Phar1101 Semester Notes PDF

lOMoARcPSD|43244509 Phar1101 semester notes Drugs That Changed The World (University of Western Australia) Scan to open on Studocu Studocu is not sponsored or endorsed by any college or university Downloaded by Esandi Wijes...

lOMoARcPSD|43244509 Phar1101 semester notes Drugs That Changed The World (University of Western Australia) Scan to open on Studocu Studocu is not sponsored or endorsed by any college or university Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 5 Learning Outcomes 1. Describe at a basic level how drugs work in the body, and how the body processes drugs 2. Identify the broad scientific principles used to establish whether a new medicine has actual versus promised potential in the treatment of human disease 3. Critically describe the role played by pharmaceutical innovations in changing the health of human disease 4. Identify the key drugs that produced significant changes in medicine or healthcare upon their discovery or introduction 5. Critically describe the health and social impacts that accompany the use of any pharmaceutical products IMPORTANT DATES 1864: Uk legislation standardized the ‘apothecaries’ ‘weights’ –– minims, scruples, grains, dra(ch)ms, ounces, and pounds 1963: metric system introduced to British Pharmacopoeia 1965: Australian pharmaceutical industry 1971: United States pharmaceutical industry Micrograms, milligrams (mg), grams (g), kilograms (kg), milligrams (ml), and liters (L) 1980: Anthropologists discovered what seemed to be the antibiotic tetracycline in nearly 2000 year old Nubian bones 1938: the term ‘marihuana’ appears in Australia in connection with the ‘reefer madness’ moral panic in the US ACT, 1977: Australian Marijuana party 1992: Anandamide discovered and named 20 June 2023: ‘Legalize Cannabis Party’ bill introduced in state parliaments in Victoria, NSW and WA 1839-1842 – first opium war 1844, Gardner Quincy Colton began public demonstrations of Laughing Gas in UWA (attracted thousands) FRIDAY OCTOBER 16, 1846 –– ETHER AND A DENTIST’S SUCCESS WEEK 1 –– HEALTH AND MEDICINE BEFORE THE AGE OF SCIENCE Outcomes: - 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 really know about prehistoric medicine and pharmacology? ○ Almost nothing ○ Almost no forms of modern-day ‘traditional medicine’ can be authoritatively linked to prehistoric practice ○ Diverse cultures all developed their own healing methods, including drug therapy ○ These ways of healing were based on widely-differing beliefs and practices Evidence ○ Sources for information about ancient medicine include: Cave paintings ‘The sorcerer’ Can be interpreted in any way you wish: (which may include) Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Shama figure ○ Indigenous healer ○ Cultic leader ○ Evidence of prehistoric use of psychedelic drugs ○ Alien Physical human remains e.g. skeletons, skulls, bog bodies Bones ○ A 7000 year old skull was found in Sudan with bore holes. It was believed to be trepanation (medicinal skull drilling) but there is no evidence to suggest why it was done, whether it was done pre- or post- mortem Bog bodies and ‘icemen’ (glacier mummies) (body is slightly flexible, hair + color, stomach contents, dna, etc. are still intact) ○ Tollund Man New analysis of stomach contents 12-24 hours before his death, he ate a hearty meal that was cooked in a claypot (porridge containing barley and flax; maybe also fish, weed seeds – pale persicaria He was infested with parasites –– stomach contained proteins and eggs from intestinal worms, probably from contaminated food or water ○ Otzi (glacier mummy found) Age: found through measuring his thigh bone Traces of arsenic found means he was sometimes present where metal ores were being smelted Nails: horizontal grooves (Beau’s lines) were observed, meaning he was in great physical stress Parasites and pathogens: two human fleas were found in his clothes Oldest evidence of Lyme disease in his DNA The eggs of whipworm (irritating intestinal parasite) were found in his digestive tract Archaeologists noticed that he had tattoos that were all over his joints, making them wonder if it was a form of medicinal treatment, rather than purely decorative Theory that he had arthritis Some fragmentary items which may be tools What evidence do we have for prehistoric medicinal drug use? ○ We have no conclusive physical evidence of prehistoric drug use as we would recognize it ○ Plant remains found in prehistoric teeth and stomachs may have been food rather than drugs ○ Pollen traces in a setting may not be indicative of medicinal plant use ○ We can guess if we find local medicinal plants in a particular area, but these may be recently introduced ○ Why assume medicine? Why not beauty, religion, commerce, politics, etc.? ○ There is a huge amount of ‘may’ and ‘could’ and ‘possibly’ in written research around these areas Is recorded history better? ○ 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 millenia are missing, in some cases Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Recorded history may only apply to literate/noble class of that society ○ Only the broadest generalizations are possible about early civilizations and medical practice ○ We are still guessing in a lot of cases Did ancient medicine use the scientific method? ○ No, 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 (although they are ingredients that we can use) What is the scientific method? (will be TESTED) ○ Consists of Organized efforts To come up with explanations of nature (natural phenomenon) Always modifying and correcting these Through systematic observations Method vs. random stuff ○ 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 practiced observation ○ However, you can have a fully equipped lab and still not be using the scientific method ○ You can be out on the open field and be using the scientific method to test something ○ It is a method or approach that you take to a problem Strengths of the scientific method ○ It allows discovery to proceed in an organized way ○ Eliminates repetition ○ Encourages us to change or revise explanations –– or questions, or hypotheses –– in the face of the evidence ○ It provides a clear audit trail ○ The results should be communicable and replicable ○ All these combine to speed up innovation and make it safer Hippocrates, the father of medicine? ○ Referred to as ‘the father of modern medicine’ This is not true because: We know almost nothing of his life from actual historical sources Plato mentions him in passing in two dialogues Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 We do not know who wrote the Corpus Hippocraticum (the Hippocratic Corpus –– the body of work attributed to ‘Hippocrates’) ○ What did the Hippocratic approach really do? It systematized the description of disease duration (short term, long term) Also systematized some elements of basic clinical observation It did not use the scientific method to develop hypotheses about illnesses and test different remedies objectively This approach may have held back the development of scientific medicine ○ What held it back? THE HUMORAL THEORY - The word ‘humor’ comes from the greek word ‘chymos’ meaning ‘sap’ (something liquid and moving) → prominent in the Hippocratic Corpus - The human body was thought to contain four principal humors, matching four elements of earth, air, fire, and water that made up the universe - Illness 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 - Human theory legacy: - Dominated western medicine for centuries - It was almost unbudgeable as a way of thinking about the human body, health and illness - Probably originated in observations that were misplaced - Doctors themselves supported and promoted this theory - Those who questioned it and used observation-based methods to experiment on their patients were called ‘empiris’ and ‘quacks’ and were denounced - The world of humoral theory - Ancient greeks - Ayurvedic –– 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 So when did medicine become scientific? ○ What we now recognize 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 did not 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 received ideas Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 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 descriptors of things based on observation and experience indicate that a particular phenomenon is testable The end of humoral theory ○ These new ways of thinking broke the centuries-old grip of humoral theory on western medicine ○ Humoral theory literally did not measure up ○ New causes were found for disease 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 to make this better? ○ An industrial revolution ○ 18th century onwards: use of microscope, improved timing devices, grinders, distillation equipment, moulds ○ Isolation elements = artificial compounds now possible ○ Standardize 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’ ANCIENT DRUGS Objectives: 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 How do we measure the ‘success’ of a drug? 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 BUT these measures do not capture all the effects of a drug on society: ○ E.g. mental hospital closures only tell us that mental hospitals closed ○ It does not tell us whether the quality of life of the former patients improved or not It is almost impossible to measure the effects of ancient drugs on populations because of confounding factors How do we know what ancient drugs were used and why? Modern anthropology has identified traditional practices in some cultures BUT we cannot authoritatively link that to ancient civilizations Finding evidence that particular groups ritually bathed, or tattooed, or ingested clays tells us very little about their ideas about medicine and health We know they HAD ideas about health and illness But unless they: wrote them down and these ideas sustained, and we can understand them clearly, we do not really know what those ideas were The Pozzino shipwreck cargo –– ‘medicine chest’ 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 ○ 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 In 2015: ancient remedy proved effective against MRSA Bald’s Leechbook recipe ○ Scientists recreated a 9th century Anglo-Saxon remedy using onion, garlic, and a part of a cow’s stomach ○ This successfully and repeatedly killed methicillin-resistant staphylococcus aureus (MSRA) ○ Recipe: Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Equal amounts of garlic and another allium (onion or leek), finely chopped and crushed in a mortar for 2 minutes Add 25mh of English wine (taken from a historic vineyard near Glastonbury) Dissolve oxgall (bovine salts) in distilled water, add and then keep chilled for nine days at 4c. ○ The recipe only worked when followed exactly (needed the right combination of ingredients, right preparatory method, right waiting time) ○ Changing any of these reduced its efficacy against staphylococcus What do we really know about ancient use of medicinal drugs? It is a bit of a mixed bag (a lot of guesswork) Easy to credit a culture with ‘advanced’ knowledge of medicine through chance use of particular drugs Plant Sources (eTute 2 –– bioprospecting) - Leaves: tobacco, hemp, geranium, lavender, mint - Gums, sap, resins: aloe, balms - 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 Psychoactive/CNS stimulating plants Hemp plant –– leaves and buds Opium poppy –– seed-head Coca leaves –– chewed Betel nut –– chewed Kava leaves –– chewed Tobacco –– smoked or chewed Peyote –– a cactus which produces mescalin Mushrooms –– psilocybin (often found in magic shrooms) Mineral sources Clay –– kaolinite Chalk Red ochre –– iron salts Mercury Arsenic 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 1st century CE Antiseptic and anesthetic properties ANCIENT NUBIAN BEER AS MEDICINE? ○ In 1980, anthropologists discovered what seemed to be the antibiotic tetracycline in nearly 2000 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 do not know Other sources Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ 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 papyri 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 Spell and ointment for leucoma (opacity in cornea) Gall was used to treat trachoma for at least two millennia Gall is an irritant and cauterizing 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 Transliteration and recipe––Ebers Papyrus For reducing plentiful urine––proportions, but not actual measures Ancient Rome––(Pedanius) Dioscorides Author of De Materia Medica, the first authoritative Western pharmacopeia (c. 50-70 CE) Hugely influential throughout Europe until 19th century Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Carefully noted the exact measurements of drugs that he gave to patients (a step forward in the history of pharmacology) Describes about 600 plants––not all can be identified even now Also includes animal products and minerals Still contains some magical uses for plants, e.g. talisman against snakes Poterion ○ A large shrub with long branches (soft, flexible, thin, little and round leaves). Whole shrub surrounded with a thin wooly down and prickly; flowers small and white ○ Sharp and sweet-scented seed ○ Grown in sandy and hilly countries, roots two or three feet underground, strong and sinewy The roots (cut and smeared on) heal cut-apart sinews and wounds Positive effects of tragacanth on wound healing were demonstrated in 1 small clinical trial Decoction (taken as a drink) of it is good for disorders of the strength Phrynion (andidotum) or known as neurada to lions ○ When cut close to the ground, they send out a fluid like gum Roman medicine––Galen 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 Medicamentorum (on the Composition of Drugs) Strongly influenced by Hippocratic approach and humoral theory Carefully noted the exact measurements of drugs that he gave to patients Also believed in theriac––a mystery substance with 64 ingredients which could cure any illness in human beings Classical Islam 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 AI-Rhazi (863-930 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) 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 galactagogues Paracelsus (1493-1541 CE) Devoted mineralogist and toxicologist Challenged the theory-based approach to medicine Championed the use of mercury to treat syphilis Believed in humoral theory, alchemy, the occult, astrology Paracelsian remedies ○ For tuberculosis––eat the longs 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 ○ Cannabidiol has anticonvulsant properties ○ Chamomile shows some anticonvulsant properties Eighteenth century in Europe 1700s––flourishing new science of botany fuelled new drug experimentation More experimentation and better communication in medicine Folk remedies scrutinized more closely = digitalis treatment for heart conditions Humoral theories persisted Did ancient people use aspirin? Aspirin’s key ingredient is salicylic acid ○ Isolated in 1800s from willow bark ○ Therefore any ancient recipe mentioning willow must mean that this culture understood the pain-relieving properties of salicylic acid? ○ Not true Why we know this Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Effective drugs do exist in nature (like opiods, for example) It is 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 A standardized modern dose of 40-60mg of salicin would be very hard to obtain from simply chewing willow bark or drinking tea 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? Short answer: some of them, sometimes Long answer: we do not really know because ○ We usually cannot replicate the recipes––we do not know the right quantities or ingredients ○ We do not know the right conditions under which to make the drug (shelf-life of ingredients, containers, other confounds) ○ It is 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 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 is fun and occasionally successful It might lead to new pathways in research for isolating effective trace elements WEEK 2 –– WHAT HAPPENS TO DRUGS IN THE BODY Aim: to convey a basic appreciation of essential pharmacokinetic factors that control the behavior of medicines within the human body PD = pharmacodynamics PK = pharmacokinetics What the drug does to the body What the body does to the drug Every drug has its own distinct pharmacodynamic properties and its own pharmacokinetic properties WHY ARE DRUGS TAKEN AT DIFFERENT INTERVALS? Pharmacology: the branch of pharmacology that studies the behavior of drugs as they move into, around, and out of the body ○ In chem: kinetics = the rate or speed at which chemical reactions occur ○ In pharmacology, kinetics is concerned with the rates at which drug levels in blood rise and fall Essentially, 4 fundamental “ADME” processes control these changes Absorption → Distribution → Metabolism → Excretion → urine WHAT HAPPENS AFTER TAKING A PILL “Pharmaceutical phase” ○ Ingestion → disintegration & dissolution → individual drug molecules → “pharmacokinetic phase” absorption → distribution/metabolism → excretion The core of pharmacokinetics = knowledge of drug concentrations in blood Administer drug to subjects → collect a series of blood samples → prepare samples for analysis → measure drug levels in samples ○ “Plasma Concentration-Time Profile or Curve” Plasma concentration-time profile help us define the ‘therapeutic window” for a particular drug Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Patients only benefit from drugs when blood levels are within the ‘therapeutic window” Most drugs produce drug-dependent plasma concentration-time profiles The width of the therapeutic window shows how safe a drug is for patients The goal of pharmaceutical innovation is to widen the therapeutic window within a drug class The 4 ADME processes control the shape of plasma concentration-time profiles ADME 1 –– ABSORPTION (How well does a drug enter the body) The most convenient way of taking a medicine is via mouth (“oral route of administration”) Drug absorption is the process whereby ingested drug molecules relocate from the interior of the GI-tract into the portal blood (drains from gut into the liver) Often, less than 100% of the ingested dose makes it into the portal blood ○ Some remain unabsorbed ○ Some may be metabolized in the gut wall F(oral) = Oral Bioavailability: Fraction (F) of a drug dose reaching the systemic circulation after ingestion Examples ○ Paracetamol → F ~ 88% ○ Codeine → F ~ 50% ○ Mercaptopurine → F ~ 12% Why Bioavailability (F) is often less than 100% Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 REASONS FOR POOR BIOAVAILABILITY (POOR ABSORPTION) OCTANOL-WATER PARTITIONING 1) Drug is too big (MW>600g/mol) Assesses solubility of drug in simple 2-phase 2) Drug is not greasy enough system: water and octanol (model organic solvent) a) Too “hydrophilic” (water-loving) ○ Octanol floats on water layer b) Needs some “lipophilicity” (fat-loving) to Add drugs, mix, settle cross lipid-rich cell membranes in gut ○ Lipophilic drugs go into octanol, wall hydrophilic drugs into water 3) Drug carries a charge (“ionized”) ORALLY-ADMINISTERED DRUGS NEED A BALANCE OF a) E.g. protonated amine group (-NH3+) SOLUBILITY PROPERTIES b) Only neutral molecules passively cross lipid membranes 4) Drug is metabolized in the gut wall 5) Drug is pumped back into the gut a) “Membrane transporters” = “molecular turnstiles” in cell membranes i) Limit tissue entrance by drugs ADME 2 –– DISTRIBUTION (where does a drug go after TWO OPPOSITE SCENARIOS entering the blood) A) Tissue penetrating drug 1) Where drugs go once in the bloodstream reflects B) Blood associated drug their “physicochemical properties” a) I.e. lipophilicity, hydrophilicity, ionization, etc. 2) Some drugs mainly remain in the blood a) E.g. bound to blood proteins such as albumin 3) Other drugs penetrate into tissues a) E.g. muscle b) Fat (if very lipophilic) c) Influenced by extent of blood flow to the tissue 4) Getting drugs into the brain is hard because of “blood-brain barrier” a) Tight junctions between cells in capillaries Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 b) Strong expression of drug transporters DRUGS DIFFER IN THEIR TISSUE PENETRANCE CAPACITY ADME 3 – METABOLISM (does the drug’s chemical structure DEFINITION OF DRUG METABOLISM get changed in the body?) “The chemical alteration (i.e. structural modification) of 1) Drugs enter the body if they are lipophilic, but they drugs by drug-metabolizing enzymes (DME) in the body” might accumulate in body tissues a) Cause harm in vulnerable organs (“toxicity”) 2) The body’s solution is to convert them into water-soluble metabolites a) Then removed by the kidneys into urine 3) The body expresses hundreds of drug-metabolizing enzymes (DME’s) a) Gut wall b) Liver c) Kidney d) Other tissues 4) Protect us against drugs, pollutants, industrial chemicals, food-borne chemicals DRUGS USUALLY GAIN WATER-SOLUBILITY DURING METABOLISM Parent drug → 1) oxidative metabolism | Metabolite I → 2) conjugative metabolism → metabolite 2 → urine Parent drug is greasy and lipophilic Metabolite 1 has gained hydrophilicity but is still quite lipophilic Metabolite 2 is very hydrophilic 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 retain pharmacological activity ○ I.e. “active metabolites” –– contribute to pharmacology of parent drug Some drugs are inactive until metabolized (“pro-drugs”) Some drug metabolites are toxic (e.g. paracetamol liver damage) 1. Parent drug “fits” drug 2. Some metabolites “fit” into 3. Most metabolites don’t “fit” binding site on receptor receptos (“active”) into receptors (“inactive”) ADME 4 –– EXCRETION (how are drugs that are not DEFINITION OF EXCRETION metabolized removed from the body?) “The permanent removal of unchanged drugs from the body 1) About 25% of current medicines are not via body fluids and secretions, expired air or tissue shedding appreciably metabolized a) Pass through gut wall and liver unchanged 2) Such drugs are excreted unchanged by the kidneys into urine (most common) a) The kidneys also remove drug metabolites 3) A few percent of all drugs are excreted unchanged into the bile a) Drain via bile duct into large intestines Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 4) Other minor routes of excretion include: a) Breast milk (nursing mothers) b) Expired air (e.g. ethanol) c) Minor: sweat, hair, skin 5) Membrane transporters act as excretory drug pumps into urine, bile, milk, etc. THE SPEED OF EXCRETION + METABOLISM DETERMINES THE HALF-LIFE OF DRUGS & THEIR DOSING FREQUENCY SUMMARY 1: HOW THE BODY USUALLY PROTECTS ITSELF AGAINST DRUGS In general, hydrophilic drugs undergo little metabolism ○ Excreted unchanged in urine Lipophilic drugs are converted to hydrophilic metabolites that are then removed by kidneys and excreted by urine A FEW REAL WORLD DRUG EXAMPLES Hydrophilic drugs (mainly appear in urine as unchanged Lipophilic drugs (mainly appear in urine as metabolites, not “parent” drug) parent drug) Penicillins (broad-spectrum antibiotics) Morphine (strong painkiller) Cephalosporins (broad-spectrum antibiotics) Efavirenz (HIV drug) Gentamicin (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 LECTURE SUMMARY: PHARMACOKINETICS Before a drug produces an effect it must enter the body and access the tissues where its main receptors are 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 WEEK 2, PART 2 –– HOW DO DRUGS WORK IN THE BODY? (PHARMACODYNAMICS) Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Learning Outcomes Describe drug and drug targets Describe three types of drug names and their intended audience and characteristics Name four groups of proteins as drug targets, recognizing the significance of receptors as drug targets Describe four receptor superfamilies and their characteristics Describe agonist, antagonist, affinity, efficacy, concentration-response relationship, potency, and EC50 in the context of ligand-receptor interaction Describe dose-effect relationship and therapeutic index DRUGS AND DRUG TARGETS Drug: a substance that produces a biological effect when introduced into the body ○ Often used to treat symptoms, not causes; exceptions e.g. antimicrobial drugs ○ Used as treatment and prevention, e.g. anti-HIV drugs Drug target: proteins or other biomolecules to which a drug directly binds to produce a biological effect DRUGS –– THREE TYPES OF DRUG NAMES A marketed drug is known by three types of drug names Type of drug name Intended audience Chemical name (medicinal) chemists Describes the (complex) chemical structure of drugs Generic name Pharmacologists stems/roots to indicate the origins, use, actions, or structure of drugs Brand name (trade name) General public Invented by drug companies for marketing purposes ○ Different brand names by different manufacturers and in different countries ○ Intended to be catchy and memorable Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 PROTEINS AS DRUG TARGETS (I) Drugs Drug target (R/C/T/E) Drug action Indication Atorvastatin (E) HMG-CoA reductase Inhibit High cholesterol Fluoxetine (T) serotonin transporter Inhibit Depression Penicillin (E) bacterial transpeptidase Inhibit HIV infection Saquinavir (E) HIV protease Inhibit HIV infection Morphine (R ) opioid receptor Activate Pain Diazepam (R ) GABA(A) receptor Modulate Anxiety Alcohol (R ) GABA(A) receptor Modulate PROTEINS AS DRUG TARGETS (II) Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 RECEPTORS AS DRUG TARGETS –– SUPERFAMILIES In pharmacology, receptors are proteins that recognize and respond to endogenous chemical signals (i.e., substances naturally produced by our body) ○ Recognize → act as a cell’s “sensing elements” ○ Respond → transduce chemical signals into a change in cell activity Receptor superfamily Location of receptors Endogenous ligand Time scale of action Ligand-gated ion channels Cell membrane Fast neurotransmitters Milliseconds G protein-coupled receptors Cell membrane Hormones, slow Seconds neurotransmitters Enzyme-linked receptors Cell membrane Cytokines, growth factors Minutes Nuclear receptors Intracellular Steroid hormones Hours DRUGS THAT TARGET RECEPTORS Agonist: binds and activates receptors – mimic the actions of endogenous ligands Antagonist: binds but does not activate receptors – blocks the actions of endogenous ligands Modulators Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 INTERACTION BETWEEN A DRUG AND ITS TARGET Affinity: the ability of a drug to bind to its target ○ A target (e.g. receptors) has small cavities (binding site(s)) for ligand (L) binding A binding site is a special arrangement of amino acids (and their functional groups) 3D fit –– conformational flexibility Chemical forces of attraction LIGAND-RECEPTOR INTERACTION (I) –– AFFINITY Agonists and antagonists are ligands ○ Agonist Binds and activates receptors – mimic the actions of endogenous ligands ○ Antagonist Binds but does not activate receptors – block the actions of endogenous ligands LIGAND-RECEPTOR INTERACTION (II) –– EFFICACY Efficacy: the ability of a drug to produce a given response from the target ○ Agonist Binds and activates receptors – mimic the actions of endogenous ligands ○ Antagonist Binds but does not activate receptors – block the actions of endogenous ligands Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 LIGAND-RECEPTOR INTERACTION (III) Concentration-response relationship: the relationship between increasing drug concentration and magnitude of response ○ Graded response, not all or nothing LIGAND-RECEPTOR INTERACTION (IV) Potency: the amount of a drug, expressed as the concentration or dose, required for a given level of effect Agonist potency is commonly measured as EC50 ○ The effective concentration needed to produce 50% of the maximum response to the agonist A lower EC50 value indicates higher potency Antagonist potency is commonly measured as IC50 ○ The inhibitory concentration that reduces 50% of the response to an agonist DOSE-EFFECT RELATIONSHIP A fundamental concept in pharmacology and toxicology ○ Applicable to therapeutic effects and toxic effects 1) Dose is too low → drug is unlikely to produce a therapeutic effect 2) Optimal dose → drug produces significant therapeutic effect and few adverse/toxic effects 3) Dose is too high → drug produces a larger therapeutic effect but also likely adverse/toxic effects THERAPEUTIC INDEX Dose-effect relationship ○ Applicable to therapeutic effects and toxic effects ○ ED50 (effective dose, 50%) and TD50 (toxic dose, 50%) Inform therapeutic index (TI = TD50/ED50) DRUG IN ACTION –– MORPHINE (I) DRUG IN ACTION –– MORPHINE (II) Desirable Analgesia Undesirable Respiratory depression (most Reduced airway reflexes dangerous) Miosis (pupillary constriction) Nausea and vomiting Euphoria Constipation Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Sedation Dependence Codeine (prodrug) is metabolized to morphine (an active metabolite) by cytochrome P450 (CYP) 2D6 WEEK 3 –– THE OLDEST DRUGS → ALCOHOL PT. I Learning Outcomes Describe the basic chemistry of alcohols and the processes involved in the production of ethanol by yeast Summarize four types of alcoholic beverages in terms of sources, production, and alcohol content Describe the pharmacokinetics of alcohol Describe the main effects of alcohol on the brain and human behavior and the disinhibition hypothesis Describe the action of two key receptors in mediating the effects of alcohol on the brain Describe alcohol use disorder and the contribution of metabolism to alcohol toxicology, identifying the key topic metabolite of alcohol that causes DNA and protein damage WHAT IS ALCOHOL? Molecules containing 1 or more hydroxyl groups (OH-) attached to a carbon atom (C ) that can be attached to other C atoms ○ E.g. Methanol (1 carbon), 1-Propanol (3- carbons, 1- Butanol (4- carbons), etc.) Ethanol (EtOH, 2- carbon), is the alcohol widely consumed by humans) Many alcohols are toxic ○ E.g. Methanol → causes eye injury (e.g. vision loss in “Moonshine” drinkers during the Prohibition Era in America) THE MAKING OF ETHANOL Ethanol is made by yeast during glucose utilization It 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 makes ethanol a good hand sanitizer THE HISTORY OF ALCOHOL: GENERAL ASPECTS While the sugar source used varies across cultures (e.g. grains vs. fruit), knowledge of fermentation is common across history ○ Arose independently in mainly civilizations ○ May have been practiced deliberately as early as 10,000 BC (Stone Age) Alcohol production related to ‘civilization’ = emergence of stable communal life ○ Alcohol usage is complex in human societies Not the same as alcohol abuse Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Complex interplay of religious, economic, medical and recreational motives Patchy historical record in ancient world THE HISTORY OF ALCOHOL ANCIENT EGYPT (c3000 BC – 300 BC) Early producers of beer from barley ○ Bread and beer were dietary samples 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 THE HISTORY OF ALCOHOL ANCIENT ROME Wine had enormous social and economic value ○ Extensive trade in wine across Empire, notably ‘Falernian wine (made near Naples) Wine Shops, 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 criticized; moderation is a virtue Comparable attitudes extended throughout Mediterranean empire TYPES OF ALCOHOLIC BEVERAGES : BEER Most popular alcoholic beverages 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 ○ 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 TYPES OF ALCOHOLIC BEVERAGES : WINE Produced from fruit ○ Commonly grapes, berries, stone fruit ○ Produced first in temperate fruit-growing regions: Europe, lower Caucasus, Balkans → Mediterranean Longer fermentation time than beer Higher alcohol content than beer ○ E.g. 10 to 14% ethanol (v/v) Carbonated or sparkling wines = ‘fizzy’ wines ○ Carbonation produced traditionally by 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’ TYPES OF ALCOHOLIC BEVERAGES : SPIRITS Produced by process of distillation Technically quite complex – later development (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 ○ E.g. approx. 35-50% ethanol or higher Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 SOME EXAMPLES OF SPIRITS Type Source Rum Sugarcane products incl. molasses Vodka Potatoes, grains and sometimes fruit Whiskey Fermented grain mash TYPES OF ALCOHOLIC BEVERAGES : FORTIFIED WINE Wine to which spirits have been added ○ Increases alcohol content significantly ○ Can keep wine from spoiling (antiseptic) ○ Lasted longer on sea voyages Originated in c1700s in countries with strong maritime (sea-based) economies ○ > alcohol content than unfortified wines, About 18 to 20% ethanol SOME EXAMPLES OF SPIRITS Type Source Port Wine + neutral grape spirit Sherry Wine + brandy Vermouth Wine + neutral spirit + oils, herbs, flavoring THE PHARMACOKINETICS OF ALCOHOL : BASIC CONSIDERATIONS Ethanol displays what chemists call amphipathic or amphiphilic character ○ I.e. a combination of water-loving (hydrophilic) and fat-loving (lipophilic) properties Together with its very small size, these amphipathic properties are key to the pharmacokinetic properties of ethanol ○ I.e. accounts for its characteristic ADME properties E.g. its rapid absorption and wide tissue penetrance THE PHARMACOKINETICS OF ALCOHOL : ABSORPTION After oral consumption, alcohol is quickly absorbed into the blood ○ Peak blood alcohol concentrations (BAC) occur within 30 minutes on an empty stomach Absorbed mostly from the upper intestine but also the stomach ○ Food can delay gastric emptying and alcohol absorption (esp. Solid food) The peak BAC (Cmax) depends on type of beverage and amount ingested ○ Due to the rate of oral absorption exceeding metabolism/excretion THE PHARMACOKINETICS OF ALCOHOL : DISTRIBUTION Wide distribution within body via blood ○ Penetrates tiny gaps between cells (paracellular uptake) Mainly distributes into total body water, TBW Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Vol(Dist) approx. 40-45 L in adults Due to some lipid solubility, alcohol readily crosses membranes, although penetrance into body fat is poor ○ Explains why a higher peak BAC is seen in females ingesting the same volume of alcohol as males Smaller body size Bodily proportion of TBW < in males Lower EtOH-metabolizing enzymes in the gut THE PHARMACOKINETICS OF ALCOHOL – METABOLISM Metabolism in gut wall (minor) and liver (major) protects body against EtOH Mainly 95% by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) ○ Both enzymes need the cofactor NAD ○ I.e. 2 mol NAD to metabolize 1 mol EtOH (46g) This exceeds NAD capacity of liver ○ Therefore EtOH metabolism is saturated under normal conditions of human use I.e. fixes mass of alcohol metabolized per hr Approx. 8g/hr in 70kg human ○ Polymorphisms in ADH and ALDH genes influence EtOH and acetaldehyde metabolism E.g. increased ALDH2*2 polymorphism in east asians results in flushing, and a decreased acetaldehyde metabolism Higher risk of head and neck cancer ALTERNATE ROUTES TO ACETALDEHYDE IN HEAVY DRINKERS Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 THE PHARMACOKINETICS OF ALCOHOL : EXCRETION A tiny amount of EtOH is excreted directly by kidneys (in urine) Similarly, some EtOH is excreted in exhaled breath (about 5% of total) ○ I.e. release of EtOH vapors into airspace as blood passes through alveolus As a result, EtOH concentrations in expired air generally correlate with BACs ○ Basics for breathalyzer use in drivers Breath EtOH also influenced by genetic factors ○ E.g. variants in ADH1B gene (*1 = wildtype, *2 = variant form of gene) THE PHARMACODYNAMICS OF ALCOHOL : EFFECTS ON THE BRAIN As a classic psychoactive agent, the central nervous system (CNS) is the main target for the PD effects of EtOH ○ I.e. affects mind and behavior Contrary to popular belief, EtOH is not really a brain stimulant Belongs to broad class of nonselective CNS depressants ○ Depress functioning of brain to produce calming, relaxation, disinhibition, drowsiness, coma, death CNS effects and blood EtOH levels BAC (% v/v) Symptoms 0.05% Euphoria, talkativeness, relaxation 0.1% CNS depression, nausea, possible vomiting, impaired motor and sensory function, impaired cognition > 0.14% Decreased blood flow to brain 0.3% Stupefaction, some analgesia, possible unconsciousness 0.4% Possible death > 0.55% Death MECHANISM OF ETOH ON BRAIN FUNCTIONS : SPECIFIC OR NONSPECIFIC? EtOH is a tiny, simple molecule (low potency) Challenging to attribute CNS effects to specific actions on defined receptors Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Long thought (wrongly?) that EtOH mainly produces nonspecific effects of neural membrane fluidity With modern research, new clarity on dose-dependent effects on particular receptors ○ E.g. identification of possible EtOH binding sites ○ EtOH receptors are often ion channels that regulate ion flows into nerve cells Effects on CNS receptors vary between acute (immediate) and chronic (Long-term) use ○ Complex adaptive changes also occur MECHANISM OF ALCOHOL ON BRAIN FUNCTIONS : TWO KEY RECEPTORS (THERE ARE MANY OTHERS TOO) Receptor type Normal role of receptor Role in CNS effects on Outcome in acute alcohol alcohol Glutamate receptors Glutamate is a major Ethanol binds to NMDA-type Neuronal inhibition (“NMDA” subtype) excitatory amino acid receptors, decreasing their involved in communication responsiveness to released between brain cells involved glutamate in learning, memory, and other roles. It normally switches on target neurons GABA(A) receptors (a The inhibitory Ethanol binds to the same Neuronal inhibition ligand-gated ion channel) neurotransmitter protein subunit on the GABA aminobutyric acid (GABA) receptor as volatile regulates chloride entry into anesthetics, causing strong neurons, causing sedation + inhibition decreased anxiety. It normally switches off target neuron ETOH AND THE BRAIN : THE DISINHIBITION HYPOTHESIS EtOH produces graded, reversible depression of behavior and cognition ○ Affects both value assigning parts of the 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. increased talkativeness, sociability, etc. This inhibition of inhibitory processes is termed “disinhibition” ○ Alcohol can also inhibit som excitatory processes (e.g. glutamatergic neuronal pathways) **Note: the behavioral manifestations of disinhibition vary between individuals + influenced by genetic endowment, mental expectations and the environment in which drinking occurs** THE PROBLEM OF ETOH ABUSE: ALCOHOL USE DISORDER (AUD) In vulnerable individuals, compulsive heavy use ○ Est. 18 million affected by AUD (USA, 2018) ○ Est. economic impact about 250 billion p.a. (USA) ○ Est. 5.9 million deaths p.a. Globally (WHO, 2015) Involves EtOH tolerance due to faster liver metabolism (increased CYP450, not ADH) ○ AUD-affected subjects survive BACs up to 8 times lethal levels in alcohol-naive people But, CYP-mediated metabolism of EtOH produces toxic radicals (such as liver damage) Very high social and medical impact ○ Failed relationships and employment loss ○ Psychiatric symptoms, neurotoxicity and severe cognitive disruption ○ Need for organ transplants and long-term care ALCOHOL TOXICOLOGY : DISEASE THAT ACCOMPANY AUD EtOH has causal role in > 60 diseases ○ Top 10 contributor to WHo global disease burden (about 4%) Includes health disorders that are wholly attributable to alcohol ○ Alcoholic label often attached to names Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Alcoholic liver disease Alcoholic cardiomyopathy Alcoholic neuropathy Cancer (multiple sites) ○ Role for toxic aldehydes – acetaldehyde and oxidized lipid fragments (MDA, 4-HNE) in cell damage in these conditions EtOH also exacerbates diseases that are partially attributable to alcohol ○ E.g. falls, infectious disease WEEK 3 CONTINUED –– FROM REEFER MADNESS TO HIGH ECONOMY Learning Outcomes Describe the botanical profile of cannabis Describe the 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 WHAT IS CANNABIS? One of the world’s oldest crops (hemp harvested in China 8500 years ago), however, it is very mysterious Current broad use of the term ‘cannabis’ is often vague, unscientific, and confusing Unsure if the genus Cannabis is monotypic (one species) or polytypic (three or more species) Why is it so weird? Ancient origin Extremely long evolutionary and domestication history (including artificial selection) → may have wiped out other variants Widespread geological dispersal Prohibition made it hard to investigate scientifically DOPE VS. ROPE Present-day genetic distinction is essentially ‘dope vs rope’ ○ Narrow-leaf drug (NLD) and broad-leaf drug (BLD) biotypes (both indica) ○ Narrow-leaf hemp (NLH) biotype (a sativa) A ‘THIRD STRAIN – RUDERALIS Molecular genetics is providing increasing evidence that cannabis is a polytypic genus Some classify cannabis as a three subspecies ○ Indica ○ Sativa ○ Ruderalis Ruderalis plants are small and yield relatively little medicine with low potency Seems to have different flowering and life cycle These strains are typically avoided by breeders and cultivators ○ Medical cannabis is usually indica or sativa strains (whatever they may be) CANNABIS IN THE US Hemp grown in North American colonies from early seventeenth century (by slaves) American hemp industry peaked before 1860 –– declined after the Civil War (loss of slaves; rise of industrialization) Medicinal cannabis included in the American pharmacopeia by 1851 Imported from India via Britain Medical uses were sporadic and ill-defined By the early 1900s, US government began experimenting with domestic production of drugs, including cannabis RECREATIONAL USES Early reports of recreational cannabis use in the US –– Southwest and the port of New Orleans, c. 1900 New term ‘marijuana’ → smoked version of cannabis indica Racist fears about Mexican immigrants and drug trade In 1915, El Paso, Texas was the first US municipality to ban the non-medical cannabis trade (fears of Mexican drug trade) Street name was ‘muggles’ Recreational marijuana smoking spread rapidly during the 1920s ○ Industrial hubs like Kansas and Chicago – working class, youth, black associations ○ Jazz musicians like Louis Armstrong brought ‘reefers’ to various gig across the country THE 1950S AND 1960S Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 1950s Beatnik movement — cannabis use 1960s –– growing counterculture American soldiers sampled Thai and Vietnamese varieties while serving in Vietnam Mostly imported cannabis –– wild cannabis has little THC By the 1970s, harvesting of wild cannabis was common in the US Led to chemical pesticide spraying by local governments 1980S AND THE US WAR ON DRUGS –– DOPE GOES INDOORS Greater US state and federal law enforcement campaigns After 1989, growers moved largely indoors –– labs, hydroponics 1996: California became the first state to re-legalize marijuana for medicinal use Indoor growing became the norm 2012: Colorado and Washington state re-legalize adult use of marijuana Both states focused on regulating (and privileging) energy guzzling indoor cultivation AUSTRALIA’S CANNABIS STORY As with America, medicinal cannabis available in colonial Australia No data on extent of use Opium was seen as a much more dangerous drug of abuse and traffic (racist associations with Chinese) 1938: the term ‘marihuana’ appears in Australia in connection with the ‘reefer madness’ moral panic in the US Medicinal cannabis finally phased out in the 1960s in Australia Destruction of wild crops in 1970s Similar Vietnam War and counterculture influences in Australia HOW IS IT TURNED INTO PRODUCT Most cannabis produced and consumed in the world is herbal: dried flowers and smallest leaves and stems of the female cannabis plant Sinsemilla (seedless) crops: remove all male plants from field Hashish (grass) or resin: paste-like substance obtained by compressing the resin glands (trichomes) of the female cannabis plant Bhang: edible paste-like cannabis, used in foods and drinks during some Hindu and/or Sikh religious occasions Butane hash oil (BHO): a solvent-extracted, cannabis resin concentrate made with liquid butane Rosin: solventless extract – heat and pressure with heating hydraulic press Edibles: gummies, tea, powders, butter/oil, brownies PHARMACODYNAMICS Cannabis is a polypharmaceutical substance (comprised of many compounds, including cannabinoids) Those of primary interest are ○ Cannabidiol (CBD) ○ Tetrahydrocannabinol (THC) ○ Cannabinoid receptors are located throughout the body: brain, major organs, connective tissues, glands, immune cells ○ The human body has cannabinoid receptors Meaning the human body has endocannabinoids ○ Anandamide → discovered and named in 1992 Responsible for biological effects such as increasing appetite, decreasing nausea, decreasing pain sensitivity, and providing anti-inflammatory activity CANNABINOID RECEPTORS The two major identified cannabinoid receptors in the body are CB1 and CB2 G-protein-coupled receptors (eTute 1) CB1 receptors: mostly CNS and peripheral NS CB2 receptors: mostly immune cells and spleen; also GI tract, skeletal muscle, skin, cardiovascular system, reproductive system, liver CB2 receptor agonist [stimulate a response] are targets of emerging research due to their potential analgesic, anti-inflammatory, and immune-modulating properties ○ https://www.azolifesciences.com/article/Comparison-of-Receptor-Pharmacology-in-Cannabinoids.aspx HOW IT GETS INTO THE BODY Inhaled smoke: cannabinoids travel rapidly from the lungs to the blood and brain ○ Leads to higher levels of THC in blood plasma Ingested: absorbed from the intestines → metabolized in the liver (first-pass metabolism) ○ Leads to lower levels of THC in blood plasma WHAT GOES WHERE Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 All cannabinoids are not equal THC had equal affinity to both CB1 and CB2 (partial agonist) Synthetic cannabinoids are ‘fussy’ – highly selective agonists or antagonists to one of the receptor types CBD does not directly affect either CB receptor (antagonist) ○ It modifies the receptor’s ability to bind endocannabinoids ○ E.g., CBD enhances the activity of anandamide ○ CBD is thought to interact with several other receptors like the receptor and serotonin (5-HT) receptors HOW DOES THE THC GET YOU HIGH It may cause short-term dopamine flooding (and long-term blunting of dopamine effects THC seems to unplug the brain’s default mode network (how we daydream and think about past and future) Psychedelics such as LSD and psilocybin seem to have a similar effect on the brain’s default mode network Difficulties in studying this phenomenon: illegality, subjective experience of ‘high’ PHARMACOKINETICS – SMOKING Depends on ○ Route of administration ○ Cannabinoid involved ○ Physical characteristics of the user Both THC and CBD are highly lipophilic → they like to snuggle in your fat cells ○ THC produces the ‘high’ ○ CBD acts without euphoric effects Bioavailability of inhaled THC is highly variable: between 10% and 35% The THC content also varies depending how it is inhaled ○ Doobs: less THC content partially due to pyrolysis at higher temperatures and loss due to side smoke; more tar and impurities ○ Vaping: highest content of THC and cleaner vapor Smoking effect can occur within seconds; can be fully apparent within minutes; lasts up to 3 hours PHARMACOKINETICS – EDIBLES The amount of THC absorbed from edibles depends on your body mass index, metabolism, gender, and eating habits Bioavailability of THC and CBD from edibles also widely variable – 4% to 12% Edibles can have a longer effect compared to inhaled THC – 6-12 hours ○ But a higher risk of toxicity THC and CBD content labeling may be inconsistent: as high as 23% for under-labeling and 60% for over-labeling THC – EVIDENCE FROM META-ANALYSES Human brain has considerable neuronal plasticity = potentially vulnerable to ongoing THC use due to effects of cannabinoid receptors Literature overall supports causal and correlational relationships with ongoing THC use ○ Reduced cognitive and motivational abilities – verbal memory and attention (reversible with abstinence? Variables like use, age, THC content can moderate risk?) ○ Associated psychosis, depression, anxiety, addiction, violence ○ Robust relationship between chronic marijuana use and increased risk of suicide ○ Pediatric exposure highly risky ○ Risks to adolescent brain: brain connectivity, CNS gray matter, altered CB1R signaling, potential short-term memory dysfunction via hippocampal changes = increased risk of neurodevelopmental conditions, psychosis ○ https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2782160 Cannabis smoke inhalation increases risks of pneumonia, bronchiolitis, pneumothorax, emphysema, and pulmonary hemorrhage Evidence suggests cannabis smoke is carcinogenic Cardiovascular system ○ Increased myocardial oxygen demand ○ Pro-oxidative stress ○ Decreased myocardial contractility ○ Promotion of atrial and ventricular arrhythmia ○ Arrhythmia ○ Stroke ○ Arterial dissection ○ Myocardial infarction ○ Sudden cardiac death MEDICINAL USES OF CBD – THE MOST RECENT EVIDENCE Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Presently available data do not allow any firm recommendations for the use of cannabinoids (usually CBD) in pain management or opioid use disorders Three examples ○ Adult cancer-related pain → addition of cannabinoids to opioids did not reduce cancer pain ○ Acute pain management → low-quality evidence that cannabinoids may be a safe alternative for a small but significant reduction in subjective pain score –– only with intramuscular injection ○ Movement disorders → not enough good quality data to determine that any forms of cannabis are effective There is some evidence for other areas (examples only) ○ Treatment resistant epilepsies → some evidence that CBD oil is a good adjunct therapy ○ Multiple sclerosis → potential therapeutic systematic effects, including alleviation of pain, spasticity, and bladder dysfunction ○ Nausea from cancer treatment → good evidence for relief Two principal objections to medicinal CBD use ○ We have better medicines already available for these conditions ○ There are known and unknown interactions between CBD and other standard treatments, some of which are potentially harmful Cannabis in medicine: an evidence-based approach (Springer, 2020) –– UWA Lib THERAPEUTIC GOODS ADMINISTRATION (TGA) AUSTRALIA Cat 1: CBD medicinal cannabis product (CBD > 98%) – prescription only (Schedule 4) Cat 2: CBD dominant medicinal cannabis product (CBD > 60% and > 98%) – controlled drug (schedule 8) Cat 3: balanced and medicinal cannabis product (CBD < 60% and > 40%) – controlled drug (schedule 8) Cat 4: THC dominant medicinal cannabis product (THC 60% - 98%) – controlled drug (schedule 8) Cat 5: THC medicinal cannabis product (THC > 98%) – controlled drug (schedule 8) CURRENT CANNABIS LAWS IN AUSTRALIA State/territory Recreational Medicinal ACT Legal: < 50g of marijuana, 2x plants per CBD oil and other cannabis products for person both personal and medicinal use NT Illegal Current medical needs = access through TGA guidelines for pain and nausea from cancer treatments, neuropathic pain, and epilepsy. CBD oil with a medical certificate WA Illegal Medicinal marijuana or CBD oil with qualifying condition and no history of substance abuse or specific mental conditions such as bipolar disease SA Illegal Either palliative care patient, aged 70 or older, or by prescription for marijuana or CBD oil NSW Illegal CBD oil – as long as other cannabinoids (such as THC) don't exceed 2% of the product. Legal for adults with terminal illness VIC Illegal Medical certificate needed. CBD oil by prescription only QLD Illegal 2020 – medicinal use with doctor’s prescription; CBD oil TAS Illegal Medicinal marijuana and CBD oil if Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 patients have severe or chronic conditions that have been to be relieved by the substance. Prescription only LEGALIZE CANNABIS PARTY – BILL 20 June 2023: bill introduced in state parliaments in Victoria, NSW and WA Legalize cannabis party has representation in all three states’ upper houses Bill would allow adults to possess and grow small quantities of cannabis at home Similar to ACT model The bill is not currently supported by WA’s ALP government (Roger Cook) LEGALIZATION – THE HIGH ECONOMY Impact of legalization of recreational and medicinal use in the US ○ 23 US states allow adult recreational use, 38 allow medical sales ○ 2020: legal sales = 17.5 billion, a 46% increase from 2019 ○ By comparison, craft beer industry in the US = 41 billion in annual sales ○ Estimated creation of just over 6,000 new full-time jobs in retail and production ○ Also marketing, data analysts, lawyers, health professionals ○ Reduction of cannabis-related criminal convictions – similar use rates, but black people are 3.6 times more likely to be arrested for marijuana possession compared to whites ○ State and federal taxes, fair wages, infrastructure and regulation all cost small business owners They cannot always make profit ○ California – very complex state laws: selling 500g for $3,000 illegally, or selling 500g for $600 legally? ○ Most cannabis trade is still illegal ○ Illicit cannabis sales estimated at $100 billion each year ○ Both legal and illegal sellers use a mix of bricks-and-mortar, e-commerce and ‘rideshare’ type delivery systems ○ Legal traders rely on government to shut down illegal traders ○ Historical push for legalization has always been about recreational use But legalization came first for medicinal cannabis – based on tenuous medical evidence ○ Is legalizing medicinal use a way of smoothing the path to increased legal recreational use? SUMMARY Cannabis is tricky and elusive, botanically and chemically Although it is a very old drug, it is still misunderstood because of the legal/illegal divide It has a recent modern history that has made this more complicated It is still hard to develop a global picture of its growth, trade, and uses It has different ways of preparation and use for extraction and ingestion Its two main interesting cannabinoids behave differently in the body: ○ THC is fun, but tends to be mostly harmful to the body ○ CBD is less fun, and can be therapeutic, but the evidence base is still very much in development There are both risks and benefits associated with the legalization of recreational and medicinal cannabis WEEK 4 –– MORPHINE AND THE QUEST FOR PERFECT PAIN CONTROL Aim of lecture: to explore the historical and scientific factors surrounding the discovery and human usage of the powerful pain-relieving drug morphine HISTORY OF MORPHINE Derived from resin of the opium poppy (papaver somniferum) ○ Distinct from common poppies ○ Long history of human usage 2100 BC ○ Sumerian clay tablet, one of the oldest lists of prescription medicines ○ Hul Gil, the ‘joy plant’ 1500 BC ○ Greek statue with poppy seeds in hair and closed eyes suggesting sedation 300 BC to 100 AC ○ Recommended for use before surgery by Greco-Roman physicians such as Theophrastus, Celsus, Galen HARVESTING OPIUM – A SPECIALIST TASK Wait 2 weeks after petals fall ○ When pods turn dark and crown sticks up it is lanced with special knife (3-4 blades – cut 1-1.5 mm) Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Timing on the day is crucial and resin or sap is allowed to seep overnight Pharmacological activity takes a few hours to emerge ○ Wait for sap to turn brown and sticky ○ Scraped using a blunt knife (up to 5 or 6 times) HISTORY OF MORPHINE – MODERN 1804 ○ Morphine (alkaloid) isolated from poppy by German pharmacist Friedrich Serturner ○ After Morpheus, Greek god of dreams 1817 ○ First distributed commercially by Serturner and Co 1827 ○ Commercialized by Georg Merck (1825-73) in his small pharmacy in Darmstadt (Germany) HISTORY OF MORPHINE – HEROINE 1874 ○ Heroin – acetylated morphine – made in UK pharmacy (Wright) ○ Distasteful to his dogs 1897 ○ Felix Hofmann prepared heroin at Bayer (German company) ○ Heinrich Dreser fanatically promoted heroin as safe alternative to morphine ○ Widely sold OTC in USA, Europe, etc (e.g. cough mixture, “soothing syrups” for children HISTORY OF MORPHINE – MILITARY 1843 ○ Dr. Alexander Wood (Scottish) invents hypodermic syringe ○ Pioneers i.v. morphine use (wife fatally overdosed) 1859-1865 (US Civil War) ○ About 400,000 troops became addicted to opium ○ “The returning veteran … had a leather thong around his neck and a leather bag (with) Morphine Sulfate tablets, along with a syringe and a needle issued to the soldier on his discharge… This was called the “Soldier’s Disease” (Gerald Starkey) HISTORY OF MORPHINE – THE OPIUM WARS 17th century – British took control of Indian opium-producing areas 1750 – Opium became main commodity of British trade with China (1767: 2000 chests per year) 1839-1842 – first opium war Begins after Lin Zexu, a chinese commissioner, confiscates illegal foreign opium imports (Britain sent warships in response) 1856-1860: Second Opium war (Britain and France vs. China) HISTORY –– THE OPIUM CRAZE 17 and 18th century Britain, etc. ○ High prevalence of tuberculosis (painful lung condition – opium helped control pain) ○ Also used to toothache (very prevalent prior to modern dentistry) Also its euphoric effects made it popular for recreational purposes ○ Especially among societal elites, the literati, intellectuals ○ 1821, Confessions of an English Opium Eater Thomas De Quincey 19TH CENTURY BRITISH PARLIAMENTARIAN –– WILLIAM WILBERFORCE Pioneering antislavery politician, social activist, philanthropist (1759-1833) 1807 passage of his anti slavery Bill “one of the turning events in the history of the world” Took opium for 45 years (addicted) ○ Struggle with opium’s hallucinatory powers and its depressions Took opium before addressing British House of Lords HISTORY OF MORPHINE –– THE US EXPERIENCE Early 20th century – major US epidemic of heroin addiction ○ 1914, Harrison Narcotic Act (federal regulation and taxation of opioids) New York, 1915-1920s, heroin black market began (compact drug) Emergence of i.v. heroin abuse Addicts began collecting and selling scrap metal (“junkies”) ○ 1922: NY, heroine linked to 260 murders ○ 1924: Congress banned production THE SCIENCE OF MORPHINE: PAIN RELIEF Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 Morphine is the prototype opiate –– our best analgesic (pain relieving drug) ○ Binds to opioid receptors in brain and spinal cord (Strong agonist) Inhibits transmission of pain signals from periphery ○ Decrease in brain’s perception of pain Also causes euphoria (contentment and well being → reason for abuse) TYPE OF OPIOID RECEPTORS Inhibitory G-protein receptors – contain around 400 amino acids and 7 transmembrane domains 3 major classes (90% amino acids are identical in each) MORPHINE MIMICS THE EFFECTS OF NATURALLY OCCURRING ENDORPHINS (STRUCTURAL SIMILARITIES) Endorphins (from endogenous and morphine) = small neuropeptides ○ Made in CNS by controlled digestion of protein precursor (pre-PMC) ○ Released during pain, pleasure, and stress Suppress pain transmission but also cause euphoria (e.g. exercise, etc) ○ Short duration effect ○ Quickly broken down by metabolism Morphine and its derivatives have longer duration of action MEDICINAL CHEMISTS HAVE CREATED MANY MORPHINE-LIKE NARCOTIC ANALGESICS NARCOTIC DRUGS VARY IN THE TIMING OF THEIR PROPERTIES AND DURATION OF EFFECT OPIOID RECEPTORS ARE MAINLY LOCATED IN THE CNS, GI-TRACT AND NERVE ENDINGS IN PERIPHERAL TISSUES MEDICINAL USES OF MORPHINE AND OPIOID ANALGESICS Goals in opioid therapy: Pain relief Improved quality of life Improved functional capacity Uses: Strong and moderate acute pain Palliative care (esp. cancer) Treatment of diarrhea Relief from coughing Use for chronic pain questionable (e.g. back pain) OPIOID ADDICTION Definition: compulsive use of drugs for nonmedical reasons; it is characterized by a craving for mood altering drug effects, not pain relief Morphine and related drugs have very high addiction optential ○ Physical dependence and tolerance occur readily (i.e. user needs higher doses to achieve euphoric response) ○ Also a high capacity for psychological dependence Withdrawal symptoms can be incapacitating (but rarely fatal) Opioid addiction is damaging to individuals, families, communities, etc ○ Societal attitudes swing between libertarianism and prohibition SWINGING SOCIETAL ATTITUDES TOWARDS OPIOIDS “Everybody can have them” → risk of abuse, addiction, harm) “Nobody can have them” → underutilization robs patients of pain relief, creates black markets) THE CONTEMPORARY OPIOID EPIDEMIC In the USA in 2017 ○ 11.4 million people misused prescription opioids ○ 130+ deaths daily from opioid-related OD’ Close to 50,000 deaths p.a. ○ 81,000 people used heroin for first time 15,482 deaths attributed to heroin NAS: A SAD CONSEQUENCE OF THE OPIOID EPIDEMIC NAS: neonatal abstinence syndrome ○ A drug withdrawal syndrome in newborns due to maternal use of opioids during pregnancy Symptoms (soon after birth) ○ Irritability ○ Poor sucking reflex Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Poor weight gain ○ Seizures ○ High muscle tone (hypertonia) ○ Autonomic nervous system dysfunction Major implications for neonatal intensive care units (NICUs) ○ Increased hospitalization of newborns ○ Increased cost of caring for newborns Lifelong consequences for affected individuals LECTURE CONCLUSIONS (Morphine and pain control) Medical knowledge of opium poppy resin (papaver somniferum) is >4000 years old ○ Early 19th century – extraction of morphine Morphine is a strong receptor agonist that exerts analgesic actions on pain-signalling neurons in the spinal cord and CNS ○ Many semisynthetic and synthetic narcotic analogues available Significant side-effects include high abuse potential and respiratory depression The modern opioid epidemic is the latest phase of humanity’s longest struggle in using these powerful drugs safely and effectively WEEK 4 –– ANESTHESIA Aim of lecture: Explore the historical, scientific and clinical factors surrounding the discovery and development of general anesthesia (GA) agents SURGICAL HORRORS BEFORE ANESTHETICS: THE ANCIENT WORLD “The surgeons take great care to make the patients bear the cutting quietly. They cut as tenderly as possible, even giving in a little, and giving time for the patient to take a break.” [while the subjects] “wail against those who are cutting them”... [the surgeons] “ignore these things and consider only the health of the patients.” THE EARLY MODERN ERA (18TH CENTURY) Last resort (surgeons did operations rarely) Brutal tools → severed tissue fast Many ‘assistants’ → for patient restraint Hot cauterizing tools (to stop blood loss) Patient reflexes → risk of injuries High mortality → blood loss and infections Patients had to assume certain postures PERSONAL ACCOUNT “A terror which passes all description” ○ “Yet––when the dreadful steel was plunged into the breast––cutting through veins––arteries––flesh-–nerves––I needed no injunctions not to restrain my cries. I began a scream that lasted intermittently during the whole time of the incision–– and I almost marvel that it rings not in my ears still. So excruciating was the agony” – Fanny Burney A ghastly ordeal for surgeons too ○ “When all was done, and they lifted me up that I might be put to bed … I then saw my good friend Dr Larrey, pale nearly as myself, his face streaked with blood, and his expression depicting grief, apprehension, and almost horror.” Fanny Burney KEY EVENTS IN THE 19TH CENTURY EMERGENCE OF MODERN ANESTHESIA LAUGHING GAS (NITROUS OXIDE) PAVES THE WAY A gaseous oxide of nitrogen (N20) → the only early agent still in wide use Isolated by Joseph Priestly in 1770s – “dephlogisticated nitrous air” First animal studies by Humphrey Davy ○ Pneumatic institute, Bristol, UK ○ Mice, fish, snails, earthworms, lizards – “seemingly dead” Fully recovered in shallow water Intense activity before insensibility Once satisfied of safety, Davy self-inhaled with very pleasurable effects April 1799, inhaled 4 quarts from silk bag: “extraordinary powers of action” Started a craze among Europe’s elites KEY EVENTS IN THE 19TH CENTURY EMERGENCE OF MODERN ANESTHESIA CARBON DIOXIDE AND AN ITALIAN DOG’S TALE Odorless and colorless gas discovered in 1750s by Joseph Black Downloaded by Esandi Wijesooriya ([email protected])  lOMoARcPSD|43244509 ○ Associated with “bad air” in mine shafts Grotto Del Cane, Naples ○ Tourist attraction at base of volcano CO2 released from fissures produced reversible collapse of unfortunate dogs Henry Hill Hick