Pharmacodynamics Flashcards
Pharmacodynamics
The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors responsible for their ultimate drug effects.
Ligand
any molecule that binds to a receptor
Drug
exogenous ligand
Neurotransmitters, hormones, peptides
endogenous ligands
Receptor
protein molecule on cell surface or within the cell that is the initial site of action of a biological agent
receptor examples
neurotransmitters, hormones, peptides, drugs
Extracellular receptors
are localized to the cell surface and bind water-soluble ligands (e.g. neurotransmitters)
intracellular receptors
bind lipid-soluble ligands within the cell (e.g. steroid hormone receptors)
extracellular receptor types are common targets for
psychoactive drugs
Ligand-gated ion channels
Postsynaptic neurotransmitter receptors
G-protein coupled receptors (GPCR)
Metabotropic receptors
Intracellular second messenger
Receptor kinases
Common for cytokine, peptide hormone receptors (e.g. Insulin)
intracellular receptor types are common targets for
steroid hormones and lipophilic compounds (and some drugs)
intracellular chemicals
Glucocorticoids (stress hormones)
Androgen/estrogens (sex hormones)
Endocannabinoids (intracellular GPCR)
Intracellular receptors are located
in cytoplasm
Hormone receptors
Translocate to nucleus on hormone binding
Function as transcription factors
Directly induce changes in gene expression by binding to specific response element
Agonist
interactions are those that elicit a biological effect on the receptor
Antagonist
interactions are those preventing or blocking a biological effect
dose-response
With increasing concentration of agonist, the biological response is greater.
Potency
ED50 is the dose required to elicit a half-maximal effect.
TD50
is a measure of the potency of a drug at eliciting a toxic response.
LD50
measures the potency at eliciting a lethal effect.
Therapeutic index
reflects the margin of safety between drug efficacy and adverse effects
therapeutic index calculation
TI = TD50 / ED50
In contrast to agonists, antagonists can be
be reversible or irreversible
Reversible antagonists can be displaced by the
endogenous agonist
Competitive antagonism
Reduces agonist potency but not efficacy
Non-competitive antagonists cannot be
displaced by agonists
Irreversible antagonists
Binds irreversibly to the same binding site as an endogenous ligand
Non-competitive antagonists Reduce drug
efficacy and sometimes potency
Allosteric modulators
Binds to a different site on the receptor than the endogenous ligand
Allosteric modulators Affects receptor
function through other conformational effects on the protein
Partial agonists
Binds same site as endogenous ligand but elicit a less than maximal response
Partial agonists Can
decrease efficacy of the endogenous agonist
Inverse agonists
Binds receptor with constitutive activity
Has opposite effect to full agonist
Tolerance
Diminished effect of a given dose of drug over time
Cross-tolerance
can cause drug interactions
Sensitization
Enhancement of a particular drug effect on repeated exposure
Cross-sensitization
occurs between drugs acting on the same receptor (e.g. cocaine and amphetamines)
Metabolic tolerance
Increased metabolism through enzyme induction
Decreased bioavailability of drug
Pharmacodynamic tolerance
Changes in nerve cell function in response to drug
Receptor down-regulation results in saturation and diminished effect
Behavioral tolerance
Context-specific tolerance
Habituation
First administration causes greater alteration of normal behaviour
Conditioning
Environment or paraphernalia act as a conditioned stimulus to initiate response
Persistence of tolerance influenced heavily by
metabolic and pharmacodynamic mechanisms
Drug dependence results from
tolerance mechanisms and is considered a key component contributing to drug addictions
Dependence is the
requirement for drug use in order to maintain ‘normal function’ after the development of drug tolerance
Tolerance to opiates is proposed to develop as a result of
compensatory mechanisms to restore homeostasis
Dependence =
withrawals
Classifications (DSM, ICD) use
dependence as the key descriptor of addictions
Addiction may be better defined as
compulsive drug-seeking behaviour
substance/behavioural addictions as
impulse control disorders
Intoxication
Clinically significant problematic behavioural and psychological changes associated with substance intake
Withdrawal
Substance-specific problematic behavioural change resulting from discontinuation of use
Gateway Hypothesis
he use of a drug of a lower stage is necessary but not sufficient for progression to a higher stage
