Health and Medicine Before the Age of Science PDF

Health and Medicine Before the Age of Science PHAR1101 Drugs that Changed the World Dr Philippa Martyr By the end of this lecture you will be able to …  Critically describe current sources of knowledge about medicine in the pre- science era.  Describe the scientific method.  Describe humoral...

Health and Medicine Before the Age of Science PHAR1101 Drugs that Changed the World Dr Philippa Martyr By the end of this lecture you will be able to …  Critically describe current sources of knowledge about medicine in the pre- science era.  Describe the scientific method.  Describe humoral theory.  Describe how and when Western medicine made the transition from guesswork to science. What do we  Almost nothing! Isn’t it wonderful? really know  Almost no forms of modern-day ‘traditional medicine’ can be authoritatively linked to prehistoric practice about  Diverse cultures all developed their own healing methods, including prehistoric drug therapy medicine and  These ways of healing were based on widely-differing beliefs and practices pharmacology?  Sources for information about ancient medicine include:  Cave paintings Where’s the  Physical human remains e.g. skeletons, skulls, bog bodies evidence?  Some fragmentary items which may be tools  ‘The Sorcerer’, from the cave known as ‘The Sanctuary’ in Montesquieu-Avantès, France, dated c.12000BCE Cave paintings Reconstructions of ‘The Sorcerer’  Cave paintings can be interpreted in any way you wish... Interpretations of this image include: Just a Shaman figure reminder of Indigenous healer Cultic leader the original … Evidence of prehistoric use of psychedelic drugs Alien (I'm not kidding) Bones 7000 year old skull with hole bored in it – found in Sudan. Believed to be trepanation (medicinal skull drilling) but there is no evidence to suggest why this was done, or whether it was done pre- or post- mortem. Tools Bog bodies and ‘icemen’ (glacier mummies) Tollund Man, bog body, Denmark, c.4th century BCE – ritually strangled? Hanged?   New analysis of stomach contents of bog body ‘Tollund Man’  12 to 24 hours before his death, he ate a hearty meal!  It was cooked in a clay pot  Porridge containing barley and flax; maybe also fish Tollund Man  Weed seeds - pale persicaria (Persicaria lapathifolia)  Tollund Man was infested with parasites – stomach contained proteins and eggs from intestinal worms, probably from contaminated food or water Ötzi, glacier mummy, Tyrol region, c.4th century BCE - murdered   Age: Ötzi’s thigh-bone = likely age of 45.  Height: In life, 1.60 m tall (mummy size 1.54m)  Weight: In life, around 50kg. Very wiry and strong.  Hair: dark, medium-long hair and worn loose.  Traces of arsenic = Ötzi was sometimes present where metal ores were being smelted.  Nails: horizontal grooves, or Beau’s lines, were observed on the Ötzi fingernail = great physical stress.  Parasites and pathogens: Two human fleas were found in Ötzi’s clothing.  Oldest evidence of Lyme Disease in Ötzi’s DNA.  The eggs of whipworm, an irritating intestinal parasite, were found in his digestive tract.  Archaeologists noticed that Otzi’s tattoos were all made over his joints, which made them wonder if it was a medicinal form of treatment, rather than purely decorative Ötzi   We have no conclusive physical evidence of prehistoric drug use as we would recognise it.  Plant remains found in prehistoric teeth and stomachs may have been food, rather than drugs. What evidence  Pollen traces in a setting may not be indicative of medicinal plant do we have for use. prehistoric  We can guess if we find local medicinal plants in a particular area, but these may be recently introduced. medicinal drug  Why assume medicine? Why not beauty, religion, commerce, use? politics?  There is a huge amount of ‘may’ and ‘could’ and ‘possibly’ in written research around these areas.   If we want to carry out reliable comparisons with modern scientific medicine, we must go to recorded history.  Early recorded history is very fragmented – entire millennia are missing in some cases.  Recorded history may only apply to the literate/noble class of that Is recorded society. history better?  Only the broadest generalisations are possible about early civilisations and medical practice.  We are still guessing/hypothesising in some cases. Did ancient medicine use the scientific  No. method?  Ancient recorded medical practices shows signs of observation (sometimes), of measurement (sometimes), of practical skills (sometimes), and of technology (sometimes).  None of these by themselves is the scientific method.  The ‘scientific method’ consists of organised efforts What is the to come up with explanations of scientific nature, method? always modifying and correcting these  through systematic observations How it works   This is because modern thinking often confuses ‘science’ with things like technology and equipment.  Ancient communities often had quite sophisticated technology and equipment at their disposal, and they certainly practised observation. Method versus  However, you can have a fully equipped laboratory and still not be random stuff using the scientific method.  You can be out in an open field and be using the scientific method to test something.  It is a method or approach that you take to a problem.   It allows discovery to proceed in an organised way.  It eliminates a lot of repetition.  It encourages us to change or revise explanations – or questions, Strengths of or hypotheses – in the face of the evidence. the scientific  It provides a clear audit trail. method  The results should be communicable and replicable.  All these things combine to speed up innovation and make it safer.   Hippocrates of Cos (c.406-370 BC?) is referred to as ‘the father of modern medicine’.  This is not true. Hippocrates,  We know almost nothing of Hippocrates’ life from actual historical the father of sources.  Plato mentions him in passing in two dialogues. medicine?  We don’t know who wrote the Corpus Hippocraticum (the Hippocratic Corpus – the body of work attributed to ‘Hippocrates’).   The Hippocratic approach DID systematise the description of disease duration (short-term, long-term).  The Hippocratic approach DID systematise some elements of What did the basic clinical observation. Hippocratic  The Hippocratic approach DID NOT use the scientific method to develop hypotheses about illnesses and test different remedies approach objectively. really do?  The Hippocratic approach may have held back the development of scientific medicine. This is what  The word ‘humor’ comes from the Greek word Χυμός, or chymos, which means ‘sap’. held it back  Prominent in the Hippocratic Corpus.  The human body was thought to contain four principal humors, matching the four elements of earth, air, fire and water that made up the universe.  Illnesses were caused by imbalance and excess in the four bodily humors.  Humoral theory was the single most enduring idea in Western medicine from the time of the ancient Greeks onwards WATER AIR FEMININE MASCULINE Phlegmatic = phlegm Sanguine = blood Greek phlegma = inflammation; Latin sanguis = blood phlegein = 'to burn' Aries Capricorn Taurus Aquarius Gemini Pisces EARTH FIRE FEMININE MASCULINE Melancholic = black bile Choleric = yellow bile Greek melan = black, khole = Greek kholē = bile; kholera = bile diarrhoea Libra Cancer Scorpio Leo Saggitarius Virgo Symbol of sulphur on flask = Symbol of mercury on flask masculine principle = feminine principle Humoral theory’s legacy  Humoral theory dominated Western medicine for centuries.  It was almost unbudgeable as a way of thinking about the human body, health and illness.  It probably originated in observations that were misplaced.  It was not tested using the scientific method.  Doctors themselves supported and promoted this theory.  Those who questioned it and used observation-based methods to experiment on their patients were called ‘empirics’ and ‘quacks’ and were denounced. The world of humoral theory  Ancient Greeks  Ayurvedic medicine – five elements: air, fire, water, earth, ether/space  Traditional Chinese medicine – five elements: wood, fire, earth, metal, water  Roman medicine  Classical Islamic medicine  Medieval European medicine  Renaissance medicine  Eighteenth century European medicine  People get sick Why do people Bleeding works. and die, and we can’t seem get sick all the If they die, it's to stop this time, with so because they happening many different deserved to. illnesses? You can’t do Gods? that! Theory is Demons? Un-scientific what holds medicine Curses? Diet? Injury? together! medical Humors? thinking Bleeding will Some people balance an sometimes excess of blood recover when we in the body that bleed them causes illness. heavily. So when DID medicine become scientific?  What we now recognise as ‘science’ dates from no earlier than around the early Middle Ages - 1200s CE.  Scientific approaches to all different kinds of human learning really began to flourish in the eighteenth century.  Scientific medicine didn’t really take off until well into the nineteenth century. How the scientific method got involved in medicine and pharmacology  Eighteenth century European philosophy:  Rationalism: The idea that we acquire knowledge through the use of reason, rather than from received ideas.  Inductivism: The idea that we can observe nature and then develop laws based on observation which can be tested and confirmed.  Empiricism: The idea that descriptions of things based on observation and experience indicate that a particular phenomenon is testable.  These are the building blocks of the modern scientific method. Johann Christian Reil and modern pharmacology  1797 - Johann Christian Reil - An Article on the Principles for a Future Pharmacology:  … we are not able to explain the action of drugs because we do not know their composition or the disposition of the human body in sickness or in health, or how they act on one another.  Until now an explanation of how drugs work, and therefore a science- based pharmacological discipline has not been possible.  The only way pharmacology can improve is to carry out tests, note the results carefully and subsume the isolated observations into higher- level rules…  All other methods are wrong and all attempts to find a principle to explain these things in any other way is a waste of time. Goodbye, humoral theory!  These new ways of thinking broke the centuries-old grip of humoral theory on Western medicine.  Humoral theory literally didn’t measure up.  New causes were found for diseases and illnesses.  These were measurable and followed particular patterns and durations.  They responded to particular drugs and treatments consistently pretty much every time.  This made medicine a lot less risky and a lot more effective. What do you need to do this better?  An Industrial Revolution!  18th century onwards: use of microscope, improved timing devices, grinders, distillation equipment, moulds.  Isolate elements = artificial compounds now possible.  Standardise doses.  Mass-produce remedies = cheaper.  Advertise and market products - wider audience.  Better communication between researchers.  Industrial processes also created new drugs by accident.  … all of which is the beginning of ‘Big Pharma’! In tomorrow’s lecture … We will ask some interesting questions:  What sorts of drug recipes have survived from ancient times?  Did any of these actually work?  Does any of this matter? Ancient Drugs: did they work? By the end of this lecture, you will be able to …  Describe how historians try to reconstruct ancient drug use.  Describe common natural drug sources.  Know the names of key drug innovators and their important texts.  Provide arguments for and against the reconstruction of ancient medicines.   We can measure the reduction in deaths caused by a particular disease.  We can measure the closure of hospitals such as TB facilities or mental hospitals. How do we  But these measures don’t capture all the effects of a drug on a society: measure the  For example, mental hospital closures only tell us ‘success’ of a that mental hospitals closed.  It doesn't tell us whether the quality of life of the drug? former patients improved or not.  It’s almost impossible to measure the effects of ancient drugs on populations because of confounding factors.   Modern anthropology has identified traditional practices in some cultures.  BUT we can’t authoritatively link that to ancient civilisations. How do we  Finding evidence that particular groups ritually know what bathed, or tattooed, or ingested clays, tells us very little about their ideas about medicine and health. ancient drugs  We know they HAD ideas about health and illness. were used, and  But unless they: why?  wrote them down, and  this has survived, and  we can understand them clearly,  we don’t really know what those ideas were. The Pozzino shipwreck cargo – ‘medicine chest’  Pozzino shipwreck (Tuscany) – nearly 2000 years old.  Discovered in 1974; excavated 1989-90.  Doctor’s chest, including numerous wooden and tin vials; some medical instruments as well.  X-rays of sealed container = five tablets, each about 4cm wide by 1cm thick.  Samples => zinc 75% - smithsonite (zinc carbonate) and hydrozincite (zinc hydroxycarbonate).  Also contained small amounts of animal and vegetal lipids, beeswax, pine resin, pollen grains and starch grains. The container and the zinc tablets Is it medicine? And if so, what sort?  Pliny and Dioscorides both describe how zinc compounds (calamine) used to treat eyes and skin complaints.  The Latin calamina = calamine, a mix of smithsonite and zinc silicate => calamine lotion today. Is it medicine? If so, what sort?  Were these tablets collyria? (tablets which could be dissolved into an eye salve)  Collyria are usually stamped and shaped slightly differently?  There is pine resin in the tablets – was it there to prevent microbial degradation?  Was the pine resin an active ingredient instead?  We have more questions than answers! 2015: ancient remedy proved effective against MRSA   Make an eyesalve against a wen: take equal amounts of cropleac and garlic, pound well together, take equal amounts of wine and oxgall, mix with the The original alliums, put this in a brass vessel, let stand for nine nights in the brass vessel, wring through a cloth and recipe clarify well, put in a horn and at night apply to the eye with a feather; the best medicine. – Bald’s Leechbook Bald’s Leechbook recipe  Scientists recreated a 9th Century Anglo-Saxon remedy using onion, garlic and part of a cow's stomach.  This successfully and repeatedly killed methicillin-resistant staphylococcus aureus (MRSA).  Equal amounts of garlic and another allium (onion or leek), finely chopped and crushed in a mortar for two minutes.  Add 25ml (0.87 fl oz) of English wine - taken from a historic vineyard near Glastonbury.  Dissolve ox gall (bovine salts) in distilled water, add and then keep chilled for nine days at 4C.   The recipe only worked against MRSA when it was followed exactly: Following the  You needed the right combination of ingredients  The right preparatory method recipe!  The right waiting time  Changing any of these reduced its efficacy against staphylococcus. Weights and measures  If we want to test ancient drug formulas, we need to understand their weights and measures.  Unfortunately, these have varied considerably over time.  Roman system persisted into Europe.  Lots of local variations on these for centuries.  In 1864, UK legislation standardised the 'apothecaries' weights' - minims, scruples, grains, dra(ch)ms, ounces and pounds.  1963: metric system introduced to the British Pharmacopoeia.  1965: Australian pharmaceutical industry.  1971: United States pharmaceutical industry.  Micrograms (µg), milligrams (mg), grams (g), kilograms (kg) - millilitres, litres What do we really know about ancient use of medicinal drugs?  It’s a bit of a mixed bag – lots of guesswork.  Easy to credit a culture with ‘advanced’ knowledge of medicine through chance use of particular drugs.  Do you need to know how something works to use it effectively?  YES!  Don’t try ancient drug recipes at home – quantities unreliable, potencies unknown, often highly toxic ingredients! Plant sources (eTute 2 - Bioprospecting)  Leaves: tobacco, hemp, geranium, lavender, mint  Gums, sap, resins: aloe, balsam  Roots: ginger, galangal, turmeric, valerian, echinacea, liquorice  Bulbs: lotus bulb, autumn crocus (colchicine)  Flowers: chamomile, calendula  Seed-heads: hemp, poppy  Spices (dried plant parts): pepper, cinnamon, nutmeg, cloves, cumin   hemp plant – leaves and buds  opium poppy – seed-head Psychoactive /  coca leaves - chewed CNS  betel nut - chewed stimulating  kava leaves - chewed plants  tobacco – smoked or chewed  peyote - a cactus which produces mescalin  mushrooms - psilocybin   Clay – kaolinite  Chalk  Red ochre – iron salts? Mineral  Mercury  Arsenic sources  Metal containers, e.g. bronze  Verdigris – copper carbonate – artists’ pigment  Gold, silver, antimony, zinc Alcohol as medicine  Beer - universal drink  Wine or vinegar: hugely common as medicine - Hippocratic Corpus, Galen, Celsus  Roger Bacon (c.1214-1294) The Cure of Old Age, and Preservation of Youth - healing properties of wine.  Distilled spirits – not until after around 1 st century CE.  Antiseptic and anaesthetic properties. Ancient Nubian beer as medicine?  In 1980 anthropologists discovered what seemed to be the antibiotic tetracycline in nearly 2,000-year-old Nubian bones.  Did it come from their beer recipes?  Beer (as in Ancient Egypt) was made from bread.  Sprouted grains were milled into flour – soil bacterial Streptomyces could have entered process.  Nubian brewers made bread with tough outer crust and raw interior.  This was mixed with water and unmilled grains, and fermented into beer – full of tetracycline produced by Streptomyces.  Is this really ‘antibiotic’ use? We don’t know. Other sources  Raw honey  Insects – blister beetle = cantharides; spiders; ants; locusts  Animal organs and tissues – ox gall (bile salts); hair, horns, dung  Human body parts – hair, urine, blood, fat  Mummies – powdered for asphalt and ingested in medicines – artist’s pigment  Manuscripts – spells written on slips of paper and swallowed Ancient Egypt  The Ebers Papyrus:  Longest and most famous of the ancient Egyptian medical papyrii.  Contains herbal and magical remedies for common complaints.  Most of its ‘medical’ treatments are based on purging.  Body contains toxins that cause illness, which need to be expelled from the body. Ebers Papyrus – spell and ointment for leucoma (opacity in cornea). Gall was used to treat trachoma for at least two millennia. Gall is an irritant and cauterising agent. Shamanism  Ancient Egyptian medicine fits the pattern of shamanism.  Amulets, sacrifice, augury/prophecy, divination, cursing, advice, teaching, trances, communication with animals or the dead.  Common global practice.  Combined role of spiritual and physical healer.  Could be male or female.  Bridge between spirit world and physical world.  For reducing plentiful urine – proportions, but not actual measures: Transliteration and recipe – Ebers Papyrus Hippocratic Corpus – ulcer dressing recipe An ulcer dressing:-  The dried gall of an ox, the finest honey, white wine, in which the shavings of the lotus have been boiled, frankincense, of myrrh an equal part, of saffron an equal part, the flowers of copper, in like manner of liquids, the greatest proportion of wine, next of honey, and least of the gall.  Another:-Wine, a little cedar honey, of dried things, the flowers of copper, myrrh, dried pomegranate rind.  Another:-Of the roasted flowers of copper half a drachm, of myrrh two half-drachms, of saffron three drachms, of honey a small quantity, to be boiled with wine.  Gall and wine are both astringent.  Raw honey is antiseptic.  Copper salt preparations stimulate wound healing through the production of collagen and elastin.  Pedanius Dioscorides (40-90 CE):  Author of De Materia Medica, the first authoritative Western pharmacoepia (c.50-70 CE).  Hugely influential throughout Europe until 19th Ancient Rome - century. Dioscorides  Describes about 600 plants – not all can be identified even now.  Also includes animal products and minerals.  Still contains some magical uses for plants, eg. talisman against snakes. Dioscorides, ‘Roots’ (Book 3 of De Materia Medica)  POTERION  a large shrub with long branches — soft, flexible like a bridle, thin, similar to tragacanth — the leaves little, round. The whole shrub is surrounded with a thin woolly down and is prickly; the flowers are small and white. The seed (to one who tastes it) has a sweet scent and is sharp with no use. It grows in sandy and hilly countries. The roots are underneath, two or three feet long, strong and sinewy. When cut close to the ground they send out a fluid similar to gum. The roots (cut and smeared on) heal cut-apart sinews and wounds, and a decoction of it (taken as a drink) is good for disorders of the strength. It is also called phrynion, or andidotum, and the Ionians call it neurada.  Astragalus poterium, Astragalus arnacantha, Astragalus gummifer — Small Goat’s Thorn?  Positive effects of tragacanth on wound healing were demonstrated in 1 small clinical trial.  Clinical trial data are lacking to recommend use for any indication.  Galen of Pergamon (129-216 CE):  Influence extended well into the 1600s in Europe.  Is likely to be the author of most of the works attributed to him (over 500).  Two-part treatise De Compositione Roman Medicamentorum (On the Composition of Drugs). medicine -  Strongly influenced by Hippocratic approach and humoral theory. Galen  Carefully noted the exact measurements of drugs that he gave to patients.  BUT: Also believed in theriac – a mystery substance with 64 ingredients which could cure any illness in human beings.   Islamic world preserved Greek manuscripts from decline of Rome to early 1200s CE.  Heavily influenced by classical ideas – Greek, Roman - of medicine and herbalism.  Humoral theory underpinned Islamic approach to drug therapy. Classical Islam  Al-Rhazi (864-930 CE) – wrote extensively on diseases and treatments.  Introduced mercury-based compounds to pharmacopeia.  Ibn Sina (Avicenna) (980-1037 CE) – his book Al Qanun contains more than 700 drug preparations.  The Canon of Medicine (Al Qanun fit-Tibb) ‫‘( القانون في الطب‬law in medicine’)  To help produce breast-milk:  Eat the udders of sheep and goats [sympathetic magic].  An ounce of tree-worms or dried earthworms in barley water, drunk for several days.  Juices from the heads of salted fish, taken in water with dill.  Sesame, ground up and mixed with wine.  Dill seed (3 oz), seed of blue melilot (1 oz), leeks (1 oz), clover seed (1 oz), fennel seed (1 oz) – mix into a drink with fennel juice, honey, and butter. Earthworms are used as medicine in many Asian cultures. Dill is a purported galactagogue, but no scientifically valid clinical trials support this use. Fennel is still considered to be a natural galactagogue. Sesame seeds are also used traditionally as galactagogues. Paracelsus (1493-1541 CE)  Devoted mineralologist and toxicologist.  Challenged the theory-based approach to medicine.  Championed the use of mercury to treat syphilis.  BUT – believed in humoral theory, alchemy, the occult, astrology. Some Paracelsian remedies  For tuberculosis – eat the lungs of a fox [sympathetic magic]  Reported from Galen - a charm against epilepsy – hang a peony, that has been picked at an auspicious time, around your neck.  Against epilepsy: 6lb wine, 10 drams cantharides, flowers of tapsi, cannabis, chamomile, St Johns Wort, 6 hands-full. Crush and mix it together – allow it to draw in the rays of the sun or in the heat of manure for one month. Distill and add betony, resin, frankincense, earthworms. Distill for a further 8 days.  Cannabidiol has anticonvulsant properties.  Chamomile shows some anticonvulsant properties. The eighteenth century in Europe  1700s – flourishing new science of botany fuelled new drug experimentation.  More experimentation and better communication in medicine.  Folk remedies scrutinised more closely = digitalis treatment for heart conditions (Week 5).  BUT: humoral theory persisted!  Aspirin’s key ingredient is salicylic acid:  Isolated in 1800s from willow bark … Did ancient  … therefore, any ancient recipe mentioning willow must meant peoples use that this culture understood the pain-relieving properties of salicylic acid? aspirin?  Not true!   Effective drugs do exist in nature (like opioids, for example).  But it's usually in very tiny amounts - not therapeutic doses.  White willow bark (Salix alba) has quite a low concentration of salicin, compared to other Salix species. And why we  A standardised modern dose of 40-60mg of salicin would be very hard to obtain from simply chewing willow bark or drinking tea. know this  The tannins in the plant can be toxic at this dose.  Isolating salicin from willow bark came via modern experiments over quite a long time.  Making salicin into something useable – aspirin – took yet more time in modern pharmacological laboratories. So do ancient drugs work?  The short answer is: Some of them, sometimes.  The long answer is: We don’t really know because -  We usually can’t replicate the recipes - we don’t know the right quantities or ingredients.  We don’t know the right conditions under which to make the drug (shelf-life of ingredients, containers, other confounds).  It’s not always responsible to try if the ingredients are dangerous, e.g. mercury.  It takes time, patience, careful experimentation, and transparent reporting of results (including failures) to develop a drug recipe that works for most people, most of the time.  Most of these conditions could not be found in the ancient world! And is it worth it?  Even if we can replicate an ancient recipe:  they deteriorate over time and have very limited shelf-life.  they usually cannot be easily mass-produced.  they cannot be easily transported.  BUT: it’s fun and occasionally successful.  It might lead to new pathways in research for isolating effective trace elements. Next week …  Biological foundations – it’s human biology time!  Please ensure you complete eTute 1 next week, ideally before your lectures?  What happens to drugs in the body – Phil B  How drugs work in the body – Ricky C  PHAR1101 – Drugs That Changed the World 11 am, Wednesday July 31 What Happens to Drugs in the Body? Assoc Prof Phil Burcham Division of Pharmacy (School of Allied Health, UWA) Division of Pharmacology & Toxicology (School of Biomedical Science, UWA)  Outcomes for this Lecture 1) Define “pharmacokinetics” and distinguish it as a separate domain of drug- related knowledge from pharmacodynamics 2) Identify the key features of a plasma concentration-time curve and explain their significance to the beneficial and harmful effects of drugs (i.e., explain the concept of a “therapeutic window” and identify its key features) 3) Identify 4 key pharmacokinetic processes and their defining features that control the fate of drugs in the body: Absorption, Distribution, Metabolism, Excretion 4) Explain the importance of metabolism and excretion in controlling the duration of drug effects in the human body. 5) Identify lipophilicity and hydrophilicity as determinants of the pharmacokinetic behaviour of drugs. Show an awareness of how the octanol-water partitioning method provides some insight into these phenomena.  Aim of Lecture To convey a basic appreciation of essential pharmacokinetic factors that control the behaviour of medicines within the human body.  Every Drug is Like a Two-Sided Coin PD PK PD = pharmacodynamics PK = pharmacokinetics “what the drug does to “what the body does to the body” the drug” i.e. Every drug possesses its own distinct pharmacodynamic properties and its own pharmacokinetic properties. Why are Drugs Taken at Different Intervals?  Pharmacokinetics Provides the Answer! Definition: The branch of pharmacology A ABSORPTION that studies the behaviour of drugs as they move into, around and out of the body. In chemistry: D DISTRIBUTION kinetics = the rate or speed at which chemical reactions occur In pharmacology, kinetics is concerned with the M METABOLISM rates at which drug levels in blood rise and fall – Essentially, 4 fundamental “ADME” processes EXCRETION control these changes E urine  What Happens After Taking a Pill “PHARMACEUTICAL PHASE”...................................................................................... individual.............................. drug....... molecules DISINTEGRATION INGESTION & DISSOLUTION “PHARMACOKINETIC PHASE” ABSORPTION METABOLISM DISTRIBUTION EXCRETION  The Core of Pharmacokinetics = Knowledge of Drug Concentrations in Blood from Drug-Treated Individuals ADMINISTER DRUG COLLECT A SERIES PREPARE SAMPLES MEASURE DRUG OF BLOOD SAMPLES FOR ANALYSIS LEVELS IN SAMPLES TO SUBJECTS GRAPH BLOOD Drug concentration in CONCENTRATIONS AGAINST TIME This known as a “Plasma blood Concentration-Time Profile or Curve” drug dosing Time Knowing Plasma Concentration-Time Profiles Help Us Define the “Therapeutic Window” for a Particular Drug MTC = (Minimum DRUG Toxic Concentration) (patient TOXICITY suffers) Drug concentration “Therapeutic in blood (patient Window” benefits ) MEC = (Minimum (no Effective benefit) Concentration) Therapeutic = healing outcome or relief of drug dosing Time disease symptoms Patients Benefit from Drugs Only When Blood Levels are within the “Therapeutic Window” Drug concentration Peak effect “Therapeutic (Cmax) Window” in blood benefit starts stops Duration of effect benefitting MEC drug dosing Time Most Drugs Produce Dose-Dependent Plasma Concentration-Time Profiles MTC = (Minimum DRUG Toxic Concentration) TOXICITY Drug concentration Dose too high “Therapeutic in blood Window” Dose about right Dose too low drug dosing Time The Width of the Therapeutic Window Shows How Safe a Drug Is MTC TOXICITY TOXICITY Drug concentration in blood Drug concentration in blood MTC Wide Narrow Therapeutic Therapeutic Window Window MEC MEC Drug B – riskier for Drug A – patients safer for patients Time Time therapeutic therapeutic dose dose  The Goal of Pharmaceutical Innovation is to Widen the Therapeutic Window within a Drug Class “Gen-1” “Gen 2” Drug “Gen 3” Drug Innovator Drug TOXICITY MTC TOXICITY TOXICITY MTC Drug concentration in blood Drug concentration in blood Drug concentration in blood MTC Narrow Wide Intermediate Therapeutic Therapeutic Therapeutic Window Window Window MEC MEC Time Time Time The 4 ADME Processes Control the Shape of Plasma Concentration- Time Profiles DISTRIBUTION METABOLISM Drug concentration & EXCRETION in blood ABSORPTION Time drug dosing  ADME 1 – Absorption How Well does a Drug Enter the Body? The most convenient way to take a medicine is by mouth (“oral route of administration”) Drug Absorption is process whereby FOral = Oral Bioavailability ingested drug molecules relocate from Fraction (F) of ingested drug interior of GI-tract into the portal blood dose that reaches the systemic (drains from gut into the liver) circulation after ingestion. Often, less than 100% of ingested dose Some examples: makes it into the portal blood Paracetamol: F ≈ 88% Some may remain unabsorbed Codeine: F ≈ 50% Some may be broken-down in gut wall Mercaptopurine: F ≈ 12%  drug Why Bioavailability (F) is 100 mg often less than 100% portal vein gut wall systemic circulation liver metabolism 55 mg 40 mg 5 mg (unabsorbed) faeces F = 0.55 or 55% Reasons for Poor Bioavailability (Poor Absorption) Octanol-Water Partitioning  Assesses solubility of drug in simple 1) Drug is too big (MW>600 g/mol) 2-phase system: water & octanol (model organic solvent) 2) Drug is not greasy enough  Octanol floats on water layer Too “hydrophilic” (= “water loving”)  Add drugs, mix, settle  Lipophilic drugs go into octanol, Needs some “lipophilicity” (= “fat-loving”) to cross lipid- hydrophilic drugs into water rich cell membranes in gut wall Lipophilic Hydrophilic drug drug 3) Drug carries a charge (“ionised”) E.g. protonated amine group (-NH3+) octanol octanol Only neutral molecules passively cross lipid membranes 4) Drug is metabolised in gut wall water water 5) Drug is pumped back into gut Orally-Administered Drugs Need a Balance of Solubility Properties “membrane transporters” = “molecular turnstiles” in cell Hydrophilicity membranes Lipophilicity (“affinity for water”) (“greasiness”) Limit entrance of drugs into body  ADME 2 – Distribution Where does a drug go after entering the blood? 1)Where drugs go once in the blood stream reflects their “physicochemical properties” Two Opposite Scenarios A) Tissue-Penetrating Drug i.e. lipophilicity, hydrophilicity, ionisation, etc blood 2)Some drugs mainly remain in the blood E.g. bound to blood proteins such as albumin tissues 3)Other drugs penetrate into tissues E.g. muscle Fat (if drug is very lipophilic or “greasy”) B) Blood-Associated Drug 4)Getting drugs into the brain is hard because of blood “blood-brain barrier” tissues Tight junctions between cells in capillaries Strong expression of drug transporters Drugs Differ in their Tissue Penetrance Capacity Image (mod.): Burcham, PC, Introduction to Toxicology (2014)  ADME 3 – Metabolism Does the drug’s chemical structure get changed in the body? 1)Greasy drugs might accumulate in body tissues Cause harm in vulnerable organs (“toxicity”) Definition of Drug Metabolism 2)The body’s solution is to convert them into “The chemical alteration (i.e. water-soluble metabolites structural modification) of drugs by drug-metabolizing Then removed by the kidneys into urine enzymes (DME) in the body.” 3)The body expresses hundreds of drug- metabolising enzymes (DME’s) DME Lipid Gut wall active membrane site Liver Kidneys Drug 4)Protect us against drugs, pollutants, industrial OH chemicals, food-borne chemicals metabolite of drug Drugs Usually Gain Water-Solubility During Metabolism “parent” drug Parent drug is octanol greasy and 1) Oxidative lipophilic water metabolism Metabolite 1 has Metabolite I gained hydrophilicity octanol but is still quite OH 2) Conjugative water lipophilic metabolism Metabolite 2 Metabolite 2 octanol is very O hydrophilic water urine  Metabolism Usually Makes Drugs Less Active By changing drug structure, metabolism often reduces activity Metabolite has less affinity for receptor (poorer “fit”) However, some drug metabolites do possess some pharmacological activity i.e. “active metabolites” – contribute to the effects of the “parent” drug on the body Some drugs are inactive until they are metabolised in the body (“pro-drugs”) Some drug metabolites are toxic (e.g., paracetamol liver damage is due to a minor metabolite) 1. Parent Drug “fits” Drug 2. Some Metabolites “fit” 3. Most Metabolites don’t “fit” Binding Site on Receptor into Receptors (“active”) into Receptors (“inactive”) Metabolite 1 Metabolite 2 drug OH O drug receptor drug receptor drug receptor  ADME 4 – Excretion How are drugs that aren’t metabolised removed from the body? 1)≈¼ 25% of human medicines are not metabolised Definition of Excretion “The permanent removal of Pass through gut wall and liver unchanged unchanged drugs from 2)They are mainly excreted by the kidneys in urine the body via body fluids The kidneys also remove drug metabolites and secretions, expired air or tissue shedding.” 3)A minority of drugs are excreted into the bile blood to urine Drain via bile duct into large intestines Kidney epithelial 4) Other minor routes of excretion include: cell Kidney nephron Breast milk (nursing mothers, e.g., cocaine) expired air (e.g., ethanol) Transporters 5) Membrane transporters act as excretory drug pump drugs into pumps into urine, bile, milk, etc urine at kidneys The Speed of Excretion + Metabolism Determines the Half-Life of Drugs & their Dosing Frequency Drug concentration in blood 100 METABOLISM & EXCRETION 50 Half-life = t1 – t2 (hrs) 0 t1 Time t2 drug dosing  Summary 1: How the Body Usually Protects Itself Against Drugs  In general, hydrophilic drugs undergo little or no metabolism  Excreted unchanged in urine  Lipophilic drugs are converted to hydrophilic metabolites that are then removed by kidneys and excreted in urine Hydrophilic drug Lipophilic drug Excreted directly Metabolised by kidneys in liver (unmetabolised) Hydrophilic drug Urine Transported metabolite via blood  A Few Real-World Drug Examples Hydrophilic Drugs Lipophilic Drugs (mainly appear in urine as (mainly appear in urine as unchanged “parent” drug) metabolites, not the parent drug) Penicillins (antibiotics) Morphine (strong painkiller) Cephalosporins (antibiotics) Efavirenz (HIV drug) Gentamycin (strong antibiotic) Diazepam (anxiety medicine) Metformin (diabetes drug) Chlorpromazine (anti-psychosis medicine) Summary 2: Metabolism is the Main Way Drugs are Removed from the Bloodstream Primary Clearance Route (Top 200 Medicines) Bile (faeces) Kidneys (direct to urine) Metabolism in liver Redrawn from Smith et al (2012)  Lecture Summary: Pharmacokinetics Any effective drug must enter the body and access the tissues where its main receptors are located  It must achieve adequate concentrations in the vicinity of its receptors  i.e., not be metabolized or excreted too fast  Pharmacokinetics is concerned with: How drugs get into the body, Where drugs go within the body, Whether their structure changes while in the body How drugs exit the body  i.e. Pharmacokinetics (PK) = “what the body does to the drug” Includes 4 main processes (“ADME”):  Absorption, Distribution, Metabolism, Excretion www.eupati.eu (mod.)  Going Further Buxton, IL (2022) Chapter 2: Pharmacokinetics, In: The Pharmacological Basis of Therapeutics, 14th edition, McGraw-Hill, New York. [Quite advanced] Waller DG (2022) Chapter 2: Pharmacokinetics, In: Medical Pharmacology & Therapeutics, 6th edition, McGraw-Hill, New York. PHAR1101 Drugs that Changed the World How drugs work in the body? Dr Ricky Chen  Learning outcomes After completing this lecture, you should be able to distinguish between pharmacokinetics and pharmacodynamics describe drug and three types of drug name and their characteristics for a marketed drug describe drug target and list four groups of human proteins as drug targets describe a select number of drugs explored in PHAR1101 in terms of (i) classification of drug target, (ii) drug target, (iii) drug action, and (iv) clinical use provide the full name and describe the main characteristics of four receptor superfamilies describe agonist, antagonist, affinity, efficacy, concentration/dose-response relationship, potency, and EC50 in the context of ligand-receptor interaction and therapeutic index describe the action of morphine in the context of pharmacokinetics and pharmacodynamics PHAR1101 and the Pharmacology major PHAR1101 Drugs that Changed the World historical aspects pharmacological aspects pharmacokinetics alcohol pharmacodynamics opioids antibacterial drugs antidepressants anti-HIV drugs anxiolytics thalidomide and toxicology anaesthetics antihypertensives cancer treatment Level 2 PHAR2210 PHAR2220 Level 3 PHAR3310 PHAR3320 PHAR3311 PHAR3321 From pharmacokinetics to pharmacodynamics drugs human body pharmacokinetics pharmacodynamics what the body does to a drug what a drug does to the body  Drugs Drug - a substance that produces a biological effect when introduced into the body o treat symptoms, not causes; exceptions, e.g., antimicrobial drugs o treatment and prevention, e.g., anti-HIV drugs small molecules biologics morphine penicillin antibodies peptides (e.g., enfuvirtide)  Types of drug name A marketed drug is known by three types of drug name Type of drug name characteristics (medicinal) chemists chemical name describes the (complex) chemical structure of drugs pharmacologists generic name stems/roots to indicate the origins, use, actions, or structure of drugs 1 public invented by drug companies for marketing purpose brand name (or trade name) o different brand name by different manufacturers and in different countries 2 o intended to be catchy and memorable HIV protease inhibitor (-navir), e.g., darunavir ritonavir 1 2 saquinavir  Drug targets Drug target are molecules (often proteins), the function of which can be modulated by a drug to produce a biological effect drugs small molecules biologics pathogen proteins other pathogen biomolecules human proteins other human biomolecules Drug targets - human proteins 1 receptors (R) 3 2 ion channels (C) 2 1 3 transporters (T) 1 4 4 enzymes (E) Reiser et al. (2014)  Drug targets - human proteins most drugs binds to and inhibit the function of their drug target The drugs or drug classes in the table below are covered by subsequent lectures in this unit. clinical use Drug or drug class Classification of drug target Drug target Drug action (indication) alcohol receptor GABAA receptor modulate - morphine receptor opioid receptor activate pain relief nitroglycerin enzyme guanylate cyclase activate treat angina pain statins enzyme HMG-CoA reductase inhibit lower cholesterol penicillin enzyme transpeptidase inhibit antibacterial benzodiazepines receptor GABAA receptor modulate treat anxiety (anxiolytics)  Interaction between a drug and its drug target Drug affinity is the binding strength of a drug to a target a drug target has small cavities [binding site(s)] for ligand (L) binding o special arrangement of amino acids (and their functional groups) L Van Der Waals increasing hydrogen strength of bond ionic L complementary 3D shapes covalent distance between strength of chemical forces of attraction ligand and target chemical forces complementary 3D shapes chemical forces of attraction L total number of bonds  Cyclooxygenase (COX)-2 selective inhibitors isoleucine to valine substitution at position 523 - a side pocket 1 to accommodate bulkier substrates wider channel opening 2 cyclooxygenase (COX)-2 selective inhibitors isoleucine valine o side chain fits the side pocket 1 2 Knights et al. (2010) Mollace et al. (2005)  Receptors as drug targets In pharmacology, receptors are proteins that recognise and respond to endogenous chemical signals recognise - act as a cell’s “sensing elements” respond - transduce chemical signal into a change in cell activity receptor location of time scale an example superfamily receptors of action ligand-gated ion GABAA cell membrane milliseconds channels receptor G protein-coupled opioid 2 receptors 2 cell membrane seconds receptor 1 enzyme-linked cell membrane minutes - receptors nuclear receptors 1 intracellular hours - Reiser et al. (2014)  Ligand-receptor interaction (I) Drug affinity is the binding strength of a drug to a target Drug efficacy is the ability of a drug to elicit a response once bound to a drug target agonist: binds and activates receptors, therefore mimic the actions of endogenous ligands affinity ✓ efficacy ✓ signal transduction change in cell activity receptor receptor antagonist: binds but does not activate receptors, therefore blocks the actions of endogenous ligands affinity ✓ efficacy  signal transduction change in cell activity receptor receptor  Ligand-receptor interaction (II) Dose/concentration-response relationship is the relationship between the dose/concentration of a drug and the magnitude of the response produced graded response, not all or nothing glycine (mM) % of max response glycine (mM)  Ligand-receptor interaction (III) Drug potency refers to the amount of a drug, expressed as the concentration or dose, needed to produce a defined effect 100 % of max response Agonist potency commonly measured as the effective concentration (EC50) / dose (ED50) required Drug A Drug B to produce 50% of the maximum response 50 a lower EC50 or ED50 indicates higher potency ED50 ED50 0 log [drug dose] Fentanyl and morphine are both opioid analgesics. Fentanyl is ~100x more potent than morphine  Dose-effect relationship Fundamental to pharmacology and toxicology 1 dose is too low → drug is unlikely to doses produce doses produce produce a therapeutic effect therapeutic effect toxic effect 2 optimal dose → drug produces 3 sufficient therapeutic effect and few effect adverse/toxic effects 2 3 dose is too high → drug produces a larger therapeutic effect but also likely adverse/toxic effects 1 log [drug dose]  Therapeutic index ED50 (effective dose, 50%) and TD50 (toxic dose, 50%) TD50 narrow TI o inform therapeutic index (TI = ) ED50 effect doses produce doses produce therapeutic effect toxic effect log [drug dose] effect wide TI effect ED50 log [drug dose] TD50 log [drug dose] Drug in action - morphine (I) morphine mimic the action of endorphin (endogenous morphine) classification of drug target G protein-coupled receptor  opioid receptor receptor human protein (receptor superfamily) signal transduction change in cell activity pain relief the general structure of a G protein-coupled receptor  opioid receptor-mediated signal transduction  Drug in action - morphine (II) codeine and paracetamol to full-term Desirable effect: analgesia (pain relief) treat episiotomy pain healthy male Undesirable effects, e.g., Day 2: drowsiness and respiratory depression (most dangerous) constipation so codeine Day 7: difficulty in dose halved miosis (pupillary constriction) breastfeeding and lethargy reduced airway reflexes Day 10: stored milk Day 11: paediatric visit - constipation regained birthweight dependence continued the tablets Day 12: grey skin and for two weeks fallen milk intake blood [morphine] in [morphine] in milk neonate Day 13: found dead measured 70 ng/ml measured 87 ng/m (typical 0~2.2 ng/ml) (typical 1.9~20.5 ng/ml) no anatomical anomalies prodrug metabolised by CYP2D6 pharmacologically active excreted into codeine morphine breast milk mother: CYP2D6 ultrarapid metaboliser elevated blood [morphine] elevated [morphine]  Summary - what you have learned difference between pharmacokinetics and pharmacodynamics drugs types of drug name drug targets important drugs you will learn later in PHAR1101 interaction between a drug and its drug target receptors as drug targets - agonist, antagonist, affinity, efficacy, concentration/dose-response relationship, potency, EC50, and therapeutic index (use eTute 1 to reinforce your understanding) morphine as an example to bring different concepts together revisit this lecture as needed throughout the semester PHAR1101 – Drugs That Changed the World 11 am, Wednesday August 7 The Oldest Drugs - I: Alcohol Assoc Prof Phil Burcham Division of Pharmacy, School of Allied Health Division of Pharmacology, School of Biomedical Science  Lecture Outcomes 1) describe the basic chemistry of alcohols and the processes involved in the production of ethanol by yeast 2) summarise four types of alcoholic beverages in terms of sources, production, and alcohol content 3) describe the pharmacokinetics of alcohol 4) describe the main effects of alcohol on the brain and human behaviour and the disinhibition hypothesis 5) describe the action of two key receptors in mediating the effects of alcohol on the brain 6) describe alcohol use disorder and alcohol metabolism in chronic heavy drinkers 7) describe the relevance of metabolism to alcohol toxicology and name the toxic metabolite of alcohol that causes DNA and protein damage  Aim of Lecture To explore the historical and scientific issues surrounding alcohol use within human societies, giving particular attention to its pharmacokinetics, effects on the brain and capacity to cause harm in heavy drinkers. Acknowledgment: This lecture draws some content from earlier PHAR1101 lectures developed by Drs. Martyr and Martin-Iversen.  “Alcohol” – What Is It? OH OH H C H Alcohols = small organic molecules containing 1 or OH H C H H C H more hydroxyl groups (OH-) attached to a carbon H C H H C H H H C H atom (C) that can be attached to other C atoms H H  e.g., Methanol (1-carbon), 1-Propanol (3-carbons, Methanol Ethanol 1-Propanol 1-Butanol (4-carbons), etc) (Boiling Point = 65°C) BP = 78°C BP = 97.4°C Ethanol (EtOH, 2-carbon), is the alcohol widely OH OH consumed by humans H C H OH H C H Many alcohols are toxic H C H H C H H C H  e.g. Methanol – causes H C H H C H H C H eye injury, e.g., vision H C H H C H loss in “Moonshine” H C H H C H H C H drinkers during H C H H H C H Prohibition Era in USA H H (1920-1930s) 1-Butanol 1-Pentanol 1-Hexanol BP = 117°C BP = 137°C BP = 157°C  Ethanol is Made by Yeast During Glucose Utilisation Ethanol is a metabolite made by Brewer’s yeast (S Cerevisiae) during the metabolism of sugars (glucose) to extract energy for their needs Such “fermentation” requires the absence of oxygen (O2) (i.e. “anaerobic” conditions) Cell growth is carefully monitored in fermentation vats since excessive alcohol levels are toxic to yeast  (Such toxicity towards microorganisms makes ethanol a good hand sanitiser!)  History of Alcohol – I: General Aspects  While the sugar source used varies across cultures (e.g. grains vs. fruits), knowledge of fermentation is common across history  Arose independently in many civilisations  May have been practiced deliberately as early as 10,000 BC (‘Stone Age’)  Alcohol production related to ‘civilisation’ = emergence of stable communal life  Alcohol usage is complex in human societies  Not same as alcohol abuse  Complex interplay of religious, economic, medical & recreational motives Siduri  Patchy historical record in ancient world Babylonian wine goddess (‘The Innkeeper’)  History of Alcohol - II: Ancient Egypt (c3000 BC – 300BC) Early producers of beer from barley  Bread and beer were dietary staples The god Osiris taught people to make beer (grain was sacred)  Included in wedding contracts Brewing may have been a state monopoly  Used as currency for trade  Cleopatra VII – first tax on alcohol Strong religious/cultic element:  Brewing could occur in temples, notably those of the goddess Hathor (beer was sacred to her)  Clay containers of beer placed in burial chambers for the afterlife Osiris and Hathor – Egyptian beer deities  History of Alcohol - III: Ancient Rome Wine had enormous social and economic value Roman Empire ≈117 AD  Extensive trade in wine across Empire, notably ‘Falernian’ wine (made near Naples) Wineshops, taverns central to Roman communities  Daily consumption of wine with meals for both sexes and children Strong acceptance of alcohol within social context  Excess is criticised; moderation is a virtue  Comparable attitudes extended throughout Mediterranean empire  Types of Alcoholic Beverages - I: Beer Most popular alcoholic beverage globally  Historically has low alcohol content  E.g., 4 to 6% ethanol (v/v)  Higher sugar (“carbs”) content than most other alcoholic beverages Made from starchy grains, e.g. barley, wheat, maize, corn, rice Traditional Zulu beer sorghum-based  Basic idea: Mix grain with water, leave in a warm place to promote fermentation Ancient beers: Thick, fibrous, usually non-carbonated, “mildly alcoholic porridge.” Modern Beers: Clear, carbonated, higher alcohol content, need modern industrial technology to produce on large scale. A modern mass- produced beer  Types of Alcoholic Beverages - II: Wine Produced from fruit  Commonly grapes, also berries, stone fruits  Produced first in temperate fruit-growing regions: in Europe, lower Caucasus, Balkans -> Mediterranean Longer fermentation time than beer Higher alcohol content than beer A home-made cherry wine  E.g. 10 to 14% ethanol (v/v)  Carbonated or sparkling wines = `fizzy’ wines  Carbonation produced traditionally by a secondary fermentation in the bottle  Modern mass production adds CO2 artificially (cheaper)  Only Champagne-district wines, within-bottle fermentation (methode champenoise), can be marketed as ‘champagne’ $15/bottle $600/bottle  Types of Alcoholic Beverages - III: Spirits Produced by process of distillation Technically quite complex so a later development than fermentation (c 1st century AD?)  Boiling a fermented product and capturing the alcoholic steam in a condenser  Drips down the condenser and is collected  Greater concentration of alcohol in the distillate Distilling apparatus, c500s –  E.g., ≈ 35-50% ethanol (v/v) or higher Zosimus (Greek) Some Examples of Spirits Type Source Rum Sugarcane products incl. molasses Vodka Potatoes, grains and sometimes fruits Whiskey Fermented grain mash ‘Moonshine’ – spirits from corn, USA, c1900  Types of Alcoholic Beverages - IV: Fortified Wines Wine to which spirits have been added  Increases alcohol content significantly  Can keep wine from spoiling (antiseptic)  Lasted longer on long sea voyages Began c1700s in countries with maritime economies  > alcohol content than unfortified wines,  ≈ 18 to 20% (v/v) Spain and Portugal Some Examples of Spirits Type Source Port wine + neutral grape spirit Sherry wine + brandy wine + neutral spirit + oils, herbs, Vermouth flavourings  The Pharmacokinetics of Alcohol – Basic Considerations Ethanol displays what chemists call Polar end confers water solubility amphipathic or amphiphilic character  i.e., a combination of water-loving (“hydrophilic”) and fat-loving (“lipophilic”) properties Together with its very small size, these ampithathic properties are key to the pharmacokinetic properties of ethanol  i.e., account for its characteristic ADME properties Nonpolar end  E.g., rapid absorbance and wide tissue confers fat solubility penetrance or “greasiness”  Pharmacokinetics of Alcohol – I: Absorption After oral consumption, alcohol is quickly absorbed into the blood  Peak blood alcohol concentrations (BAC) occur within 30 min on an empty stomach Absorbed mostly from the upper intestine but also the stomach  Food can delay gastric emptying & alcohol absorption (esp. solid food) In this study conducted in unfed human The peak BAC (“Cmax”) depends on volunteers, peak BAC levels were influenced type of beverage & amount ingested by the alcohol content of the ingested  Due to the rate of oral absorption beverage, with BAC after Spirits > Wine > exceeding metabolism/excretion Beer. (Mitchell et al (2014)  Pharmacokinetics of Alcohol – II: Distribution Wide distribution within body via blood  Penetrates tiny gaps between cells (“paracellular uptake”) 84 kg male Mainly distributes into total body water, TBW  VolDist approx. 40-45 L in adults Due to some lipid solubility, alcohol readily crosses membranes, although penetrance into body fat is poor  Explains why ↑ peak BAC seen in females ingesting same volume of alcohol as males 59 kg female  Smaller body size  Bodily proportion of TBW < males  ↓ EtOH-metabolising enzymes in gut Image: drugrehab.com  Pharmacokinetics of Alcohol – III: Metabolism  Metabolism in gut wall (minor) and liver (major) protects body H3C CH2 OH Ethanol (EtOH) against ethanol  Mainly (95%) by alcohol dehydrogenase (ADH) & aldehyde ADH (cytosolic) dehydrogenase (ALDH)  Both enzymes need the cofactor NAD H3C CH O Acetaldehyde*  i.e., 2 mol NAD to metabolise 1 mol ethanol (46 g) * Toxic → hangover symptoms  This exceeds NAD capacity of liver  Therefore wethanol metabolism is saturated under normal ALDH (mitochondria) conditions of human use  i.e., fixed mass of alcohol metabolised per hr H3C COOH Acetic acid  Approx. 8 g/hr in 70 kg human  Polymorphisms in ADH and ALDH genes influence ethanol & acetaldehyde metabolism  e.g., East Asians, ↑ ALDH2*2 polymorphism, “flushing”, ↓ acetaldehyde metabolism  ↑ risk of head & neck cancer Alternate Routes to Acetaldehyde in Heavy Drinkers Dominant in Boosted in light drinkers heavy drinkers Modified from Burcham (2014)  Pharmacokinetics of Alcohol – IV: Excretion A tiny amount of ethanol is excreted directly by kidneys (in urine) Similarly, some ethanol is excreted in exhaled breath (about 5% of total)  i.e., release of EtOH vapours into airspace as blood passes through alveolus Impact of ADH1B Genotype on As a result, ethanol concentrations in expired Breath Alcohol in Human Volunteers (Aoyama et al, 2017) air generally correlate with BACs  Basis for breathalyser use in drivers Breath ethanol also influenced by genetic factors  e.g., variants in ADH1B gene (*1 = wildtype, *2 = variant form of gene)  Pharmacodynamics of Alcohol: Effects on the Brain CNS Effects & Blood EtOH Levels As a classic psychoactive agent, the BAC SYMPTOMS (% v/v) central nervous system (CNS) is the Euphoria, talkativeness, main target for the PD effects of 0.05% relaxation ethanol CNS depression, nausea,  i.e., affects mind and behaviour possible vomiting, impaired 0.1% Contrary to popular belief, ethanol is motor and sensory function, not really a brain stimulant impaired cognition Belongs to broad class of nonselective >0.14% Decreased blood flow to brain CNS depressants Stupefaction, some analgesia, 0.3% possible unconsciousness  Depress functioning of brain to produce calming, relaxation, disinhibition, 0.4% Possible death drowsiness, coma, death >0.55% Death  Is the Effect of Ethanol on Brain Functions Specific or Nonspecific? Ethanol is a tiny, simple molecule (low potency) X-Ray Crystal Structure of Ethanol Binding to a Challenging to attribute CNS effects to specific actions on Ligand-Gated Ion Channel defined receptors  Long thought (wrongly?) that ethanol mainly produces nonspecific effects on neuronal membrane fluidity With modern research, new clarity on dose-dependent effects on particular receptors  E.g., identification of possible ethanol binding sites  Ethanol receptors are often ion channels that regulate ion flows into nerve cells Effects on CNS receptors vary between acute (immediate) & chronic (long-term) use  Complex adaptive changes also occur (from Cui and Koob, 2017)  Two Important Ethanol Receptors in Human Brain (Note: There are many others too!) Receptor Outcome in Normal Role of Receptor Role in CNS Effects Type Acute Alcohol Glutamate is a major excitatory Ethanol binds to NMDA- Glutamate amino acid within brain cells type glutamate receptors, Receptors involved in learning, memory & Neuronal decreasing their (“NMDA” other roles. After release from Inhibition responsiveness to released subtype) nerve cells, it normally switches glutamate. on target neurons. The inhibitory neurotransmitter Ethanol binds to the same GABAA -aminobutyric acid (GABA) protein subunit on the Receptors (a regulates chloride entry into Neuronal GABA receptor as volatile ligand-gated neurons, causing sedation + Inhibition anaesthetics, causing ion channel) decreased anxiety. It normally strong inhibition. switches off target neurons. The GABA-Gated Ion Channel is a Key Target for Ethanol and Many Other Drugs Walsh, CT (2018) Cell, 175: 10-13  EtOH & the Brain: The “Disinhibition Hypothesis” Ethanol produces graded, reversible depression of behaviour and cognition Affects both value assigning parts of brain  limbic system - produces emotions  frontal cortex - executive functions At low doses, main outcome is suppression of inhibitory neuronal networks that produce social restraint  Can be mistaken as CNS stimulation  e.g., ↑ talkativeness, sociability, etc Note: The behavioural manifestations of disinhibition vary This “inhibition of inhibitory processes” is between individuals + influenced by termed “disinhibition” genetic endowment, mental  Alcohol can also inhibit some excitatory processes expectations and the environment (e.g., glutamatergic neuronal pathways) in which drinking occurs. Biphasic Effects of Alcohol Related to Blood Alcohol Concentrations in Humans (from Cui and Koob, 2017)  The Problem of Ethanol Abuse: Alcohol Use Disorder (AUD) In vulnerable individuals, compulsive heavy use  Est. 18 million affected by AUD (USA, 2018)  Est. economic impact ≈250 billion p.a. (USA)  Est. 5.9 million deaths p.a. globally (WHO, 2015) Involves EtOH tolerance due to faster liver metabolism (↑CYP450, not ADH)  AUD-affected subjects survive BACs up to 8× lethal levels in alcohol-naïve individuals  BUT, CYP450-mediated metabolism of ethanol produces toxic radicals (→ liver damage) Very high social and medical impact:  Failed relationships & employment loss  Psychiatric symptoms, neurotoxicity & cognitive disruption  Need for organ transplants & long-term care  Alcohol Toxicology– Diseases that Accompany AUD Role of Toxic metabolites in Alcoholic Tissue Damage  Ethanol has causal role in > 60 diseases Ethanol  “Top 10” contributor to WHO global disease burden (~4%) alcohol  Includes disorders that are “wholly attributable to alcohol” dehydrogenase  “Alcoholic” label often attached to names:  Alcoholic liver disease Acetaldehyde  Alcoholic cardiomyopathy (chemically reactive)  Alcoholic neuropathy  Cancer (multiple sites) Protein & DNA damage  Role for toxic aldehydes - acetaldehyde & oxidised lipid fragments (MDA, 4-HNE) in cell damage in these conditions Cell injury including mitochondrial impairment,  Ethanol also exacerbates diseases that are “Partially altered gene expression & immune cell activation (e.g., attributable to alcohol” toxic cytokines)  e.g., falls, infectious disease Induction of Aldehyde-Induced DNA & Protein Damage (“Adducts”) Following Alcohol Consumption in Humans Radicals attack lipids “Lipid peroxidation” Heyman et al (2018)  Lecture Conclusions Ethanol is a product of yeast fermentation with a long history of human use  The dose of alcohol ingested depends on the beverage consumed, with the alcohol content of beer < wine < fortified wines < spirits Alcohol is quickly absorbed from the GI-tract and is readily distributed within body water  Alcohol is metabolised primarily by ADH in a zero-order reaction (saturated under normal drinking) Ethanol effects on human behaviour involve disinhibition via effects on GABAA and NMDA receptors Alcohol use disorder (AUD) takes a heavy toll on human wellbeing due in part to organ damage caused by toxic aldehydes formed during ethanol abuse  Further Reading 1) Abrahao KP et al (2018) Alcohol and the brain: Neuronal molecular targets, synapses, & circuits, Neuron, 96: 1223-1238. 2) Buxton, IL (2022) Chapter 23: Alcohol, In: The Pharmacological Basis of Therapeutics, 14th ed, McGraw-Hill, New York. 3) Cui, C & Koob, GF (2017) Titrating tipsy targets: the neurobiology of low-dose alcohol. Trends Pharmacol Sci. 38: 556–568. 4) Heymann HM, Gardner AM, Gross ER (2017) Aldehyde-induced DNA and protein adducts as biomarker tools for Alcohol Use Disorder. Trends Mol Med. 24: 144-155. 5) Jones, AW (2019) Alcohol, its absorption, distribution, metabolism, and excretion in the body and pharmacokinetic calculations. WIRE’s Foresnic Sci;1:e1340. 6) Le Dare, B et al (2019) Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects. Drug Met Reviews, 51: 545-561. 7) Li, JJ (2006) Laughing Gas, Viagra & Lipitor, p. 129-131, OUP. 8) Singal, A. K. and Mathurin, P. (2021) Diagnosis and treatment of alcohol-associated liver disease: A Review. JAMA. 326: 165-176. 9) Yang, W et al (2022) Alcohol Use Disorder: Neurobiology and Therapeutics, Biomedicines, 10, 1192. From Reefer Madness to High Economy: Cannabis Dr Philippa Martyr PHAR1101 Drugs that Changed the World By the end of this lecture, you will be able to...  Describe the botanical profile of cannabis.  Describe key events in the cultivation and use of cannabis in the US and Australia.  Describe the basic pharmacodynamics and pharmacokinetics of cannabis.  Describe the benefits and limitations of cannabis as a medical treatment, based on current evidence.   One of the world’s oldest crops (hemp harvested in China 8500 years ago).  However, cannabis is very mysterious.  Current broad use of the term ‘cannabis’ is often vague, unscientific, and confusing. What IS  Unsure if the genus Cannabis is monotypic (one species) or polytypic (three or more species?) cannabis,  Why so weird? anyway?  ancient origin.  extremely long evolutionary and domestication history (including artificial selection) – may have wiped out other variants.  widespread geographic dispersal.  prohibition made it hard to investigate scientifically.   Molecular genetics is providing increasing evidence that cannabis is a polytypic genus.  Some classify cannabis as three sub-species:  Indica  Sativa A ‘third strain’  Ruderalis  Ruderalis plants are small and yield relatively little medicine with – ruderalis? low potency?  Seems to have a different flowering and life cycle.  Ruderalis strains are t