PCL218

Homeostasis

A tendency to maintain a balanced internal state.

Pharmacodynamics

what the drug does to the body; how a natural substance/drug/natural product has an effect on the body

Pharmacokinetics

what the body does to the drug; process: absorbed, distributed, metabolized, and eliminated

Receptor

target/site of aaction of a compound in the body

Effects of adrenaline

bronchioles dilate, blood pressure increases, heart rate increases, digestive activity decreases, pupils dilate, liver converts glycogen to glucose

Natural (Agonists)

substances within the body that have evolved to produce a response when they bind to and "switch on" a receptor

agonist drugs

mimic natural agonists within the body, binding to receptors to create the same effect but often with a much more significant physiological response

antagonists

work by binding to a cell's receptor and blocking access to the receptor from agonists in the body

dose-response curve

relationship between drug dose and magnitude of drug effect

Naloxone

opioid antagonist that blocks opioid receptors and reverse effects of overdose

Tolerance

decreased response to same dose with repeated exposure which is caused by compensatory mechanisms that oppose the effects of the drug

Degradation and Excretion

1) liver: enzymes transform drugs into water soluble metabolites

2) kidney: traps water-soluble compounds for elimination via urine

3) lungs: alcohol on breath

4) breast milk: alcohol and drugs

grapefruit juice

increases in concentration of oxycodone in the body; there is a compound in grapefruit juice that acts on an enzyme in the liver responsible for metabolizing oxycodone

Endogenous

naturally occurring compound in the body, produced within the body

components of a pharmacological system

1) natural activators (Agonists): endogenous ligands

2) receptors

3) enzymes that degrade these compounds

Endocannabinoids

Anandamide, 2AG, A class of unconventional neurotransmitters that are chemically similar to the active components of marijuana

endocannabinoid system

brain function, cardiovascular effects, effects on liver, ocular pressure, digestive effects, reproductive system

CB1 in the brain

amygdala: emotion, fear

cortex: cognitive function, attention, motivation

hypothalamus: appetite

hippocampus: learning and memory

brain stem/spinal cord: vomit reflex, pain control

CB1 receptor

inhibits neurotransmitter release, just as dopamine, serotonin, GABA and Glutamate (can inhibit an inhibitor)

when do we make endocannabinoids?

changes in environment: hunger, exercise, stress, pain, time of day

FAAH

Fatty acid amide hydrolase, the enzyme that destroys anandamide and metabolizes it to arachidonic acid

endocannabinoids and memory function

1) working memory and cognition: promotes retrieval and consolidation

2) traumatic memories: promotes fear extinction and inhibits retrieval of fearful memories

Anandamide and FAAH

FAAH inhibitions selectively increases circulating anandamide (AEA)

Rimonabant

a drug that blocks CB1 receptors, and thus decreases appetite, but also increased depression/suicide

single nucleotide polymorphism

a variation in a single base pair in a DNA sequence that leads to population differences in physiology

SNPS in FAAH

different levels of expression of FAAh protein is associated with a common SNP, which 38% of individuals of european descent are carriers

FAAH genetic variation

FAAH (C): more active, so anandamide is inactivated more quickly

FAAH (A): less active, so anandamide levels are increased

FAAH SNP (AA) and stress

reduced stress and anxiety responses, increased fear extinction, less PTSD, reduced reactivity towards threat and increased reactivity toward reward

FAAh SNP and post operative nausea and respiratory depression

CC genotypes had less risk of PONV and RD than CA and AA

FAAH case study

felt no pain, no anxiety or depression, memory lapses. microdeletion that began downstream from the 3 end of FAAH

effects of THC

Brain function: euphoria, memory, anxiety, relaxation, hunger

digestive effects: increased food intake

Cardiovascular effects: increased heart rate, increased blood pressure

ocular effects: lower pressure, red eyes

balance

CB1 receptor function

inhibits neurotransmitter release. (decrease in GABA or Glutamate, increase in dopamine and serotonin)

hyperemesis

excessive vomiting, associated with chronic, high dosage use of cannabis

Metabolism of THC

delta-9-THC :psychoactive

11-OH-THC (hydroxy THC): psychoactive

11-COOH-THC (Carboxy THC) : inactive

What is tested in preclinical models

1) efficacy: does it work?

2) mechanisms of action: how?

3) toxicity: what doses are toxic?

In vitro

a medical experiment that is performed only in a laboratory dish or test tube

In vivo

a medical experiment or a test that is performed on a living organism

variables in cells that can describe a drug

Affinity, selectivity, efficacy

affinity

how well a drug binds to a receptor

selectivity

how well a drug binds to our receptor of interest versus other receptors (they can have high affinity for other compounds)

efficacy

how well a drug causes an effect (sometimes we want to block rather than activate a receptor)

Parameters of an ideal drug

high affinity

highly selective

high or low efficacy, depending on if it is blocking or activating the receptor

tetrad test

hypomotility, catalepsy, hypothermia, analgesia

hypomotility

decrease in movement

catalepsy

fixed posture and rigidity; putting them in a position they wouldn't normally be in (bar test)

hypothermia

drop in body temperature by 3-5 degrees C

analgesia

decreased ability to feel pain: thermal pain, exposing tail to higher temperature/paw on hot plate

elevated plus maze

time spent in open arms = less anxious

time spent in open arms= more anxious

utilizes natural preferences of mice

CB1 Knockout Mice

physical: decrease in body weight, body fat, food intake, increased HPA axis

behaviour: reduces response to reward, increased anxiety/depression like behaviours. stress sensitivity

effects in outcomes of preclinical studies depends on

• species

• strains (CB1 or CB2 knockout)

• doses/route of administration

• how long it is used

-disease model used

-behaviour tests

Requirements of medicine

therapeutic target

selectivity

suitable pharmacokinetics

metabolic stability

good bioavailability

reliability

clinical efficacy

safety/absence of serious unwanted effects

cannabis and pain

EC levels are increased during pain, Cb receptors are found in the pain pathway, and CB receptors reduce pain when activated

clinical evidence for effectiveness

pain in MS, nausea and vomiting, Epilepsy

Epigenetics

how environmental influences affect the expression of their genes. during development, the DNA that makes up our genes accumulates chemical marks that determine how much or little of the genes is expressed. The collection of chemical marks is the epigenome

adolescent cannabis consumption

systematic review found that consumption was associated with increased risk of developing depression and suicidal behaviour later in life, even in the absence of a premorbid condition

cannabis and brain development

• in utero THC increased mesolimbic dopamine system, which enhances heroin-seeking profiles in adult rat offspring

• EC system is a key mediator for the maturation of the prefrontal cortex, which mediates cognitive function

cannabis use in pregnancy

leads to low birth weight babies

cannabis use in pregnancy (mice)

increased: anxiety, hyperactivity, opioid seeking

decreased: synapse formation, glutamate signalling, dopamine levels, memory consolidation, socialization, short term memory, synaptic plasticity

altered: gene expression, neuroendocrine signals in the hypothalamus

medicine

the science and practice of establishing the diagnosis, prognosis, treatment and prevention of disease

science

a systematic enterprise that builds and organizes knowledge int he form of testable explanations and predictions about the universe (methodology)

the scientific method

1) make an observation