Pharmacodynamics and Drug Tolerance Flashcards
What is pharmacodynamics?
The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors responsible for their ultimate drug effects.
Define ligand
any molecule that binds to a receptor
What is a drug?
exogenous ligand
Give some examples of endogenous ligands
Neurotransmitters, hormones, peptides
What is a receptor?
protein molecule on cell surface or within the cell that is the initial site of action of a biological agent (neurotransmitters, hormones, peptides, drugs)
What are the 3 criteria a receptor must meet?
1.Saturability
2.Specificity
3.Reversibility
What does saturability mean?
*Finite receptors per cell
*Dose-response should reveal saturability
What does specificity mean?
High binding affinity to elicit a biological response
What does reversibility mean?
*Binding to receptors should be reversible
*Ligand should be dissociable and recoverable
*Distinguishes receptor-ligand interactions from enzyme-substrate interactions
What are extracellular receptors?
Extracellular receptors are localized to the cell surface and bind water-soluble ligands (e.g. neurotransmitters).
What are intracellular receptors?
Receptors that bind lipid-soluble ligands within the cell (e.g. steroid hormone receptors)
What differentiates extracellular receptors from other receptor types?
*Common target for psychoactive drugs
*Accessible to water-soluble drugs
*Different signalling based on function of the receptor
What are ligand-gated ion channels?
*Postsynaptic neurotransmitter receptors
What are GPCR?
*Metabotropic receptors
*Intracellular second messenger
What are receptor kinases?
*Common for cytokine, peptide hormone receptors (e.g. Insulin)
What differentiates intracellular receptors from other receptor types?
*Common target for steroid hormones and lipophilic compounds (and some drugs)
includes:
*Glucocorticoids (stress hormones)
*Androgen/estrogens (sex hormones)
*Endocannabinoids (intracellular GPCR)
*Located in cytoplasm
What are hormone receptors?
*Translocate to nucleus on hormone binding
*Function as transcription factors
*Directly induce changes in gene expression by binding to specific response element
Describe receptor-ligand interactions
*Specific recognition of ligand is key to receptor function
*Agonist interactions are those that elicit a biological effect on the receptor
*Antagonist interactions are those preventing or blocking a biological effect
Describe agonist function
*Agonist activity at a receptor can be measured by examining the dose-response.
*With increasing concentration of agonist, the biological response is greater.
*Dose-response tends to follow a characteristic sigmoidal shape (S-curve).
*Potency - ED50 is the dose required to elicit a half-maximal effect.
*Comparable curve-shape of dose-response plots is suggestive of conserved mechanisms.
*While ED50 shows differing potency, all three opioids have the same efficacy.
*Aspirin differs in both potency and efficacy.
Describe therapeutic index
*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
*TI = TD50 / ED50
What does antagonism mean?
*In contrast to agonists, antagonists can be reversible or irreversible
*Reversible antagonists can be displaced by the endogenous agonist
- Three types: competitive, noncompetitive and irreversible
Describe the relationship between potency and efficacy in competitive antagonism
*Reduced agonist potency but not efficacy
What is noncompetitive antagonism?
*Non-competitive antagonists cannot be displaced by agonists
*Reduce drug efficacy and sometimes potency
What is irreversible antagonism?
*Binds irreversibly to the same binding site as an endogenous ligand
Describe allosteric modulators
*Binds to a different site on the receptor than the endogenous ligand
*Affects receptor function through other conformational effects on the protein
What are the 2 types of pharmacological agonists?
Partial and inverse
Describe partial agonists
*Binds same site as endogenous ligand but elicit a less than maximal response
*Can decrease efficacy of the endogenous agonist
Describe inverse agonists
*Binds receptor with constitutive activity
*Has opposite effect to full agonist
*Long term effects of drug use
Describe tolerance
*Diminished effect of a given dose of drug over time
*Reversible
*Dependent on frequency and dose
*Varies with different drugs
*Can be limited to specific drug effects
*Multiple mechanisms
*Cross-tolerance can cause drug interactions
Describe sensitization
*Enhancement of a particular drug effect on repeated exposure
*Prior exposure to cocaine increases repetitive and hyperactive behaviours in animals (head bobbing)
*Less common than tolerance
*Cross-sensitization occurs between drugs acting on the same receptor (e.g. cocaine and amphetamines)
What are the forms of tolerance?
Metabolic, pharmacodynamic and behavioural
What is metabolic tolerance?
Also known as drug disposition tolerance
*Increased metabolism through enzyme induction
*Decreased bioavailability of drug
What is pharmacodynamic tolerance?
*Changes in nerve cell function in response to drug
*Receptor down-regulation results in saturation and diminished effect
What is behavioural tolerance?
*Context-specific tolerance
*Involves learning and memory
*Demonstrated by tolerance in familiar but not novel environments
*Habituation
*First administration causes greater alteration of normal behaviour
*Diminished with subsequent administrations
*Conditioning
*Environment or paraphernalia act as a conditioned stimulus to initiate response
*Behavioural tolerance can be readily demonstrated in humans and in animal models. Administration of drug in a conditioned environment can elicit a different physiological response than in a novel environment.
Describe drug dependence
*Drug tolerance can occur rapidly and transiently (e.g. cocaine) or slowly and persistently (e.g. alcohol)
*Balance of factors differs for different drugs
*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
*Most significantly influenced by pharmacodynamic mechanisms
*Dependence is the requirement for drug use in order to maintain ‘normal function’ after the development of drug tolerance
How does dependence develop?
*Classic model of dependence and tolerance to opiates developed by Himmelsbachin 1943
*Tolerance to opiates is proposed to develop as a result of compensatory mechanisms to restore homeostasis
*Acute administration disrupts homeostasis
*Repeated administration initiates adaptive mechanisms that compensate to restore homeostasis
*Tolerance is the result of compensatory mechanisms
*Withdrawal of administration results in compensatory disturbance in homeostasis
How has drug dependence been demonstrated in the past?
*In vitro studies demonstrate the cellular effects of morphine
*Acute morphine treatment decreased cellular cAMP
*With chronic exposure (48 h) cAMP levels normalized to restore homeostasis
*Steady-state cAMP levels were maintained in the presence of morphine
*Withdrawal of morphine resulted in a dramatic rebound well above normal
How are addictions defined?
*Classifications (DSM, ICD) use dependence as the key descriptor of addictions
*DSM – Substance abuse disorders
*Dependence is based on physiological drug response
*Confusion arises in distinguishing medically ‘normal’ (e.g. pain management with opioids) and
problematic dependence
*Addiction may be better defined as compulsive drug-seeking behaviour
*Fits the idea of substance/behavioural addictions as impulse control disorders
*Confounded by societal norms and stigmatization
*“Addiction is a medical/psychiatric disorder [that] results from voluntarynorm-violating behaviours and thus is subject to moral judgement regardless of [terminology]” – Vanyukov et al 2012
Describe intoxication
*Clinically significant problematic behavioural and psychological changes associated with substance intake
*Result of physiological effects of substance on CNS
*Commonly disturbances of:
*Perception
*Wakefulness
*Attention
*Thinking
*Judgement
*Psychomotor behaviour
*Interpersonal behaviour
*Differences in acute/chronic intoxication
Describe withdrawal
*Substance-specific problematic behavioural change resulting from discontinuation of use
*Physiological and cognitive changes
*Clinically significant distress or impairment (social, occupational)
*Often associated with urge to re-administer to reduce symptoms
Describe the gateway hypothesis
*Proposed by Kandel, 1975
*Progressive and hierarchical staging of drug use
*Licit (alcohol, tobacco)
*‘Soft’ illicit (cannabis)
*‘Hard’ illicit (cocaine, heroin)
*“[t]he use of a drug of a lower stage is necessary but not sufficient for progression to a higher stage” – Kandeland Yamaguchi 2002
*“association implies causation if all possibilities for spurious associations have been eliminated”, while “the difficulties of establishing true causality in the social sciences” requires “the term association rather than causation [to be] emphasized” – Kandel 2002
Describe common liability
*Drug use initiation is necessary but not sufficient for development of a substance-use disorder
*Initiation does not account for risk of addictive behaviour
*Disinhibition (predisposition to impulsivity, hyperactivity, antisociality) is a predictive risk of substance-use (regardless of the substance)
*High correlation of genetic risks for various substances
*Common neurobiology of multiple substances
*Explains conserved risks for development of non-substance addictions
