Pharmacodynamics and Drug Tolerance

Question 1

What is pharmacodynamics?

Answer 1

The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors responsible for their ultimate drug effects.

Question 2

Define ligand

Answer 2

any molecule that binds to a receptor

Question 3

What is a drug?

Answer 3

exogenous ligand

Question 4

Give some examples of endogenous ligands

Answer 4

Neurotransmitters, hormones, peptides

Question 5

What is a receptor?

Answer 5

protein molecule on cell surface or within the cell that is the initial site of action of a biological agent (neurotransmitters, hormones, peptides, drugs)

Question 6

What are the 3 criteria a receptor must meet?

Answer 6

1.Saturability
2.Specificity
3.Reversibility

Question 7

What does saturability mean?

Answer 7

*Finite receptors per cell
*Dose-response should reveal saturability

Question 8

What does specificity mean?

Answer 8

High binding affinity to elicit a biological response

Question 9

What does reversibility mean?

Answer 9

*Binding to receptors should be reversible
*Ligand should be dissociable and recoverable
*Distinguishes receptor-ligand interactions from enzyme-substrate interactions

Question 10

What are extracellular receptors?

Answer 10

Extracellular receptors are localized to the cell surface and bind water-soluble ligands (e.g. neurotransmitters).

Question 11

What are intracellular receptors?

Answer 11

Receptors that bind lipid-soluble ligands within the cell (e.g. steroid hormone receptors)

Question 12

What differentiates extracellular receptors from other receptor types?

Answer 12

*Common target for psychoactive drugs
*Accessible to water-soluble drugs
*Different signalling based on function of the receptor

Question 13

What are ligand-gated ion channels?

Answer 13

*Postsynaptic neurotransmitter receptors

Question 14

What are GPCR?

Answer 14

*Metabotropic receptors
*Intracellular second messenger

Question 15

What are receptor kinases?

Answer 15

*Common for cytokine, peptide hormone receptors (e.g. Insulin)

Question 16

What differentiates intracellular receptors from other receptor types?

Answer 16

*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

Question 17

What are hormone receptors?

Answer 17

*Translocate to nucleus on hormone binding

*Function as transcription factors

*Directly induce changes in gene expression by binding to specific response element

Question 18

Describe receptor-ligand interactions

Answer 18

*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

Question 19

Describe agonist function

Answer 19

*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.

Question 20

Describe therapeutic index

Answer 20

*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

Question 21

What does antagonism mean?

Answer 21

*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

Question 22

Describe the relationship between potency and efficacy in competitive antagonism

Answer 22

*Reduced agonist potency but not efficacy

Question 23

What is noncompetitive antagonism?

Answer 23

*Non-competitive antagonists cannot be displaced by agonists
*Reduce drug efficacy and sometimes potency

Question 24

What is irreversible antagonism?

Answer 24

*Binds irreversibly to the same binding site as an endogenous ligand

Question 25

Describe allosteric modulators

Answer 25

*Binds to a different site on the receptor than the endogenous ligand *Affects receptor function through other conformational effects on the protein

Question 26

What are the 2 types of pharmacological agonists?

Answer 26

Partial and inverse

Question 27

Describe partial agonists

Answer 27

*Binds same site as endogenous ligand but elicit a less than maximal response *Can decrease efficacy of the endogenous agonist

Question 28

Describe inverse agonists

Answer 28

*Binds receptor with constitutive activity *Has opposite effect to full agonist *Long term effects of drug use

Question 29

Describe tolerance

Answer 29

*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

Question 30

Describe sensitization

Answer 30

*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)

Question 31

What are the forms of tolerance?

Answer 31

Metabolic, pharmacodynamic and behavioural

Question 32

What is metabolic tolerance?

Answer 32

Also known as drug disposition tolerance *Increased metabolism through enzyme induction *Decreased bioavailability of drug

Question 33

What is pharmacodynamic tolerance?

Answer 33

*Changes in nerve cell function in response to drug *Receptor down-regulation results in saturation and diminished effect

Question 34

What is behavioural tolerance?

Answer 34

*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.

Question 35

Describe drug dependence

Answer 35

*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

Question 36

How does dependence develop?

Answer 36

*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

Question 37

How has drug dependence been demonstrated in the past?

Answer 37

*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

Question 38

How are addictions defined?

Answer 38

*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

Question 39

Describe intoxication

Answer 39

*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

Question 40

Describe withdrawal

Answer 40

*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

Question 41

Describe the gateway hypothesis

Answer 41

*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

Question 42

Describe common liability

Answer 42

*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