part 2 Flashcards
what is cannabis extracted from?
- extract from Cannabis sativa plant….a member of the hemp family
what can be produced using different parts of Cannabis Sativa?
- stalk - fibre used to make hemp
- dried flower + leaves - used to make marijuana
- resin - used to make hashish
where did cannabis originate and how long was it cultivated for?
- Cannabis sativa originated in Central Asia
cultivated for at least 4500 years
when did cannabis reach europe?
1500BC
what is hemp and what was it used for in the past?
coarse, strong fibre extracted from the stalk
- listed in early pharmacopoeias as a medicinal/herbal plant
- early cultures believed cannabis possessed magical qualities
- used for religious and spiritual rituals to induce trance-like states
- more practical early use of hemp was to make paper
- declaration of independence was drafted on cannabis paper
what did the de materia medica and central asian cultures state about hemp and it uses?
De Materia Medica:
* hemp capable of making “the stoutest cords”
* also notes its medicinal/psychoactive effects
Greek historians report central asian cultures burning hemp on heated stones:
* “as it burns, it smokes like incense and the smell of it makes them drunk”
*as early as 450 BC
where are CB1 receptors located in the brain and what do these reigions do?
- Hippocampus
- Involved in memory
- Inhibited by cannabinoids
- Hypothalamus
- Involved in regulating appetite
- Inhibited by cannabinoid
- Cerebral cortex
- Involved in consciousness & sensory awareness
- Altered by cannabinoids
- Cerebellum
- Involved in co-ordination
- Inhibited by cannabinoid
- Brain stem/spinal cord
- Involved in pain, vomiting reflex & control of heart rate
- Inhibited by cannabinoids, (except heart rate)
what aare the similarities between cannabinoids?
- all structurally very similar
- all stimulate very similar responses
- therefore they all must be acting on same cellular target (remember the opioids
where is the cannabinoid receptor located and how does it work?
- receptor located on membrane of certain cells in the body
- cannabinoid binding to receptor is what triggers the effect of the drug
what are the two types of cannabinoid receptors?
- CB1 found in brain
- CB2 found in periphery (outside brain)
most of the effects of cannabinoids result from binding to CB1
do humans produce endogenous cannabinoids and why is this a question that should be asked?
- the fact we have receptors for cannabinoids in our body poses a question:
- do we produce our own endogenous (home-made) cannabinoids?
- the existence of these endogenous cannabinoids was discovered in 1992
what is anandamide?
- anandamide:
- binds CB receptors
- mimics the effects of cannabinoids
what are endocannabinoids?
these endogenous cannabinoids were isolated from slices of pig brain:
- the 1st to be isolated was called anandamide
- now 5 exist in total but there may be more that we havent discovered
- suggests that these compounds play an important role
- 2-arachidonoyl glycerol
- 2nd endocannabinoid discovered
when did governments start banning cannabis and what were the consequences of doing so?
in the 1990s, this caused public outcry that peaked in the 1960s
how common is cannabis usedb today?
~ 4% of World’s adult population have used it (162 million people)
~ 0.6% of World’s population are routine/regular users (22.5 million)
what is cannabis made of and what are the three main constituents of cannabis?
cannabis preparations are crude cocktails of different lipid soluble molecules
- tetrahydrocannabinol (THC or Δ9THC) main active compound (most potent)
- cannabidiol (precursor for THC)
- cannabinol (spontaneous product of THC breakdown and therefore formed by THC)
when was cannabis first isolated and identified?
1964
how does THC affect the CNS?
- loss of short-term memory
- increased confidence
- reduced co-ordination
- catalepsy (unusual fixed, comatose poses)
what is the relationship between THC proportion and activity?
the greater the proportion of THC, the greater the activity of the preparation
Role of other cannabinoids?
- the other cannabinoids add other subtle effects & characteristics
- regional variation in the proportions of cannabinoids (Oriental vs USA)
Do cannabinoid ratios differ within the plant?
yes, the ratio also differs in different parts of plant
THC in highest concentration in the resin, lowest in the stalk
this is again reflected in the how active the preparations are
resin generally higher activity than extract from other areas of the plant
how can THC affect the digestive system?
- reduced nausea and vomiting
- stimulated appetite
how does THC affect mood?
- relaxation
- sense of well-being
(“ethanol-like” effects, without the aggression) - sharpened sensory awareness
(sight and sound in particular)
other than the CNS, Digestive system and mood, what else can THC affect?
- increased heart rate
- dilation (widening) of airways
- reduced pressure within the eye
what do endocannabinoids do?
- regulates heart rate
- widens (dilates airways)
- prevents nausea/vomiting
- stimulates appetite
- increases pain threshold
- decreases sensation of pain
what was cannabis used for in the past? (WW1)
- cannabis was used as a truth serum.
- developed by a US intelligence agency during WWII
- subjects were given THC-laced cigarettes and were found:
“to be loquacious and free in their impartation of information” - used to interrogate an enforcer for Lucky Luciano (gangster & drug dealer)
- talked in detail about Luciano’s heroin operation
- on a 2nd occasion, a higher dose was tried & the enforcer passed out for 2 h
- based on ability to relax and distract subject with feelings of euphoria
- also tends to disrupt their memory of exactly what truths they may have told
what are some clinical applications of cannabinoid drugs? (1)
- Activation of the cannabinoid receptor
- uses THC or a synthetic derivative called nabilone
being developed/investigated to treat:
- nausea and vomiting in cancer chemotherapy
- to reduce weight loss in cancer and AIDS (stimulates appetite)
- glaucoma (decreases pressure in the eye)
- multiple sclerosis (increases mobility, reduces pain)
- pain
- anxiety
what are some clinical applications of cannabinoid drugs? (2)
- uses a drug called rimonabant
- potential use in treating obesity:
- blocks endocannabinoid stimulation of appetite
what is diabetes?
Increase in blood glucose (sugar), either due to a lack of insulin (type 1) or to a lack of effect of insulin (type 2).
In ancient times physicians would drink their patients’ urine to see whether it tasted sweet, “mellitus” is Greek for honey, or tasteless “insipidus”, the other much rarer form of diabetes
what does insulin do?
Insulin allows muscle and fat tissue to take up glucose and use it to produce energy and store carbohydrate, protein and fat.
In type I and type 2 diabetes, glucose uptake by these tissues is impaired and so blood glucose rises (hyperglycaemia).
what can untreated type 1 diabetes lead to?
Untreated type I diabetes leads to many complex changes in the body which ultimately cause starvation and death.
before the discovery of insulin, what was the survival time of diabetes?
between 2 weeks and 18 months
who is the worlds largest producer of insulin?
August Krogh and Nordisk in Denmark, known now as Novo-Nordisk is the world’s largest producer of insulin
when was insulin introduced to britain?
1924
how much has the NHS spent on diabetes?
> 10% of NHS budget is spent on treating diabetes and these diabetic complications.
what are the steps forward regarding diabetes?
Since insulin is destroyed by the gut, it has to be injected.
Recently, inhaled insulin was withdrawn because of unacceptable side-effects.
Stem cell technology offers hope for the future in repairing the pancreas and restoring beta cell function.
describe the discovery and development of viagra?
it was marketed in 1998 by Pfizer to treat erectile dysfunction
- sales of around £1billion per year
- partly why Pfizer is biggest pharmaceutical company in world
- also down to “luck”….they discovered Viagra “by accident
what is the drug name for viagra?
sildenafil citrate (Viagra)
What was Pfizer’s medical objective in 1985, and what condition were they aiming to treat with a new drug design focused on vasodilation?
Pfizer set out to develop a new medicine to treat angina, a condition characterized by severe pain in the heart and chest wall due to insufficient blood supply from the arteries.
The goal for Pfizer scientists was to design a drug that would induce vasodilation, causing the arteries to dilate or open up, thereby increasing the blood supply to the heart and relieving the symptoms of angina.
What was the strategy behind Pfizer’s target selection for developing a new drug to treat angina, according to the theory of vasodilation?
Pfizer’s strategy in target selection for a new angina drug was based on the theory of vasodilation.
Scientists aimed to identify a target in the artery wall, specifically an enzyme responsible for halting natural vasodilation.
By inhibiting this enzyme, they theorized that they could enhance natural vasodilation, thus helping to keep the arteries dilated for longer periods and preventing angina. This process was intended to increase blood flow to the heart, thereby relieving the severe chest pain associated with angina.
how did Pfizer use the screening assay technique during the development of its vasodilation drug?
-Pfizer’s drug looked to inhibit an enzyme which stopped natural vasodilation?
- scientists cloned the target enzyme
- designed an assay to measure the activity of the enzyme
- screened over 1500 compounds between 1986-1990
- looking for compounds that inhibited the enzyme -> this would fit their profile as a vasodilator
how did Pfizer use 3D modelling during the development of his vasodilation drug?
3D modelling
- also characterised the 3D shape of the target enzyme
- knowledge of this permits “design” of compounds that will interact with it
describe the clinical trial phase of viagra
- pre-clinical trials in animals showed no safety or toxicity issues- so UK-92480 entered Phase I trials in healthy volunteers
- the trials showed that the drug was safe and no toxic effects were reported….
- ….however, many male volunteers reported an “interesting” side-effect
-> increased frequency and duration of penile erection
what was Pfizer’s Angina treatment later used for?
In 1992 Pfizer changed direction with UK-92480
- began to investigate it as a treatment for erectile dysfunction (ED)
- work with UK-92480 and angina continued, but it lacked sufficient potency
- failed to make it as a treatment for angina
- the erection-stimulating side effects saved Pfizer from losing a LOT of money!
what is erectile dysfunction?
Erectile dysfunction (inability to obtain or sustain an erection)
- often an indication of underlying disease/problem
how does viagra work?
- UK-92480 inhibits the target enzyme (prolongs natural vasodilation)
- it turns out that there are many subtypes of the target enzyme
- UK-92480 especially potent at inhibiting the enzyme subtype in penile arteries -> therefore it is most effective at promoting penile vasodilation & erection -> less specific and potent in treating angina
what does “drug tolerance” mean?
- decrease in pharmacological effects of a drug with repeated use
- results in requirement for increased doses to achieve same effect
- often accompanies dependence/addiction
define “withdrawal symptoms”
- adverse physical and psychological effects upon stopping taking a drug
- can last days, months or indeed years
what are some examples of substance abuse from the past?
- mushrooms - stoneage
-ate mushrooms for mind-altering effects - persists today (magic mushrooms)
- Frog/Toad Venom - ancient tribes
- extracted frog/toad venom
- consumed for rituals & trance-like state
- Cojobano seeds - Taino people (prehistoric)
- ate seeds of the Cojobano tree
- reported out-of-body-type experience
what are examples of substance abuse that still exist today?
- Alcohol - brewing traced back as early as 8000 BC
- Opium - traced back to Egyptian times and before
- Cannabis - grown and in use for over 4500 years
- Cocaine - early South American civilisations
- habitually chewed Coca leaves
- “strength to the weary”
- “makes the unhappy forget their sorrows”
- these leaves are a source of cocaine
what did early civilisations believe addiction to be and what does this tell us about human nature?
illness, madness, habits, weakness, possession by evil spirits
- illustrates that addiction is part of the core of human behaviour
- its causes and consequences are nothing new
- humans will develop dependencies on anything that makes them feel good
what are addictive drugs also known as?
- they are all so-called hedonic drugs
- people associate the effects of these drugs with pleasure (hedonic effect)
- pleasure is a basic human “reward” mechanism
- designed to reinforce basic survival behaviours (eating, drinking, reproducing)
- the pleasurable effects of these drugs tends to drive humans to repeat it so the cycle of drug abuse and addiction begins
- all of them activate the reward pathway
what does the reward/pleasure pathway do and how is it regulated?
- releases a compound called dopamine (the pleasure chemical)
- responsible for humans feeling pleasure or reward
- activation of the pathway releases dopamine into many areas of the brain
- this is what we feel as pleasure
- activity is controlled down by inhibitory nerve cells
- prevents the reward pathway releasing dopamine all of the time
what are examples of natural rewards and how does this relate to the reward pathway?
- natural pleasure (sex, shopping, sport, opera etc)
- stimulates release of endogenous opioids (enkephalins…Kosterlitz)
- these inhibit the inhibitory inputs
- therefore activate the pleasure pathway (and we feel pleasure)
what is an exampleof unnatural pleasure and how is it related to the reward pathway?
drugs of abuse all have different modes of action throughout the brain
- but they also all affect the reward pathway
- do so in 1 of 2 ways:
1. Inhibit inhibitory inputs……….OR
2. Directly stimulate the pleasure pathway
- both strongly activate the reward pathway to produce dopamine
- produces the “rush” or “hit” associated with drug abuse
what are the consequences associated with unnatural reward?
- leads to addiction
- repeatedly taking the drug (which users become compelled to do)
- brain down regulates the reward pathway (less sensitive to drug stimulation)
- protective mechanism against abnormal levels of stimulation
- this means larger doses of drug required to stimulate the pathway (tolerance)
- also means pathway rarely activated without drug
- in absence of drug, user feels depressed and ill (withdrawal)
- further compulsion to relapse and take drug
what are some examples of non-chemical addictions and how do they work?
examples: sex, gambling. theft, risk
- these all activate the reward pathway (to a lesser degree than drugs of abuse)
- engaging in these activities excessively and repetitively
- excessive, abnormal stimulation of reward pathway
- brain down regulates the pathway (tolerance)
- more and more of these activities needed to gain reward (addiction)
- not continuing with these activities means little or no pathway activity
- depression and illness (withdrawal)
how do different drugs cause varying levels of dependency?
more potent -> more pleasure -> more regulation of the pathway -> more urge to take the drug -> increase in severity in withdrawal symptoms -> more likelihood of relapse
what is physical dependence?
- associated with down regulation of reward pathway (tolerance)
- also depends on down regulation of other specific targets of the drug
- this is why withdrawal varies from drug to drug
- lasts days–weeks
what is psychological dependence?
- results from the fact the brain has “learned” to connect drug with reward
- produces “craving”
- often stimulated by association
e.g. seeing a cigarette, syringe or wishing to smoke/drink when socialising - long lasting, main reason for relapse
what drug type causes the worst withdrawal symptoms?
most severe is opioid withdrawal
is drug addiction genetic?
- emerging evidence that susceptibility to addiction might be partly genetic
- research ongoing, however not yet clear which genes are involved
why is the use of cannabis in medicine controversial?
- long term usage may induce psychological (or other) problems
- the “gateway theory” suggests that use of cannabinoids may stimulate needs for stronger, more addictive drugs
what are the 5 treatments for addiction?
- Short-term Substitution
- designed to lessen withdrawal and make it more bearable
- helps break habit and re-establish control
- reduces chances of relapse
e.g.
methadone – softens opioid withdrawal
diazepam – softens alcohol withdrawal - Blocking responses
- designed to prevent the problem drugs having an effect
- tends to involves blocking the specific target of the drug
- helps prevent relapse, as taking drug will have little or no effect
- tends to be used when addict is making good progress
e.g.
can block opioid effects
can block nicotine effects - Aversion therapies
- designed to produce an unpleasant response to drug
- discourages relapse
- helps to associate drug with unpleasantness
- “unlearns” association with pleasure
e.g.
alcohol aversion therapy - induces violent nausea/vomiting in response to alcohol - Psychological therapy
- therapies 1-4 are all pharmacological
- psychological therapy also vitally required
- helps “unlearn” drug taking behaviour
- helps to understand and deal with craving
- effectively addresses the long lasting psychological dependence
- aims to help with moving forward and reducing chances of relapse
what is blood made of?
white blood cells, plasma, platelets and red blood cell
what does blood do?
- Carries oxygen to our cells where they use it to produce energy (RED BLOOD CELLS)
- Carries hormones, enzymes, nutrients and waste products around the body (PLASMA)
- Clots blood to prevent blood loss following injury (PLATELETS)
- Defends us from infection (WHITE BLOOD CELLS)
- Helps regulate body temperature
- Maintains pH of body fluids
who was Richard Lower?
1665: performed first recorded successful blood transfusion in dogs
1667: performed first successful blood transfusion in humans.Sheep-human transfusion in attempt to cure insanity
who was James Blundell?
1818: performed first successful human-human transfusion§
who was Karl Landsteiner?
1901: observed that often, but not always, blood transfusion would results in blood clumping in the recipient’s circulation
1909: classified the ABO system of blood typing
1940: identified the rhesus antigen
what is the history of blood transfusions?
Initially blood was transfused
direct from human to humanIn
1913 Edward Lindeman discovered blood could be extracted by needle from the donor and injected into the recipient, allowing the volume of transfusion to be accurately monitored.
Blood transfusion became extensively practiced out of need during World War One
what are the 8 blood types?
A+ B+ AB+ O+A- B- AB- O-
what is an antigen?
marker on a cell surface that confers information about acells identity to the immune system.
what are antibodies?
produced by B lymphocytes which are primed to recognise specific antigenic markers on cells.
If lymphocytes recognise the antigen as “self” they ignore the cell.If lymphocytes recognise the antigen as being “non-self” they trigger an immune response to destroy the antigen-expressing cell.
how are blood typing and antigens related?
Antibodies bind with antigens to cause clumping of blood cells (agglutination) in vitro and haemolysis in vivo.
People with type A blood circulate antibodies for B antigen, People with type B blood circulate antibodies for A antigen
People with blood type AB have neither A nor B antibodies
People with blood type O circulate both anti-A and anti-B antibodies.
what happens if type A blood is transfused to someone with type B blood?
1) Donor B antibodies attack recipients RBC’s which have B antigen(in practice diluted to such an extent - negligible)
2) Recipients A antibodies attack donor RBC’s which have A antigen
why is ABO grouping important when doing blood transfusions?
Type AB+: no antibodies therefore universal recipients (can receive from any ABO or Rh type) although can only donate to other AB+ individuals.
AB- individuals can receive any Rh- blood but not Rh+. As well as considering ABO grouping must also take into account Rh group too.
Type O- : no antigens therefore universal donors (can donateto any ABO or Rh type) although can only receive from O-.O+ can donate to any Rh+ recipient but not Rh
what is a stem cell and what is proliferation and differentiation?
A stem cell can be defined as a cell that has the unique ability to make a choice between proliferation and differentiation.
Proliferation will maintain the pool of stem cells (self-renewal), while differentiation (when opportunely stimulated) will allow the formation of more specialised cell types..
what are the types of stem cells and where can they be found?
Several levels of“potency”= how broada stem cells differentiation potential is:
Totipotency: Fertilized egg
Pluripotency: Embryonic stem cells Multipotency: Somatic stem cells Unipotency: Precursor cells
