l12 pharm

what is pharmacodynamics?

pharmacodynamics is the study of how drugs have effects on the body

what is the simple difference between pharmacokinetics and pharmacodynamics?

pharmacokinetics = what the body does to the drug. pharmacodynamics = what the drug does to the body

what is a drug target?

a drug target is the molecular site where a drug acts

what are the four main protein targets that most drugs act on?

receptors, ion channels, transporters, and enzymes

what is the most common mechanism of action for many drugs?

many drugs work by interacting with receptors in the cell membrane or inside the cell

what is a receptor?

a receptor is a protein that a drug or natural signal can bind to, causing a biological response

what is an agonist?

an agonist is a drug that binds to a receptor and activates it

what does receptor activation depend on?

receptor activation and biological response usually depend on the concentration of the activating drug

what does a dose-response or concentration-response curve show?

it shows how the biological response changes as drug concentration increases

what is an antagonist?

an antagonist is a drug that binds to a receptor and blocks or reduces the effect of an agonist

what is efficacy?

efficacy is the maximum response a drug can produce

what is potency?

potency is how much drug is needed to produce a response

what is affinity?

affinity is how strongly a drug binds to its receptor

what is desensitisation?

desensitisation is when constant drug exposure leads to a reduced response over time

what was the aim of this lecture?

to use synthetic cannabinoids as an example to introduce key pharmacodynamic concepts

why do we care about pharmacodynamics?

because it explains why drugs that act at the same receptor can have very different strengths, effects, and toxicities

what is Cannabis sativa known for?

it has been used for psychoactive effects for thousands of years

what is the major psychoactive compound in cannabis?

THC, or Δ9-tetrahydrocannabinol

when was THC identified as the major psychoactive substance in cannabis?

1964

what effects can THC produce?

relaxation, sense of wellbeing, sharpened sensory awareness, reduced short-term memory, and impaired motor coordination

what does psychoactive mean?

psychoactive means a substance affects the brain or mind

what does lipophilic mean?

lipophilic means fat-soluble

why was THC initially thought to interfere with cell membranes?

because THC is very lipophilic/fat-soluble

how does THC actually produce many of its effects?

THC binds to and activates cannabinoid receptors on cell membranes

what are cannabinoid receptors?

cannabinoid receptors are specific receptor proteins that cannabinoids bind to and activate

what is CB1?

CB1 is the main “brain” cannabinoid receptor

what is CB2?

CB2 is the main “immune” cannabinoid receptor

why is CB1 important for psychoactive effects?

CB1 is found strongly in the nervous system, so activating it affects brain function

what are endocannabinoids?

endocannabinoids are cannabinoids naturally made by the body

why did discovery of cannabinoid receptors lead to discovery of endocannabinoids?

because if the body has cannabinoid receptors, it likely has natural molecules that activate them

what type of receptor is CB1?

CB1 is a GPCR, meaning G protein-coupled receptor

what can happen inside the cell after CB1 is activated?

CB1 activation can alter cAMP, MAPK/ERK signalling, β-arrestin recruitment, and receptor internalisation

why is a receptor not just an on/off switch?

different drugs can activate the same receptor but trigger different intracellular pathways

what are synthetic cannabinoids?

synthetic cannabinoids are man-made compounds that interact with cannabinoid receptors

why were synthetic cannabinoids originally designed?

they were designed as research tools to understand THC binding and cannabinoid receptor function

what happened to some synthetic cannabinoids after being made for research?

some were diverted into recreational drug markets

why can synthetic cannabinoids be more dangerous than THC?

they can have higher affinity, potency, and efficacy, and products may have unpredictable doses

do all synthetic cannabinoids look structurally similar to THC?

no, many synthetic cannabinoids are structurally very different from THC

why is structural diversity of synthetic cannabinoids important?

you cannot prove a compound is a cannabinoid just by looking at whether it resembles THC

what are some classes of synthetic cannabinoids?

classical, non-classical, aminoalkylindole, eicosanoid, novel, and more novel compounds

what is JWH-018?

JWH-018 is a synthetic cannabinoid found in some Spice products

what was Spice marketed as?

Spice was marketed as a “herbal high”

what was actually found in some Spice products?

the synthetic cannabinoid JWH-018

how were synthetic cannabinoids commonly added to plant material?

the powder was dissolved in solvent and sprayed onto dry plant material

why are synthetic cannabinoid products unpredictable?

the active compound and concentration may not be clearly labelled or evenly distributed

what happened in New Zealand with synthetic cannabinoids?

they were initially sold in dairies and petrol stations as “legal” or “natural highs”

why did banning individual synthetic cannabinoids not fully solve the problem?

when one compound was banned, producers changed to a different active compound

why was there growing public concern in New Zealand?

products did not clearly indicate what they contained and were associated with harm

what was the purpose of the Psychoactive Substances Act 2013?

to regulate psychoactive substances in New Zealand to protect health and minimise harm

what level of harm was allowed under the Psychoactive Substances Act principle?

approved products should pose no more than a low risk of harm

why is pharmacodynamics relevant to proving low risk of harm?

you need to know what receptors the drug binds, how strongly it activates them, and what biological effects it causes

what did the 2014 amendment say about animal testing?

animals must not be used in trials to assess whether a psychoactive product should be approved

why did the animal testing ban create a scientific problem?

it made it harder to prove whether new psychoactive products were low risk of harm

how can pharmacodynamic assays help without animal testing?

cell-based assays can test receptor binding, activation, signalling, and internalisation

what proportion of Dunedin acute psychiatric ward admissions were related to synthetic cannabis use from Jan-April 2013?

13% of admissions were related to synthetic cannabis use

what kinds of symptoms were reported with synthetic cannabinoid hospital admissions?

psychosis, hallucinations, seizures, agitation, tachycardia, hypertension, vomiting, drowsiness, and other serious symptoms

what is the important clinical point about synthetic cannabinoids?

they can cause serious psychiatric, neurological, cardiovascular, and physical toxicity

why did the lecturer correct “synthetic cannabis” to “synthetic cannabinoid”?

cannabis is the plant, while synthetic cannabinoids are man-made receptor-acting drugs and are not the same thing

what were two major synthetic cannabinoids seized in New Zealand in 2017?

AMB-FUBINACA and 5F-ADB

why was AMB-FUBINACA an important example in this lecture?

it was found in forensic samples, linked to harm/deaths, and used to demonstrate pharmacodynamic testing

what outbreak was linked to AMB-FUBINACA in New York?

a “Zombie” outbreak involving mass intoxication

what does the AK-47 24 Karat Gold example show?

plant material could contain AMB-FUBINACA at significant and potentially variable concentrations

why is dose important with synthetic cannabinoids?

a high potency drug becomes more dangerous when the dose in the product is unknown or variable

how do you prove AMB-FUBINACA is a cannabinoid if it does not look like THC?

test whether it binds to and activates cannabinoid receptors

what are the two key questions asked about AMB-FUBINACA?

does it bind cannabinoid receptors, and does it activate cannabinoid receptors?

what does it mean if a drug binds to CB1?

it physically interacts with the CB1 receptor

does receptor binding automatically mean receptor activation?

no, a drug can bind without necessarily activating the receptor

what is affinity?

affinity is how strongly a drug binds to a receptor

what concentration of AMB-FUBINACA bound 50% of CB1 receptors?

1 nM

what concentration of THC bound 50% of CB1 receptors?

50 nM

which has higher affinity for CB1, AMB-FUBINACA or THC?

AMB-FUBINACA has higher affinity

how much higher is AMB-FUBINACA affinity for CB1 compared with THC?

about 50-fold higher

what is the rule for affinity and 50% receptor binding?

the less drug needed to occupy 50% of receptors, the higher the affinity

why is affinity not the same as potency?

affinity is about binding, while potency is about how much drug is needed to produce a response

what does CB1 activation do to cAMP?

CB1 activation inhibits cAMP production

what G protein is CB1 coupled to in the cAMP pathway?

Gαi/Gi

what does Gi do to adenylyl cyclase?

Gi inhibits adenylyl cyclase

what does adenylyl cyclase normally produce?

cAMP

what happens to cAMP when CB1 is activated?

cAMP decreases

what is EC50?

EC50 is the concentration of drug needed to produce 50% of the maximal response

what does a lower EC50 mean?

a lower EC50 means higher potency

what was AMB-FUBINACA’s EC50 in the cAMP assay?

1.3 nM

what was THC’s EC50 in the cAMP assay?

19 nM

which drug was more potent in the cAMP assay?

AMB-FUBINACA

how much more potent was AMB-FUBINACA than THC in the cAMP assay?

about 14-fold more potent

what is potency?

potency is how much drug is needed to produce an effect

what does a left-shifted concentration-response curve mean?

the drug is more potent because less drug is needed to produce the response

what is ERK phosphorylation/pERK?

pERK is a signalling response downstream of receptor activation

what was AMB-FUBINACA’s EC50 in the pERK assay?

2 nM

what was AMB-FUBINACA’s Emax in the pERK assay?

100%

what was THC’s EC50 in the pERK assay?

40 nM

what was THC’s Emax in the pERK assay?

about 30%

which drug was more potent in the pERK assay?

AMB-FUBINACA, because it had a lower EC50

which drug was more efficacious in the pERK assay?

AMB-FUBINACA, because it reached a higher maximum response

what is Emax?

Emax is the maximum response a drug can produce

what is efficacy?

efficacy is the maximum effect a drug can produce

why is THC called a partial agonist in the pERK pathway?

because it activates the receptor but only reaches about 30% of the maximum response

what is a partial agonist?

a partial agonist binds and activates a receptor but cannot produce the full maximum response

what does β-arrestin-2 recruitment show?

it shows another type of receptor activation/signalling response

which drug recruited β-arrestin-2 to the cell surface?

AMB-FUBINACA