Topic 2: Pharmacodynamics and Drug Tolerance

Question 1

What are 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

What is a ligand?

Answer 2

any molecule that binds to a receptor

drug –> exogenous ligand (ligand that comes from outside the body)

neurotransmitters, hormones, peptides –> endogenous ligands (made inside the body)

Question 3

What is a receptor?

Answer 3

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 4

What is the saturability of a receptor?

Answer 4

finite receptors per cell

dose-response should reveal saturability (keep increasing dose until there’s no difference, maximum)

Question 5

What is the specificity of a receptor?

Answer 5

high binding affinity to elicit a biological response

only going to act when a specific ligand attaches

Question 6

What is the reversibility of a receptor?

Answer 6

binding to receptors should be reversible

ligand should be dissociable and recoverable (bind and leave unchanged, able to have something done later)

distinguishes receptor-ligand interactions from enzyme-substrate interactions (ligands can bind to things that aren’t receptors)

Question 7

What are the differences between extracellular receptors and intracellular receptors?

Answer 7

two distinct classes of receptors bind water-soluble or lipid-soluble ligands

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)

Question 8

What are extracellular receptors?

Answer 8

common target for psychoactive drugs; accessible to water-soluble drugs

different signaling based on function of the receptor

ligand-gated ion channels: postsynaptic neurotransmitter receptors

G-protein coupled receptors (GPCR): metabotropic receptors, intracellular second messanger

receptor kinases: common for cytokine, peptide hormone receptors (e.g. insulin)

Question 9

What are intracellular receptors?

Answer 9

common target for steroid hormones and lipophilic compounds (and some drugs): glucocorticoids, androgen/estrogens, endocannabinoids

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

Question 10

What are agonist drug interactions on a receptor?

Answer 10

interactions are those that elicit a biological effect on the receptor

can be a neurotransmitter or a drug

Question 11

What are antagonist drug interactions on a receptor?

Answer 11

interactions are those preventing or blocking a biological effect

wrong key enter lock, prevents right key from entering

Question 12

What is a dose-response curve?

Answer 12

with increasing concentration of agonist, the biological response is greater

dose-response tends to follow a characteristic sigmoidal shape (S-curve)

Question 13

What is potency?

Answer 13

ED50 is the dose required to elicit a half-maximal effect

how much do we need to get 50% response

Question 14

How do you compare drugs using a dose-response curve?

Answer 14

if curves are differing on the horizontal axis: same maximum means same efficacy, but potency is different

if curves are differing on the vertical axis: different efficacy, same potency

Question 15

What is TD50?

Answer 15

a measure of the potency of a drug at eliciting a toxic response

Question 16

What is LD50?

Answer 16

measures the potency at eliciting a lethal effect

Question 17

What is the therapeutic index (TI)?

Answer 17

reflects the margin of safety between drug efficacy and adverse effects

TI = TD50/ED50

Question 18

What are irreversible antagonists?

Answer 18

bind and never leave, so receptor is essentially dead

binds irreversibly to the same binding site as an endogenous ligand

non-competitive antagonists

Question 19

What are reversible antagonists?

Answer 19

can be displaced by the endogenous agonist

competitive antagonism

reduces agonist potency but not efficacy

Question 20

What are non-competitive antagonists?

Answer 20

cannot be displaced by agonists because they are not competing for the same spot

tend to be toxins and poisons

reduce drug efficacy and sometimes potency

Question 21

What are allosteric modulators?

Answer 21

binds to different site on the receptor than the endogenous ligand

can either increase or decrease effects

affects receptor function through other conformation effects on the protein

Question 22

What are partial agonists?

Answer 22

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

can decrease efficacy of the endogenous agonist

Question 23

What are inverse agonists?

Answer 23

binds receptor with constitutive activity

has opposite effect to full agonist

Question 24

What is tolerance?

Answer 24

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

Question 25

What is cross-tolerance?

Answer 25

can cause drug interactions

develop tolerance to drug A, already have tolerance to drug B; usually happens because they are related

Question 26

What is sensitization?

Answer 26

enhancement of a particular drug effect on repeated exposure

prior exposure to cocaine increases repetitive and hyperactive behaviors in animals (head bobbing)

less common than tolerance, but can happen at the same time

Question 27

What is cross-sensitization?

Answer 27

occurs between drugs acting on the same receptor (e.g., cocaine and amphetamines)

Question 28

What is metabolic tolerance?

Answer 28

drug disposition tolerance

body increases enzymes to break down drugs over time; it will leave body sooner

increased metabolism through enzyme induction

decreased bioavailability of drug

Question 29

What is pharmacodynamic tolerance?

Answer 29

changes in nerve cell function in response to drug; decrease in receptors for the drug to act on

receptor down-regulation results in saturation and diminished effect; could change the efficacy

Question 30

What is behavioral tolerance?

Answer 30

context-specific tolerance: body prepares itself when in the spot you take drug to negate the effect

involves learning and memory

demonstrated by tolerance in familiar but not novel environments

habituation and conditioning

one of the biggest context of overdose

Question 31

What is habituation?

Answer 31

first administration causes greater alteration of normal behavior

body wants to maintain homeostasis, body becomes used to the drug so it can negate the drugs impact, more drug is needed to overcome body’s effects

diminished with subsequent administration

Question 32

What is conditioning?

Answer 32

environment or paraphernalia act as conditioned stimulus to initiate response

Question 33

How can behavioral tolerance be demonstrated in animal and human models?

Answer 33

administration of drug in a conditioned environment can elicit a different physiological response than in a novel environment

Question 34

What is the timeline for drug tolerance?

Answer 34

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

Question 35

What is drug dependence?

Answer 35

results from tolerance mechanisms and is considered a key component contributing to drug addictions

most significantly influenced by pharmacodynamic mechanisms: how long it takes body to decrease enzymes and increase receptors

dependence is the requirement for drug use in order to maintain “normal function” after the development of drug tolerance

Question 36

What is the classic model of dependence and tolerance to opiates developed by Himmelsbach in 1943?

Answer 36

tolerance to opiates is proposed to develop as a result of compensatory mechanisms to restore homeostasis

1. acute administration disrupts homeostasis
2. repeated administration initiates adaptive mechanisms that compensatory mechanisms to restore homeostasis
3. tolerance is the result of compensatory mechanisms
4. withdrawal of administration results in compensatory disturbance in homeostasis

Question 37

What are the characteristics of in vitro studies demonstrate the cellular effects of morphine?

Answer 37

acute morphine treatment decreased cellular cAMP

with chronic exposure (48 hours) 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 behaviors: fits the idea of substance/behavioral addiction as impulse control disorders

confounded by societal norms and stigmatization

Question 39

What is intoxication?

Answer 39

clinically significant problematic behavioral and psychological changes associated with substance intake

result of physiological effects of substance on CNS

commonly disturbances of: perception, wakefulness, attention, thinking, judgement, psychomotor behavior, interpersonal behavior

differences i acute/chronic intoxication

Question 40

What is withdrawal?

Answer 40

substance-specific problematic behavioral 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

What is 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)

is false

Question 42

What are some common liabilities to developing a substance-use disorder?

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 behavior

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