency to bind to the receptor relative to its dissociation from the receptor
Kd = equilibrium dissociation constant = measure of affinity
Efficacy
= Emax = the maximum effect
the drug can elicit)
Potency = the concentration of drug needed to produce an effect
Pharmacodynamics is
the effect of a drug on the body
- Mechanism of action of drugs
- Targets for drug action
- How drugs act at the target
- How the drug produces an action within a cell - Influence of drug concentration on the magnitude of response
- Graphical representation of concentration-effect relationships
- Therapeutic versus toxic effects
Example of an agonist
e.g. epinephrine/adrenaline acts as an agonist at the β1 adrenoreceptor in the heart to increase cardiac output.
Example of an antagonist
e.g. bisoprolol acts as an antagonist at the β1 adrenoreceptor in the heart to decrease cardiac output
Receptors within a given family generally occur in several molecular varieties (subtypes)
They have similar structure but significant differences in their sequences, and often in their pharmacological properties
Identified either:
- On the basis of selectivity of agonists and/or antagonists
- Or by cloning techniques
explain the different receptor subtypes for adrenoceptors
a1 =
ag epin
anta doxazosin
b1 =
ag epin
anta bisoprolol
b2 =
ag salbutamol
anta = propranolol
Receptors in a family may occur in different subtypes - similar structure but differences in their sequences, and in pharmacological properties.
Identified either:
- On the basis of selectivity of agonists and/or antagonists
- Or by cloning techniques
explain the different receptor subtypes for adrenoceptors
a1 =
ag epin
anta doxazosin
b1 =
ag epin
anta bisoprolol
b2 =
ag salbutamol
anta = propranolol
Receptors subtypes elicit many different cellular effects due to:
- different specificities for what activates or inhibits them and
- different signal transduction mechanisms
- Receptor with bound agonist is activated
- The activated receptor has altered physical and chemical properties
- This leads to changes within the cell to cause a biological response
Based on different molecular structure and signal transduction mechanisms, 4 receptor types which respond to drugs: LEGI
- Ligand gated ion channels
- G-protein coupled receptors
- Enzyme (kinase) linked receptors
- Intracellular receptors
Based on different molecular structure and signal transduction mechanisms, 4 receptor types which respond to drugs: LEGI
- Ligand gated ion channels
- G-protein coupled receptors
- Enzyme (kinase) linked receptors
- Intracellular receptors
Ligand gated ion channels = ionotropic receptors
work by :
ligand binds to the receptor, and a channel nearby opens up to allow ions in.
then it may cause
hyperpolarisation
or depolarisation of the cell, and then cellular effects.
G-protein coupled receptors = metabotropic
work by :
GPCR’s have 7 transmembrane alpha helices, with a binding site.
interact with g proteins. all g proteins have 3 subunits. alpha beta and gamma. Specificity of response is achieved through molecular variation in α subunits -
α subunits variation gives rise to 3 main families of G-protein
Galpha-s, Galpha-i, Gq
alpha and gamma are attached by lipid anchors to the CSM.
inactive protein means it binds GDP to alpha subunit.
when ligand binds –> conformational change.
when it is activated Gs protein releases GDP and binds GTP.
alpha subunit of Gs protein dissociates and regulates target proteins/activates adenylylcyclase –> catalyze formation of cAMP from ATP. cAMP is a second messenger.
target protein can relay a signal.
when hormone or drug is no longer present the receptor reverts to its resting state. GTP on alpha subunit is hydrolyzed to GDP, and adenylyl cylase is deactivated
eg adrenoceptors are types of GPCRs.
Explain how in G-protein signal transduction there are different alpha subunit variations in the G protein which give different responses:
Galpha-s = stimulatory
Activates adenylyl cyclase Activates Ca2+ channels
Galpha-i =
inhibitory
Inhibits adenylyl cyclase
Activates K+ channels
Gq =
Activates phospholipase C
eg adrenoceptors are GPCR - explain mechanism
alpha 1 - Gq - activates PLC - vasoconstriction
alpha 2 - Gi - Inhibit
adenylyl cyclase
- Auto-inhibition of neurotransmitter release
beta 1 and 2 - Gs - Stimulate adenylyl cyclase - b1 Accelerated heart rate
- b2 Bronchodilation.
___________ is a b2 receptor agonist
SALBUTAMOL
___________ is a b1
receptor antagonist
Bisoprolol
enzyme linked receptors
work by :
extrcellular site can bind ligand. intracellular part can be an enzyme. eg receptor tyrosine kinases. protein phosphorylation –> gene transcription –> protein synthesis –> cellular effect
intracellular receptors
work by :
receptor in the nucleus. ligand enters and binds to the receptor. affects gene transcription. protein synthesis. cellular effects.
Dr A knelt on a bee and was stung on the knee. She took ibuprofen tablets to counteract the pain and inflammation of the sting. What type of target protein is the ibuprofen acting on?
Receptor
Enzyme
Ion channel
Transporter
B
What dose of aspirin is required to relieve a headache?
25-50mg
300-600mg
5-10g
B
Drug dose and response pathway:
agonist –> receptor –> agonist receptor complex –> action –> effect.
eg. salbutamol –> binds to adrenoceptor b2 –> salbutamol-b2 adrenoceptor complex –> increased cAMP –> bronchodilation
Graded dose response curves help to measure ____________
dose-response relationships .
The response of a particular system (individual patient, animal or isolated tissue) measured against agonist concentration
e.g. increasing bronchodilation in a rabbit trachea preparation in response to increasing doses of salbutamol
Graded dose-response curve
are plotted a ______________
Concentration-effect curve : agonist concentration (log scale) VS maximal effect %
Semi-logarithmic plot of agonist concentration against effect/response
Graded dose-response curve - log axis used is base ________
Base 10 logarithms (log10) are used for dose response curves
There is a 10 fold increase from one unit to the next
Why plot dose response curves?
To determine EFFICACY - Emax
POTENCY - EC50
Efficacy is -
the maximum effect
the drug can elicit
Potency is -
the concentration of drug needed to produce an effect
Potency – measure of the end effect, not just receptor binding
Although binding can be measured directly, it is usually a biological response, such as a rise in blood pressure, contraction or relaxation of a strip of smooth muscle in an organ bath, the activation of an enzyme, or a behavioural response, that we are interested in, and this is often plotted as aconcentration-effect curve(in vitro) or dose-response curve(in vivo)
Affinity is -
the strength with which a ligand binds to a receptor
A high affinity drug has a much greater tendency to bind to the receptor relative to its dissociation from the receptor.
Affinity is measured by Kd. explain Kd.
Kd = equilibrium dissociation constant. it is the concentration of ligand at which 50% of the available receptors are occupied
Kd is an intrinsic property of any drug-receptor pair
There is an inverse relationship between Kd and affinity
The ________ the Kd value the more easily the agonist binds to the receptor = greater affinity.
lower
the lower the Kd value (on concentration/x axis) the greater the affinity
The effect an agonist produces depends on: 1. the drug binding
2. the drug-bound receptor then producing a biological response.
It is measured by ___________
EC50 = concentration of ligand which produces 50% of the maximal biological effect of that system
EC50 is a measure of potency (based on the actual effect, not just the binding).
Potency is the __________ of a drug that is needed to produce a given effect
AMOUNT
**Potency depends on 4 factors:
Potency = amount of drug needed to produce a desired effect.
Potency dependent on:
1. Affinity = strength of binding = Kd
- Efficacy = activation = Emax, Ec50(=potency), full/partial agonist
- The number of receptors
- Efficiency of stimulus-response mechanisms used.
**Potency depends on 4 factors:
Potency = amount of drug needed to produce a desired effect.
Potency dependent on:
1. Affinity = strength of binding = Kd
- Efficacy = activation = Emax, Ec50(=potency), agonist/antagonist
- The number of receptors
- Efficiency of stimulus-response mechanisms used.
General rules
Agonists with high potency tend to have high affinity
The lower the Kd value the greater the affinity
The lower the EC50 value the greater the potency.
Efficacy is __________.
how does it work? explain the agonist-receptor complex and its 2 states.
Refers to the maximum effect an agonist can produce regardless of dose
When an agonist binds to a receptor, this induces a conformational change that sets off a chain of biochemical events - an ‘action’.
The agonist-receptor complex can exist in 2 states:
- AR = unactivated AR complex (no conformational change)
- AR* = activated receptor (i.e. has undergone conformational change)
OCCUPATION d/b AFFINITY
ACTIVATION d/b EFFICACY
-
There are two types of agonist, d/o EFFICACY
- Full agonist
- AR* very likely
(high efficacy)
Can produce a maximum response while occupying only a small % of receptors available
- AR* very likely
- Partial agonist
– AR* less likely
Cannot evoke maximum response the system is capable of producing, even when occupying all the available receptors
SUMMARY
The shape of the drug/receptor is a major determinant of interaction
There are four main targets of drug action Receptors Ion channels Enzymes Carriers
The four major receptor subtypes are:
- Ligand gated ion channel
- G-protein
- Enzyme linked receptor
- Intracellular receptor
The affinity of an agonist is the likelihood that it will bind to and form a stable complex with the receptor
Potency of different agonists can be compared by assessing the EC50 values – the lower the EC50 value the higher the potency
Efficacy describes the ability of an agonist, once bound, to activate the receptor
Full agonists have high efficacy and can produce a maximal response in the system
Partial agonists have lower efficacy and can not produce a maximal response in the system
