Pharmacology Flashcards
What is pharmacology?
Studying the effects of drugs on the function of living systems
What is the definition of drug?
a chemical substance of known structure, which, when administered to a living organism, produces a biological effect.
What is a medicine?
chemical preparation administered with the intention of producing a therapeutic effect.
what is the difference between the drug and the medicine?
The medicine will contain the drug (active ingredient) and stabilisers, solvents, and other stuff that make the drug more effective.
What are the disciplines that feed in to pharmacology?
- chemistry (structure and target)
- physiology (normal biological function)
- pathology ( disease/ damage - process/ cause/ progression)
What is the book that is considered one of the oldest pharmacological books?
The Ebers Papyrus (Egyptian)
What did Pedanius Dioscorides do?
Wrote 5 volume encyclopedia (De Materia Medica) Which contain details about medicines used by Greeks, Romans, and other civilizations.
What is pharmacopoeia? and what is the first pharmacopoeia?
reference book containing details of drugs and their use. De Materia Medica
What are the characteristics defining the therapies before the birth of modern pharmacology?
- based on anecdotal evidence, spiritual beliefs and availability
- no understanding of how drugs work
-not patient friendly - flimsy science
- lacked control and credibility
Who are the fathers of pharmacology? and what did they do?
Rudolf Buccheim:
- first pharmacology professor
- emphasised the importance of defining drug mode of action
Oswald Schmiedeberg
- published outline of pharmacology
- defined modern pharmacology and pharmacologist
-separated between pharmacologists and clinicians.
What is the difference between a pharmacologist and a clinician?
Pharmacologist: concerned with investigating how drugs work.
Clinicians: concerned with the use of the drugs to treat
What did make pharmacology a precise, mechanism-based science?
Critical advancements in related disciplines ( chemistry and biomedical sciences)
What is pain?
broad class of unpleasant sensations ( Stinging, burning, pinching, aching)
Why do we feel pain?
- warning from actual or potential tissue damage
- encourage to withdraw limb from danger
- promote protection of damaged tissue to aid healing
- ensures we remember the incident and learn from the experience.
What are some of the early ways to relief pain?
- spells and incantations
- diet
- exercise
- consumption of potions/ formulations
- removal of painful limb/tissue/organ
- bleeding
- purging
- burning/ scalding
(aimed to restore the humoral balance)
What is opium?
gummy substance extracted from opium poppy plant
How did Hippocrates use opium?
used opium to treat headaches, coughs, asthma, melancholy
How was opium used before it was refined?
dissolved in alcohol (tincture of opium)
What were opium uses?
medicinal and recreational: induce analgesia, euphoria, sleep, suppress coughing and prevent diarrhoea
What was the first active ingredient isolated from opium? and who isolated it?
morphine, Friedrich Serturner
What are the components extracted from opium?
morphine, codeine
What is the significant that the extraction of morphine has in the history of pharmacology?
- first isolation of an active ingredient for any drug
- first proof that pure chemical in plants and natural products were responsible for biological responses.
What was morphine marketed as?
marketed by Serturner as
- analgesic
- treatment for alcohol and opium addiction
What was one of morphine’s first use?
medicine for children!!
Who invented the hypodermic needle?
Alexander Wood
How did the hypodermic needle changed the use of morphine?
- originally morphine was taken orally ( less potent/addictive)
- intravenous administration increased its potency
- increased opioid abuse
- addiction emerged as a side-effect.
How was morphine used as a battlefield analgesic?
- ampoule of morphine with attached needle for use in WWII bc:
- effective painkiller
- effects are almost instantaneous
What is diacetylmorphine?
- Heroin
- semi-synthetic opioid
- cough suppressant and analgesic
- ways of intake
*oral - converts to morphine
*intravenous - more potent/ addictive - one of the most addictive drugs in the world
What are the four main categories of drug targets?
- receptors
- enzymes
- carrier molecules
- ion channels
drug can either stimulate (agonist) or inhibit (antagonist) the target
How did Rene Decartes describe pain pathway in Treatise of man?
1) activation of a spot on the skin surface
2) Activation pulls a thread connected to a valve in the brain
3) Allows animal spirit stored in brain cavity to flow out which is responsible for:
*pain
*withdrawal of the limb from the pain source
*focusing toward the origin of the pain
What is the modern pain pathway?
- pain source (heat)
- pain receptors
- sensory nerve
- spinal cord nerve fibre
- nerve fibre ascends spinal cord to brain
- thalamus
who discovered the opioid receptors?
Solomon Snyder
What is an opioid receptor and where can it be found?
- present in the brain and spinal cord
- bind to opioids
- has several sub-types
- explains opioid actions
How do opioids work on opioid receptors?
inhibit the nerve fibre from firing by binding to it, hence pain relief.
How did the understanding of the pain pathway allow further development and discoveries in regard to drug design?
- developing synthetic drugs based on morphine with subtle differences that alter the activity and the properties of the new drug.
What are some examples of semi-synthetic opioid drugs?
- Oxymorphone: potent analgesia/ reduced euphoria
- Oxycodone and Buprenorphine: moderate analgesia/ reduced dependence
- Methadone: mild long-lasting analgesia/ dependence replacement
- Pethidine: mild-moderate analgesia/ rapid onset/ short-acting
- Fentanyl: very potent analgesia/ rapid onset/ short-acting
How does the pain pathway work normally to limit the sensation of pain? (without opioid intake)
- Mechanism 1: rubbing
1) rubbing
2) sensory receptors connected to a nerve fibre
3) spinal cord
4) inhibition of pain signal in the spinal cord
*less pain signals reach the brain - Mechanism 2: the descending pain-inhibitory pathway
1) nerve fibre originates in the brain
2) release endogenous opioids (enkephalins/endorphins) on the spinal cord
3) inhibition of pain pathway in the spinal cord
*discovered by Kosterlitz and Hughes in Aberdeen- Kosterlitz and Hughes purified and identified the structure of 2 enkephalins
How does the descending pain-inhibitory pathway get stimulated?
- stress (adrenaline)
- emotions
- opioid drugs
What are some of the other methods of analgesia (other than opioid drugs)?
- local anaesthetics + anti-inflammatory drugs
(ibuprofen, paracetamol, aspirin)- prevent pain receptors being activated
- TENS (transcutaneous electrical nerve stimulation)
- activates inhibitory sensory fibres (like rubbing)
- general anaesthetics
- induce loss of consciousness (no memory of pain)
- acupuncture
- stimulates release of enkephalins
What is cannabis?
an extract from Cannabis sativa plant
What are some of cannabis sativa preparations?
- Stalk:
fibre used to make hemp - Dried flowers/leaves:
used to make marijuana - Resin:
used to make hashish
What was cannabis originally used for?
used for hemp
Who mentioned the medicinal/ psychoactive effects of cannabis?
- Dioscordis in De Materia Medica
- Greek historians reporting on central Asian cultures
what are the main constituents of cannabis?
- tetrahydrocannabinol (THC): main active compound
- cannabidiol: THC precursor
- cannabinol: spontaneous product of THC breakdown
*collectively termed are cannabinoids
*lipid soluble
*active and psychoactive effects
What is the most potent cannabinoid?
tetrahydrocannabinol (THC)
What region of cannabis sativa is higher in THC concentration?
Resin
What are the physiological and psychoactive effects of THC on the central nervous system?
- loss of short-term memory
- increased confidence
- reduced co-ordination
- catalepsy
What are the physiological and psychoactive effects of THC on the digestive system?
- reduced nausea and vomiting
- stimulates appetite
What are other physiological and psychoactive effects of THC?
- increases heart rate
-dilation of airways
-reduced pressure within the eyes
What are the physiological and psychoactive effects of THC on the mood?
- relaxation
- sense of well-being
- sharpness sensory awareness (sight an sound)
What is the target of cannabinoids?
cannabinoid receptor
Where can the cannabinoid receptors be found?
membrane of certain cells
What are the types of cannabinoid receptors?
- CB1 (found in the brain)
most effects result from this type - CB2 (found in the periphery)
Where does the the cannabinoid binding occur (extracellular/ intracellular)?
outside the cell (extracellular)
Where does the the cannabinoid response occur (extracellular/ intracellular)?
intracellular
How does stimulation of cannabinoid receptors affect the cell?
inhibit cell activity
how does the cannabinoid affect the hippocampus?
- inhibits the hippocampus (involved in memory)
how does the cannabinoid affect the cerebral cortex?
- alters the cerebral cortex (involved in consciousness and sensory awareness
how does the cannabinoid affect the cerebellum?
- inhibits the cerebellum (involved in co-ordination)
how does the cannabinoid affect the brain stem/spinal cord?
- inhibits the brain stem/ spinal cord except heart rate (involved in pain, vomiting reflex, and control heart rate)
how does the cannabinoid affect the hypothalamus?
- inhibits the hypothalamus (involved in regulating appetite)
Does the human body produce endogenous cannabinoid?
yes it does, called endocannabinoids
what is the first endocannabinoid to be isolated?
anandamide
how many cannabinoids discovered so far?
5
What are the functions of endocannabinoids?
*cardiovascular: regulate heart rate
*digestion: prevent nausea/vomiting, stimulate appetite
*breathing: dilate airways
*pain: increase pain threshold (decrease sensation of pain)
what is the name of the synthetic derivative of THC?
nabilone
What are the clinical applications of cannabinoid drugs:
- Activation of cannabinoid receptors
*inhibition of cannabinoid receptors
What can the activation of cannabinoid receptors treat?
- nausea and vomiting in cancer chemotherapy
- reduce weight loss in cancer and AIDS
- glaucoma (decrease pressure in the eyes)
- multiple sclerosis (increases mobility, reduce pain)
- pain
- anxiety
What can the inhibition of cannabinoid receptors treat?
- blocks effects of endocannabinoid (antagonist)
- drug used called rimonabant
-potential use in treating obesity (blocks endocannabinoid stimulation of appetite)
What are the effects of cannabinoids in short-term?
Stimulation:
euphoria, drowsiness, sensory distortion, loss of short term memory
inhibition:
nausea/vomiting, diarrhoea
What are the effects of cannabinoids in long-term?
stimulation:
depression, lethargy, addiction, psychological disturbance
inhibition:
anxiety, psychological disturbance
what does the gateway theory suggest in term of cannabinoid use?
cannabinoid may stimulate needs for stronger, more addictive drugs
what are the types of diabetes?
Type 1: body does not produce enough insulin
Type 2: body produces insulin but can’t use it well
Gestational: a temporary condition in pregnancy
What are some of diabetes complications?
stroke, blindness, heart attack, kidney failure, amputation
What is diabetes?
increase in blood glucose
How can urine be an indicator of diabetes?
diabetes mellitus - urine sweet (high concentration of glucose)
diabetes insipidus - urine tasteless (very low concentration of glucose) *rare condition
What does insulin do?
allow take up of glucose into the cell
What is the name of the condition when blood glucose rises?
hyperglycaemia
where does insulin get produced?
Beta cells in islet of Langerhans (pancreas)
What could happen if diabetes type I was left untreated?
Starvation and death
what is the survival duration of type I diabetes pre- insulin discovery?
2 weeks to 18 months post-diagnosis
What was Fred Banting idea to treat diabetes?
isolate pancreatic secretion to relieve glycosurea (glucose in urine; hyperglycaemia), trials on dogs
Who did support Banting with his idea?
prof. John J.R. Macleod
Who was Banting assistant?
Charles Best
What was the process in which Banting achieved his first success?
injection of extract of degenerated pancreas injected to depancreatised diabetic dog induced a drop in blood sugar. (following Macleod advice in preparing the extract)
Who did help Banting to make a more effective extract?
James B Collip
Who were given the noble prize for insulin discovery?
Fred Banting and JJR Macleod
What is the largest insulin producer in the world?
Novo-Nordisk
Why is injection the best method of insulin intake?
Insulin gets destroyed by the gut if taken orally.
Inhaled insulin was withdrawn because of side-effects
What is the future of diabetes treatment?
Stem cell technology - repairing the pancreas and restoring beta cells
How much is spent from the NHS budget on treating diabetes?
over 10 billion pounds per year
What are the phases of drug discovery and development?
- Drug discovery
- Development:
*preclinical development (animals)
*clinical development (5-7 years)
#phase I (healthy volunteers)
#phase II (patient, small-scale)
#phase III (patients, large-scale)
*regulatory approval (1-2 years)
*phase IV (post-marketing surveillance) (1 year)
what is the importance of the drug discovery phase?
*understanding the disease and selecting the target (enzyme, protein, receptor, etc.)
*understand how a drug molecule will act on the target (stimulation or inhibition)
*identify molecules that would bind to the target and produce the desired effect
#start with about 100 project
what is the importance of the preclinical development phase?
*Assess short-term toxicology (using animal models)
*Pharmacokinetics (body effects on the drug - absorption, metabolism, secretion, etc,)
*Formulation (how is the drug taken - orally, IV, etc)
*synthesis scale-up (how is the animal trial relate to human)
#about 20% of the compounds make it to this stage (20)
#2-5 years
what is the importance of phase I of the clinical development?
*pharmacokinetics
*tolerability and side-effects of the drug in healthy volunteers
#about 10 compounds
#1.5 year
what is the importance of phase II of the clinical development?
*assess efficacy and dosage in small-scale trials in patients
*study long-term toxicology
#about 5 compounds
what is the importance of phase III of the clinical development?
large-scaled controlled clinical trials in different places
#about 2 compounds
What are some of the important rules applied in clinical development?
*Placebo controlled
*Double-blinded trials (neither the clinician nor the volunteer knows if they are giving/getting the placebo or the actual drug)
*Randomised trials (different age groups with different disease severity)
What disease is sildenafil citrate (Viagra) used for?
erectile dysfunction
What is angina? and how does it relate to Viagra?
*severe pain in the heart and chest wall due to insufficient blood supply to the heart by arteries
*Pfizer aimed to design vasodilation drug to relieve angina
*the target was an enzyme that brings vasodilation to an end
*inhibition of the enzyme would enhance natural vasodilation
*phase I trials showed a side-effect in male volunteers (penile erection)
*Pfizer started investigations of Viagra as a treatment for erectile dysfunction
*dropped as angina treatment due to lack of sufficient potency
What is erectile dysfunction?
inability to obtain or sustain an erection (often an indication of underlying disease/ problem)
Why is Viagra effective at promoting penile vasodilation and erection but not at dilating heart arteries to treat angina?
Because there are many subtypes of the target enzyme, and Viagra turned out to be more potent at inhibiting the enzyme subtype in penile arteries.
What are the side-effects of Viagra?
-headache, hot flushes, indigestion
- not advisable to take with certain heart conditions
How did Viagra indirectly save lives?
detection of underlying diseases earlier, as males with ED seeked medical help
What is drug addiction?
the human condition where drug taking becomes compulsive
What is drug abuse?
recurrent use of illegal or harmful substances
what is drug tolerance?
decrease in pharmacological effects of a drug with repeated use
what is the withdrawal syndrome?
adverse physical and psychological effects upon stopping taking a drug
What were some of the substances that caused addiction through history?
Mushroom (stone age)
Frog/toad venom (ancient tribes)
Cojobano seeds (prehistoric)
What are the drugs of today?
Alcohol
Opium
Cannabis
Cocaine
what are the drug types of today drugs?
*opioid analgesics
Morphine (VS), diamorphine (VS)
*nervous system depressants
Ethanol (S), Barbiturates (S), Anaesthetics (M), solvents(S)
*nervous system stimulants
Amphetamine (S), Cocaine (VS), Nicotine (VS),
Caffeine (W)
*others
Cannabis (W), LSD (W)
What is the link between the addictive drugs knowing that they are very different pharmacologically and structurally and they don’t bind to the same target?
they are called hedonic drugs (their effects are associated with pleasure). all of the addictive drugs activate the reward pathway in the brain.
What is the reward pathway?
Reward pathway (mesolimbic/pleasure pathway) is responsible for the feel of pleasure or reward by releasing dopamine.
What does keep down the activity of the mesolimbic pathway?
inhibitory nerve cells which prevent the release of dopamine.
How can the pleasure pathway be activated naturally?
pleasurable social activities (sex, shopping, etc) that stimulate the release of endogenous opioids (enkephalins) which inhibit the inhibitory input.
How can the pleasure pathway be activated unnaturally ?
drugs of abuse affect the reward pathway in two ways:
1) inhibit the inhibitory inbut
2) directly stimulate the reward pathway
How does the brain react to repeated substance abuse?
down regulates the mesolimbic pathway (less sensitive to drug stimulations)
what are the consequences of the protective mechanism of the brain?
*larger doses needed to experience similar effects
*pathway rarely activated without the drug
*withdrawal effects (depression, etc) when drug absent
How do the non-chemical addictions affect the pleasure pathway?
Engaging in those activities excessively and repetitively but to a lesser degree compared to their chemical counterpart.
Does the effects vary with different drugs of abuse?
yes, more potent> more addictive> more severe withdrawal effect> more likelihood of relapse
What is the difference between physical and psychological dependence?
*physical D: associated with down regulation of the reward system and other drug targets, varies from drug to drug, lasts days-weeks.
*psychological D: brain learned to connect drug with reward, produces craving, stimulated by association, long-lasting, main reason for relapse
What are some of addiction treatments?
1) short-term substitution
methadone (opioid), diazepam (alcohol)
2) long-term substitution
methadone (opioid), nicotine patches/chewing gum
3) blocking response
blocking drug’s target, prevent relapse, giving for addicts who show good progress
4) aversion therapies
produce unpleasant response to drugs
alcohol aversion therapy> induce violent nausea/ vomiting in response to alcohol
5) psychological therapy
