L7 Intro to drug action Flashcards
Describe a receptor
Receptors are specific, complex proteins. Hormones act only on target cells
What is pharmacology?
the study of the effects of drugs on the function of living systems
Drug Effects Result From Interaction Between ___ And (components of) the ____
Drug
Organism
Pharmacokinetics describes the fate of a drug
ADME
What the body does to the drug
Pharmacodynamics is the study and measurement of drug effects
What drug does to body
Fundamental concepts in drug action (FCDA)
A drug will not work unless it is ____
A drug will not work unless it is bound
4 protein targets
- Receptors
- Enzymes
- Carrier molecules
- Ion channels
Receptors as protein targets
- Proteins that allow a chemical agent (drugs,
hormones, neurotransmitters) to initiate a change
in cell function - Receptors are the cell’s ‘sensing elements’
- Receptors provide molecular communication between chemical agent and transduction process
(FCDA) Most drugs cause their effects via ___
Most drugs cause their effects via receptors
(FCDA) Different cell types have different___ ____
Different cell types have different receptor profiles
Acetylcholine example
High densities of muscarinic acetylcholine receptors respond to substances that act on muscarinic acetylcholine receptors
Noradrenaline
High densities of alpha-adrenoceptors respond to substances that act on alpha-adrenoceptors e.g., noradrenaline
On vascular smooth cells to cause them to contract
Different cell types express different types and ___ of receptor. This determines the___ and___ to which the cell responds
densities
hormones
neurotransmitters
FDCA: Drugs can mimic or ____ the actions of___ substances
Block
endogenous
Agonist and antagonist are
ligands
Ligand
Any molecule that bonds specifically to a receptor site of another molecule.
Agonist and antagonist interact with endogeneous ligands how
Agonist mimic the action of ligand
Antagonist block action of ligand
FDCA: “Receptors show ligand____”
selectivity
Receptor ligand selectivity
- Each receptor type is activated by a small number of substances
- Receptor activation requires a good 3-D “fit” between agonist and receptor
(paracetamol doesn’t fit a vascular smooth muscle cell but phenylephrine does)
– each drug activates a certain receptor type
endogenous ligand/agonist (noradrenaline) binds to receptor (alpha-adrenoceptor) causing a change in cell function (vascular smooth muscle cell contracts). What if there is an antagonist
Will block the binding of the ligand to receptor
FCDA: ___ drugs show selectivity
Useful
Selectivity is reciprocal - what does that mean
– each drug only binds to certain receptors
– each receptor recognises only certain drugs
Phenylephrine
– binds to a-adrenoceptors in vascular smooth muscle cells – relieves nasal congestion
– binds only weakly to other receptor types
- fewer adverse effects
cardiac cell:
adrenaline → b-adrenoceptor → increased___
contractility
How most drugs cause their effects via receptors
Chemical agent → receptor → (in cell) signal transduction → change in cell functions
FDCA:___ is not absolute
Selectivity
Selectivity is not absolute means
- Most drugs act on more than one receptor
- Increasing dose activates other receptors
–– adverse effects
Diphenhydramine
Antagonist and prevents histamine binding
- can act on more than 1 receptor
Diphenhydramine in vascular smooth muscle cells
Antagonist and prevents histamine binding
decongestant
Diphenhydramine in salivary gland cell
antagonist of muscarinic acetylcholine receptors
dry mouth
Drug-induced responses
- Drugs act by binding to specific drug targets
- Agonists bind to and activate receptors
FDCA: “Agonist or antagonist (?) bind to and activate receptors”
Agonist
activate
Transducers
the portion of a sensory neuron that is responsible for converting a sensory stimulus into an electrical signal
Agonist binding to receptors
- need intermolecular forces between agonist and receptors
- Reversible
Strong attraction forces (k+1 > k-1) → high affinity for receptor
Week attraction forces (k+1 < k-1) → low affinity for receptor
Agonist activating receptors
- Bound agonist induces a conformational change in the structure of the receptor → it binds to and stimulates transducers
- Bound agonist induces high degree of receptor activation → agonist has high efficacy
- Bound agonist induces low degree of receptor activation → agonist has low efficacy
Agonist affinity and efficacy
Ability of an agonist to induce a response depends on two agonist- dependent, graded properties
- affinity and efficacy
Ability of an agonist to induce a response depends on
two
- agonist- dependent,
- graded properties
Affinity
Tendency of agonist to bind to receptors
Efficacy
Ability of agonist receptor complex to initiate a change in cell function
Agonist-induced response example asthma
Asthmatic takes salbutamol
– relaxes airway smooth muscle
– eases breathing
Salbutamol + beta 2 adrenoceptor + adenylate cyclase → relaxation of air way smooth muscle
AC is tranducer
FDCA: Drug dose is related to___ occupancy and effect
receptor
Positive relationship between drug dose and
– number of receptors occupied
– effect produced
With increasing concentrations of the agonist
– more receptors are bound and activated
– response is increased
Organ bath
a chamber in which isolated organs or tissues can be administered with drugs, or stimulated electrically, in order to measure their function
Concentration-response curves has
- Measure size of response at each agonist concentration
Plot concentration-response data as Log dose (x-axis) vs Response (y-axis)
– log-linear or semi-log graph
– sigmoidal shape, exhibits saturation, maximum effect is Emax
Agonist potency
- Concentration required to produce 50% of maximal agonist response (EC50)
- The lower the EC50, the more potent the agonist
- Potency depends on affinity and efficacy and tissue-dependent parameters (e.g., receptor density)
EC50
Concentration of drug that produces 50% of maximal response
ED50
The effective dose of a chemical that causes 50 percent of the individuals in a dose-response study to display a harmful, but nonlethal, effect
Partial agonists
- Partial agonists produce submaximal responses
– low efficacy
– low level activation
a drug that binds to a receptor and causes a response that is less than that caused by a full agonist
Agonists with low efficacy
An agonist with low efficacy may act as a
– partial agonist
- partial agonist causes < maximum response
Antagonist
- tissue exposed to both low and high efficacy agonists
- competition for receptor
- full agonist binding inhibited
Receptor antagonists
1. afinity and efficacy
2. what do they do
Antagonists bind to, but do not activate receptors
– have affinity, but no efficacy
- Since antagonists bind to the receptor, they compete with the agonist for the receptor
- Antagonists inhibit agonist-induced responses
Surmountable antagonists
- Bind reversibly to the receptor
- Agonist concentration-response curves shifted
-– no change in slope or maximum response - Size of the shift is proportional to the
-– antagonist concentration
-– affinity of the antagonist
Insurmountable antagonists
- Bind irreversibly to the receptor
-– reduces number of receptors the agonist can occupy - Reduce the maximum response and slope of agonist concentration-response curve
- The higher the antagonist concentration, the larger the response
