Chapter 3, Chemical Signalling by Neurotransmitters and Hormones Flashcards
Drug Action
Specific molecular changes produced when a drug binds to a particular target site or receptor
Drug Effects
Alterations in physiological or psychological functions
* Therapeutic effects vs. side effects
* Specific drug effects vs. non-specific drug effects
Neurotransmission
- Drugs do not create a unique or novel effect… they merely modulate neuronal function by enhancing or inhibiting the actions of a specific neurotransmitter
Drugs can affect any stage
of neurotransmission!
Receptor Specificity
- Binding affinity depends on the strength and number of noncovalent bonds between the drug and its target
- Drugs with high affinity will occupy more receptors at any given concentration than drugs with a low affinity
- Different drugs can bind the same target site, but with varying binding affinities
- E.g., Competition between naloxone and fentanyl
Receptors
Proteins on cell surfaces or within cells
Ligand
Molecule that binds to a receptor with some selectivity
* Receptors have specificity for ligands, due to their molecular shape
* ”Lock and key” mechanism
Types of Receptors
A. Extracellular receptor *
B. Intracellular receptor
- Recall: ionotropic vs. metabotropic receptors
- Example: Nicotinic receptors vs. muscarinic receptors
Receptor Action
- Ligand–receptor binding is temporary
- Ligand binding causes change in receptor shape that initiates a series of events in the cell, ultimately causing a Biobehavioral effect
Receptor Specificity and the Agonists v. Antagonists
- Agonists have the highest affinity and produce significant biological effects
- Antagonists have lower affinity and little or no efficacy
Specificity with Agonists
- Full agonists
- Partial agonists have intermediate efficacy
- Inverse agonists initiate a biological action that is opposite to that produced by an agonist
Specificity with Antagonists
- Competitive antagonists: Drugs that compete with agonists to bind receptors but do not initiate intracellular effects, reducing the effect of the agonist
- Noncompetitive antagonists bind to the receptor at a site other than the agonist binding site
- Physiological antagonism: Two drugs interact and reduce the
effectiveness of both
Receptor Binding Sites
- The GABAA receptor has multiple binding sites, which means
drugs can interact to have enhanced effects on GABA - Allosteric modulators only modify the effects of an agonist;
they have no effects when given alone
Summary for Agonists and Antagonists
- Agonists bind to receptors to produce a functional response.
- Agonists can be full, partial, or inverse agonists
- Antagonists block or reverse the effects of agonists.
- Antagonists can be competitive or noncompetitive
- Physiological antagonists bind to different sites
Receptor Subtypes
- All neurotransmitters have a number of receptors that they can act on
- Receptors may have different characteristics
- Receptors can be distributed in different tissues
Receptor Action
- Receptors have a life cycle and may be modified in a number and/or sensitivity with long-term receptor action
- Changes in receptor number take days-weeks, while changes in receptor sensitivity can be much faster
Dose-Response Relationships
- The drug effect will depend on receptor occupancy
- We assume that increased drug doses will result in increased receptor occupancy, thus causing an increased response
Dose-Response Curves
- To determine the effect of a drug, we have to study several doses and measure the change in response
- The relationship between dose and response is called the dose-response curve (DRC)
Features of the dose-response curve
- Potency: Describes the amount of the drug required to produce a given effect.
- Efficacy: Describes the extent to which a drug can produce a desired effect.
- Slope: Describes how a change in a drug’s dose relates to a change in the drug’s effect.
- Variability: Individual differences in response to a given drug dose.
- Dose-response curves are based on averages
- Individual variation in response to drug effectiveness could be
caused by a number of things
Potency
Potency refers to how well drug molecules attach to their sites of action (receptors)
* More potent drugs usually bind more tightly than less potent drugs
Efficacy
Efficacy refers to the maximum possible effect of a drug, regardless of further increases in dose
* Most drugs are not used at doses that elicit their maximal effect because of toxicity an other unwanted side effects
Agonists in the Dose-Response Curve
- Full agonists
- Partial agonists have intermediate efficacy
- Inverse agonists initiate a biological action that is opposite to that produced by an agonist
Important terms in the dose-response curve
- Maximum effect (Emax)
- Threshold dose
- Effective dose (ED50)
- Toxic dose (TD50 )
(not shown)
Describe drugs X, Y, and Z in terms of their relative potency and efficacy
* NB: When comparing drugs, maximal efficacy is usually a more important criterion to consider than potency
Effective Dose (ED)
- Comparing ED50 of different drugs shows differences in
potency - For the same effect you need: 2mg hydromorphone, 10mg morphine, more than
100mg codeine
The optimum condition for a drug
Drugs have both desirable effects and adverse side effects
* The optimum condition is to have a drug that is effective at a low dose
with no toxicity except at very high doses
Therapeutic Index Formula
- Therapeutic index (TI) = TD50 / ED50
- The greater the TI, the safer the drug
- The lower the ED50, the greater the potency, but the lower the TI, the lower the safety
- LD = lethal dose (seldom used)
- If two drugs produce a therapeutic effect that is desirable, the better drug (all things being equal) would be the one with the larger TI
The attributes of the ideal drug
- easy to administer,
- fully absorbed,
- spontaneously eliminated,
- highly selective and
- specific, and
- of high affinity,
- potency, and
- efficacy
- useful duration of action,
- high therapeutic index (no adverse effects), and
- no interactions…
However, there are no examples of
synthetic or natural drugs that satisfy all these criteria ”
Combining drugs and competitive drugs
- Competitive antagonists may be used to replace an excess of agonist
- E.g. Naloxone is a competitive antagonist of morphine
- Note change in curve placement with pretreatment
Combining drugs and noncompetitive drugs
Noncompetitive antagonists are less effective at protecting against an excess of agonist
* Note the change in the shape of the curve
Physiological antagonism in combining drugs
Two drugs may interact and reduce the effectiveness of both
Additive effects of combining drugs
two drugs may interact and enhance the effectiveness of both
Potentiation of combining drugs
two drugs may interact and enhance the effectiveness of both to produce effects greater than the sum of their individual effects
Repeated drug use
- Recall: The effect of a drug is proportional to its concentration
at its site of action, increasing with increasing dose. - A reduced drug response can manifest due to tolerance
Tolerance
diminished response to a drug after repeated exposure
* acute tolerance
* cross tolerance
Types of tolerance
- Metabolic (drug disposition) tolerance
- Pharmacodynamic tolerance
- Behavioural (learned) tolerance
Metabolic tolerance
- AKA drug disposition tolerance or pharmacokinetic tolerance
- Drugs increase their own rate of metabolism by liver microsomal enzyme induction
Pharmacodynamic tolerance
- Neural function changes to adapt to continued presence of the drug by up- or down-regulation
Behavioural tolerance
- Occurs in the same environment in which the drug was administered
- Behavioural (learned) tolerance may involve
- Pavlovian, or classical conditioning: the drug-taking procedure and/or the environment may elicit a conditioned response. It involves an individual learning to maneuver efficiently while intoxicated. Or tasks learned under the influence of a psychoactive drug may then be performed better in the drugged state
Drugs and developing tolerance
- Some drugs can cause all three kinds of tolerance, other drugs can have a tolerance to some of their effects but not others, and still other drugs do not cause tolerance at all
Physical dependence
A physiological state in which the body adapts to the chronic presence of a drug
* Withdrawal symptoms appear if the drug is abruptly stopped
Sensitization
- reverse tolerance
- Cross-sensitization
- Unlike tolerance, sensitization is
not easily reversible
Dependence and sensitization
A drug may cause either or both dependence and sensitization
*Example: Chronic exposure to psychostimulants can lead to tolerance, but sensitization or reverse tolerance, is also seen…
Pharmacogenetics
- Pharmacogenetics: Study of the genetic basis for variability in drug response among individuals.
- Goal: Identify genetic factors that confer susceptibility to specific side effects, or predict a therapeutic response.
- Pharmacoepigenetics takes into account the role of epigenetic modifications that can alter gene function and arise from environmental and behavioral factors
Personalized Medicine
Adjusting drug dose based on genotype
* Predicting how patients will respond to a medication before treatment begins would avoid the current costly and time-consuming method of trial and error
Affinity in agonists and antagonists
- Agonists have the highest affinity and produce significant biological effects
- Antagonists have lower affinity and low efficacy
potency and efficiency in graphs
potency is right to left
efficiency is down to up
competitive and noncompetitive antagonism in graphs
competitive is different starting points
non-competitive has the same starting points
Semi-log plot
- The semi-log plot is the preferred method for plotting dose-response relationships because it becomes easier to accurately determine the EC50 value (the concentration which produces 50% of the maximum response)
