Drug Discovery And Disease Flashcards
What is diabetes
Increase blood glucose
Lack of insulin
What does insulin do
Allows muscle and fat tissue to take up glucose and use it to produce energy and store carbohydrate, protein and fat
Type 1 and type 2 diabetes, glucose uptake by these tissues is impared and so blood glucose levels rise
Fred Banting
1920
Doctor practising medicine
Understood pancreatic ducts of dogs isolate glucose in urine helped them survive
Pancreatomy, dog died from infection
Inject depancreatised diabetic dog induced drop in blood sugar
James B collip
Highly skilled in extracts, far superior to those of banting and best
Who started making insulin in 1922
Eli lilly and co
Charles best
1900-1978
Falsification about discovery
Two geniuses with no support did it all on their own
Future of diabetes
Insulin destroyed by gut so has to be injected
Injales was withdrawn because of side effects
Stem cell technology offers hope for future in repairing pancreas
What is pharmaclogy definition
Studying the effects of drugs on the function of living systems
Chemistry need to know for pharmacology
Drug and its target
Drug activity directly related to its structure
Pathology in pharmacology
Need to know how disease/ damage affects organism
Understanding of disease process/cause/progression useful for designing intervention therapy
Physiology in pharmacology
How biological organism works
Need to know what normal biological function/ activity of the organism is
What is Ebers Papyrus
Oldest egyptian text
What treatments were mentioned in ebers papyrus
Asthma - herbs heated on slate so they could inhale
Constipation - prune based mixture
Cancer - nothing
Death - hald onion and froth beer
Guinea worm - wrapping end of worm around stick and removing
Who is pedanius dioscorides
Greek physician
Surgeon in army
Wrote de materia medica - identifying and naming platns used in medicine
Info from many cultures
Rudolf buccheim
1st professer of pharmacology
Emphasised importance of drug mode of action
Develop understandings of drugs, doses etc
Developed experimental pharmacology
Oswald schmiedeberg
Buccheims student
Published outline of pharmacology
Defined pharmacologist
Why were opium based analgesics developed
Pain
Oldest human ailment
Broad class of unpleasant sensations
Early pain relifs ancient rome
Spells and incantations
Diet
Excercise
Consumptions of potions
Removal of painful limb, tissue, organ
Bleeding of painful region
Purging body (laxatives)
Burning/ scalding
4 fluid components humoral balance
Blood
Phlegm (water)
Yellow bile (liver)
Black bile (gall bladder)
Hippocrates 460BC
Used opium to treat headaches, coughs, asthma, melancholy
How was morphine used when frist discovered in war
Alendar wood invented hypodermic needle
Before morphine taken orally - less addictive
Addiction emerged
Used on wounded soldiers
Opiod addicted soldiers
2 primary morphine uses
Morphine effective pain killer
Intravenous administration (injecting) is easy and effects are almost instantaneous
Heroin structural name
Diacetylmorphine
Why was heroin first used
Non addictive substrate for morphine
Ended up being more addictive
Drugs targets
Morphine heroin codeine have similar structure and effects - liely act on same target
Targets = receptors, enzymes, carrier molecules, ion channels
What does drug binding result in
Stimulate or inhibit target resulting in a biological response in the cell
What did they not know by the end of the 1800s chemistry and physiology
Chemistry = control effects
Physiology = morphine effects, how pain is communicated, mode of action of opiods
Describe descartes pain pathway
1) Particles of heat activate spot on skin surface
2) ACtivation of B pulls thread connected to valve in brain
3) Allows animal spirits stores in cavity of brain to flow out
4) Withdrawal of lef grom heat
Modern pain pathway
Pain receptor connected to sensory nerve
Enters spinal cord and connects to another nerve fibre
Nerve fibre ascends into brain (thalamus)
Thalamus relays pain message to different parts of brain
Pain is sensed and individual responds
Who discovered opioid receptor
1972
Solomon snyder
How do opiioids regulate the pain pathway
Receptors present in the brain and spinal cord
Bind to morphine receptor
Inhibits nerve fibre preventing firing
Opioids and pain pathway
Binding of opioid receptors inhibits pain fibres in brain and spinal cord
Opioid receptors on thalamus blocked by morphine
Chemistry pathology and physiology pain and treatment things known
Chemistry - works via opioid receotor
Pathology - pain results from range of diseases and injuries, opioids highly addictive
Physiology - opioid drugs work via opioid receptor, opioid receptors inhibits firing of pain fibres in pain pathway, reduce perception of pain
Rubbing an injury to easy pain
Rubbing activates sensory receptor connected to a fibre that enters the spinal cord
Fibre inhibits pain signal in spinal cord -> less pain signals make it to the brain so we suffer less
Who was hans kosterlitz
German
1st professor of pharmacology at aberdeen
What did kosterlitz and hughes do
Intrigued by reports of wounded soldiers not feeling pain during battle
Investigated whether brains can produce their own natural analgesics
Began to investigate this phenomenon in animals
What did kosterlitz and hughes discover
Pathway of nerve fibres originating in brain that could not inhibit pain pathway in spinal cord
Descending pain-inhibitory pathway
Nerve fibres release own home amde opioids called enkephalins/endophins
WHat did kosterlitz and hughes do to the 2 enkephalins structures
Purify it
How do endogenous opioids fit in the pain pathway
Inhibits pain transmission in spinal cord
Releases enkephalin
Binds opioid receptors
Inhibits pain fibre firing
How do endogenous opioids stimulate the pain pathway
Stimulated by stress, emotions, opioid drugs = controls pain and suffering, allows us to escape stress
Name 4 other methods of analgesia
Local anaesthetics + anti inflammatory drugs
TENS
General anaesthetic
Acupuncture
How do the other methods of analgesia affect the pain pathway
Local anaesthetics +anti inflammatory drugs = prevent pain receptors being activates
TENS = electrical impulses applied across the skin of the lower back, activates inhibitory sensory fibres
General anaesthetic = induces loss of consciousness, no perception of pain
Acupuncture = releases enkephalins
Cannabis original use
Hemp
Strong fibre extracted from stalk
Burnt it like incense and smell made them drunk
3 main constituents of cannabis
Tetrahydrocannabinol
Cannabidiol
Cannabinol
Cannabinoids effects
Greater THC greater activity of preparation
Regional variation in proportions of cannabinoids
Ratio differs in different parts of plants
Psychological effects of THC central nervous system
Loss of STM
Increased confidence
Reduced co-ordination
Catalepsy
Physiological digestive system effect of THC
Reduced nausea and vomiting
Stimulated appetite
Psychological effectsof THC mood
Relaxation
Sense of well being
Sharpened sensory awareness
How do cannabinoids work (receptor)
All similar structurally with similar responses
Act on same cellular target
Receptors on membrane of certain cells
Triggering effect of drug
What are the different cannabinoid receptors
CB1 = brain
CB2 = periphery (outside the brain)
Cannabinoids bind to orange region -> triggers resposne inside cell via red region
Where are the cannabinoid receptors in the brain
Hippocamous (memory, inhibited)
Cerebral cortex (consciousness, sensory awareness, altered)
Cerebellum (co-ordinaiton, inhibited)
Hypothalamus (appetite, inhibited)
Brain and spinal cord = pain and reflex control, inhibited)
What do endocannabinoids do
Regulate heart rate
Widen airways
Prevent nausea and vimittung
Stimulate appetite
Increase pain threshold
Decrease sensation of pain
How are cannabinoid receptors activated
Uses THC or nabilone
Cannabinoid drugs used to treat what
Nausea, vomiting
Reduce weight loss in cancer and aids
Glaucoma
Multiple sclerosis
Pain
Anxiety
How was cannabis used in 1940s
Truth serum in ww2
Inhibiting cannabinoid receptor using cannabinoid drugs effects
Rimonabant
Blocks endocannabinoid stimulation of appetite
Short term effects of STIMULATING cannabinoid receptors
Euphoria
Downsiness
Sensory distortion
Loss of STM
Short term effects of INHIBITING cannabinoid receptors
Nausea/ vomiting
Diarrhoea
Long term effects of STIMULATION of cannabinoid receptors
Depression
Lethargy
Addiction
Psychological disturbance
Long term effectsof cannabinoid receptor INHIBITION
Anxiety
Psychological disturbance
Drug discovery
Target selection
Lead optimisation
Pharmacological profiling
Drug development preclinical development
Pharmacokinetics
Short term toxicology
Formulation
Synthesis scale up
Drug clinical development phase 1, 2, 3
1 = healthy volunteers
2 = small group patients, dosages, long term toxicology studies
3 = large scale
How long does it takke to discovery and develop a drug
Discovery = 2-5yrs
Development = 10 ish years
What is angina
Severe pain in heart and chest wall
Artieries dont supply heart with enough blood
How is angina treated
Vasodilation
Opens arteries supplying more blood to heart
What are the arteries like in an angina patient
Partially blocked = blood reaches heart -> chest pain
Vasodilator = increase blood flow to heart -> relivees angina
Enzyme brings natural vasodilation to an end
Erectile dysfunction underlying disease
Diabetes, vascular disease, heart disease, spinal damage, prostate cancer, psychological problems, side effect of drug abuse/ smoking
What is UK-92480
Inhibits target enzyme
Prlongs natural vasodilation
Physiology of an erection flaccid and erect
Flaccid = spongy with spaces
Erect = penis stiffens and engorges, arteries dilate, penile blood flow
Drug addiction/ dependence definition
The human condition where drug taking becomes compulsive
Drug taking becomes more important than other basic needs
Often has serious knock on consequences
Involves physical and psychological dependence
Drug abuse/ substance abuse definition
Recurrent use of illegal or hamrful substances
Often centred around pleasure seeking
Can develop into addiction
Drug tolerance definition
Decrease in pharmacological effects of a drug with repeated use
Results in requirement for increased doses to achieve same effect
Often accompanies dependence/ addiction
Withdrawal syndrome
Adverse physical and psychological effects upon stopping taking a drug
Can last days, months or indeed years
Hedonic drugs
Associate effects of these drugs with pleasure
Designed to reinforce basic survival behaviours
Pleasurable effects of these drugs drive humans to repeat it
Names of reward pathway
Mesolimbic
Pleasure pathway
How to control the reward pathway
Inhibit nerve cells
Prevents releasing dopamine
Natural rewards stimulate what
Endogenous opioids
Inhibit the inhibitory inputs
Activate pleasure pathway
Unnatural reward stimulates what
Inhibits inhibitory input or directly stimulates pleasure pathway
Unnatural reward - breeds addiction
Repeatedly taking drug = brain down regulates reward pathway
Protective mechanism against abnormal levels of stimulation = means larger doses of drug required to stimulate the pathway
Non-chemical addictions
excessive 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)
Physical dependence opioid withdrawal
Downregulation of reward pathway
Depends on targets of drug
Wtihdrawal varies from drug to drug
Psychological dependence opioid drug waithdrawal
Craving
Brain learned to connect drug with reward
Stimulated by association
Long lasting, main reason for relapse
Short term substitution addiction treatment
Designed to lessen withdrawal and make it more bearable
Helps break habit and re establish control
Reduces chance of relapse
Long term substitution addiction treatment
Designed to gradually and progressively reduce drug dose
Uses controlled, prescribed form of drug
Allows brain to slowly adapt to lower doses of the drug
Re establishes natural balance
Blocking responses addiction treatment
Designed to prevent the problem drugs having an effect
Tends to involve blocking specific target od rug
Helps prevent relapse (taking drug little or no effect)
Tends to be used when addict is making good progress
Aversion therapies addiction treatment
Designed to produce an unpleasant response to drug
Discourages relapse
Helps to associate drug with unpleasantness
Unlearns association with pleasure
Psychological therapies addiction treatment
Therapies 1-4 are all pharmalogical
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 recucing chances of relapse
