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Psych 478 > Pharmacodynamics and Drug Tolerance > Flashcards

Pharmacodynamics and Drug Tolerance Flashcards

1
Q

What is pharmacodynamics?

A

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

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2
Q

Define ligand

A

any molecule that binds to a receptor

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3
Q

What is a drug?

A

exogenous ligand

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4
Q

Give some examples of endogenous ligands

A

Neurotransmitters, hormones, peptides

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5
Q

What is a receptor?

A

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

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6
Q

What are the 3 criteria a receptor must meet?

A

1.Saturability
2.Specificity
3.Reversibility

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7
Q

What does saturability mean?

A

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

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8
Q

What does specificity mean?

A

High binding affinity to elicit a biological response

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9
Q

What does reversibility mean?

A

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

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10
Q

What are extracellular receptors?

A

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

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11
Q

What are intracellular receptors?

A

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

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12
Q

What differentiates extracellular receptors from other receptor types?

A

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

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13
Q

What are ligand-gated ion channels?

A

*Postsynaptic neurotransmitter receptors

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14
Q

What are GPCR?

A

*Metabotropic receptors
*Intracellular second messenger

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15
Q

What are receptor kinases?

A

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

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16
Q

What differentiates intracellular receptors from other receptor types?

A

*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

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17
Q

What are hormone receptors?

A

*Translocate to nucleus on hormone binding

*Function as transcription factors

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

18
Q

Describe receptor-ligand interactions

A

*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

19
Q

Describe agonist function

A

*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.

20
Q

Describe therapeutic index

A

*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

21
Q

What does antagonism mean?

A

*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
22
Q

Describe the relationship between potency and efficacy in competitive antagonism

A

*Reduced agonist potency but not efficacy

23
Q

What is noncompetitive antagonism?

A

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

24
Q

What is irreversible antagonism?

A

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

25
Q

Describe allosteric modulators

A

*Binds to a different site on the receptor than the endogenous ligand

*Affects receptor function through other conformational effects on the protein

26
Q

What are the 2 types of pharmacological agonists?

A

Partial and inverse

27
Q

Describe partial agonists

A

*Binds same site as endogenous ligand but elicit a less than maximal response

*Can decrease efficacy of the endogenous agonist

28
Q

Describe inverse agonists

A

*Binds receptor with constitutive activity

*Has opposite effect to full agonist

*Long term effects of drug use

29
Q

Describe tolerance

A

*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

30
Q

Describe sensitization

A

*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)

31
Q

What are the forms of tolerance?

A

Metabolic, pharmacodynamic and behavioural

32
Q

What is metabolic tolerance?

A

Also known as drug disposition tolerance

*Increased metabolism through enzyme induction

*Decreased bioavailability of drug

33
Q

What is pharmacodynamic tolerance?

A

*Changes in nerve cell function in response to drug

*Receptor down-regulation results in saturation and diminished effect

34
Q

What is behavioural tolerance?

A

*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.

35
Q

Describe drug dependence

A

*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

36
Q

How does dependence develop?

A

*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

37
Q

How has drug dependence been demonstrated in the past?

A

*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

38
Q

How are addictions defined?

A

*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

39
Q

Describe intoxication

A

*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

40
Q

Describe withdrawal

A

*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

41
Q

Describe the gateway hypothesis

A

*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

42
Q

Describe common liability

A

*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

Psych 478 (28 decks)

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