Pharmacology Exam Notes PDF

Pharmacology Lec-1 +-----------------------------------+-----------------------------------+ | Critically describe current | **3 current sources** | | sources of knowledge about | | | **medicine in pre-science era** | 1. Cave paintings...

Pharmacology Lec-1 +-----------------------------------+-----------------------------------+ | Critically describe current | **3 current sources** | | sources of knowledge about | | | **medicine in pre-science era** | 1. Cave paintings | | | | | | - The sorcerer | | | | | | 2. Physical remains | | | | | | - Skulls-trepanation | | | | | | - Bog bodies- Tollund man | | | | | | - Glacier mummies- otzi | | | | | | 3. Tools that may be for medical | | | use | +===================================+===================================+ | Describe the **scientific | It is an organised effort to come | | method** | up with explanations of nature | | | with continuous revision and | | | correction of these explanation | | | through systematic observation | | | | | | Pros: faster and safer innovation | | | | | | - Organised discovery-minimises | | | wasted efforts | | | | | | - Reduces repetition | | | | | | - Encourages revision based on | | | evidence | | | | | | - Clear audit trail | | | | | | - Replicable and communicated | | | results | +-----------------------------------+-----------------------------------+ | Describe the **humoral theory** | The imbalance of 4 humors of the | | | body causes diseases | | | | | | 1. Phlegm- water, feminine | | | | | | 2. Black bile- earth, feminine | | | | | | 3. Yellow bile- fire, masculine | | | | | | 4. Blood- air, masculine | +-----------------------------------+-----------------------------------+ | Describe **how** and **when** | Transitioned in the Middle Ages | | western medicine made the | (1200ce) but flourished in the | | transition from **guesswork to | 18^th^ century | | science** | | | | Through 3 key principles | | | | | | 1. Rationalism | | | | | | 2. Inductivism | | | | | | 3. empiricism | +-----------------------------------+-----------------------------------+ Prehistoric medicine=before written history medicine Sources of knowledge for ancient drug medicine - We know almost nothing Sources of medical ancient medical treatment- - 1)Cave paintings - Con: interpretation is subjective - Eg- The sorcerer paintinginterpreted in different ways - 2)Physical human remains - Can show signs of injury or medical treatment - Skeletons (bones) - Eg- skull with trepanation (hole in skull) - Bog bodies - Preserves body well due to anaerobic environment - Eg- Tollund manstrangled, last meal, presence of **parasites** - icemen (glacier mummies) - eg- otziwound in back of head, tattoos, **2 human fleas** on clothing, intestinal **parasite, Lyme disease** - 3)Fragmented itemstools - But we don't know which tools are for medical practices Sources of knowledge for written history Cons: - Fragmented records - Records only apply to literate/rich class of society ∈ Systematic method - **Organised efforts** - To come up with **explanation of natural phenomenon** - With **continuous modification** **and correction** of these explanations through **systematic observation** Process: - 1\) make observation - 2\) think of interesting questions - Why does this happen - 3\) formulate hypothesis - What causes the observed thing - 4\) develop testable predictable - If my hypothesis is correct then a, b.. - 5\) gather data to test predictions - 6\) if prediction is right, develop theory \*\*\*The scientific method is not dependent on technology, whether in lab or outside, it is **a method/approach of thinking** to problem solving Strength of scientific method - **Organized discovery** - The method ensures a systematic approach to research, minimizing wasted effort. - **Elimination of repetition** - By building on existing knowledge, the method avoids unnecessary duplication. - **Encouragement of revision** - The scientific method emphasizes revising explanations, questions, and hypotheses based on *[evidence]*. - **Clear audit trail** - The process provides transparency and accountability in research - Shows how the scientist got to the result - **Communicable and replicable results** - The findings should be clearly communicated and reproducible by others. - **∴ Faster and safer innovation** - The combination of these factors leads to more efficient and reliable progress in scientific understanding. ∈ Hippocratic approach - Systemised the description of disease - Systemised **some** elements of basic clinical observation - BUT did not use the scientific method Humoral theory 1\) phlegm- waterfeminine 2\) black bile- earthfeminine 3\) yellow bile- firemasculine 4\) blood- airmasculine - Believed imbalance of 4 humors caused disease - Based on misplaced observation - Eg- diarrhoea is yellow bile - Humoral theory dominated western medicine - Denounced doctors who wanted observation-based methods ∈ Transition from guesswork to scientific method - Transition started **from Middle Ages (1200CE)** - Flourished in the **18^th^ century** 3 Core principles that caused this break - **1) Rationalism** - Knowledge is acquired through reason, not received ideas - **2) Inductivism** - Idea that we can observe nature and then develop laws based on this observation which can be tested and confirmed - **3) Empiricism** - Descriptions based on observation and experience indicate that a phenomenon is testable What else aided modern medicine on top of the rejection of humoral theory and acceptance of scientific theory: 18^th^ century industrial revolution - Technology - Microscope - Distillation etc - Allowed isolation of elements - Mass production=cheaper - Advertisement of products to mass population - ∴led to development of big pharma Lec 2- +-----------------------------------+-----------------------------------+ | **How** do historians | - Anthropology | | **reconstruct ancient drug use** | | | | - Shipwrecks- Pozzino doctor | | | chest | | | | | | - Ancient texts | | | | | | - Bald's leechbook | +===================================+===================================+ | Describe **common natural drug | | | sources** | | +-----------------------------------+-----------------------------------+ | Know the name of **key drug | - 1\) Bald's leechbook | | innovators** and their | | | **important text** | - Could cure MRSA | | | | | | - 2\) Ebero Papyrus | | | | | | - 2\) Hippocratic Corpus | | | | | | - 3\) Pedanius Dioscorides- de | | | materia medica | | | | | | - 600 plants | | | | | | - 4\) Galen of Paragon- de | | | compositione medicamentorum | | | | | | - Included exact | | | measurement | | | | | | - Believed in thelias- 64 | | | ingredient composition | | | that could cure all | | | | | | - Al-Rhazi | | | | | | - Introduced use of mercury | | | | | | - Ibn-Sina- Al Qanun | | | | | | - 700 drug preparation | | | | | | - Peracelsus | | | | | | - Toxicologist | | | | | | - Championed for use of | | | mercury | | | | | | - Cannabis and chamomile | | | epilepsy treatment | +-----------------------------------+-----------------------------------+ | Provide arguments **for** and | For- | | **against** the **reconstruction | | | of ancient medicines** | - Fun | | | | | | - Open up research on new | | | natural products for | | | potentially useful trace | | | elements | | | | | | Against | | | | | | - Limited shelf life | | | | | | - Cannot be transported easily | | | | | | - Cannot be mass produced | +-----------------------------------+-----------------------------------+ Measuring the "success" of drug - Reduction of death caused by a particular disease - Closure of specific types of hospitals - Eg- Leprosy clinics no longer needed as disease under control - Cons: - Closure of treatment clinics doesn't mean cure of disease - Eg closure of a mental health clinic - We don't know if those clinics actually improved symptoms Finding ancient drug use in history - Modern anthropology - Studying specific culture's practices to gain insight into ancient medicine - But cannot definitively link it their practices with the assumption that they knew medical reasons behind it - Shipwreck: Pozzino shipwreck - Found doctors chest containing zinc compound tablet, but **do not know the exact use** - Could be collyrea- eye solution - To treat skin irritation- like modern day calamine lotion - Pine resin- could be binding agent or active ingredient - Ancient texts - Anglo-Saxon textbook-Bald's Leechbook - Could cure MRSA if a very specific recipe used \*problem with ancient text- different ingredients, different measurement units Natural drug sources - Plants - 1-Leaves: tobacco, hemp, geranium, lavender, mint - 2-Flowers: chamomile, calendula. - 3-Roots: ginger, galangal, turmeric, valerian, echinacea, liquorice - 4-Seed heads: hemp, poppy - 5-gum/sap/resin: aloe - 6- spices: cinnamon, nutmeg, cumin - 7- bulbs: lotus bulbs - Psychoactive/CNS stimulating - 1-Hemp plant - 2-Opium poppy - 3-Tobacco - 4-Mushroom - 5-Betel nuts - 6-Coca leaves - 7-Kava leaves - 8-Peyote cactus - Minerals - Arsenal - Chalk - Clay - Red ochre - Mercury - Metals - Metal container - Verdigris (copper carbonate) - Also used as paint - Alcohol- antiseptic and anaesthetic - Beer - Ancient nubian bones had tetracycline- from beer made from contaminated grains - However not clear if they knew antibiotic properties - Wine/vinegar - Distilled spirits - Other - Raw honey - Insects - Animal parts- horns, dung - Human parts- hair, urine, fats - Mummies- asphalt used to preserve them so they are powdered and eaten for asphalt - Paint-mummies brown - Manuscripts- spells written and swallowed Ancient texts and authors - 1\) Bald's leechbook - Could cure MRSA - 2\) Ebero Papyrus - 2\) Hippocratic Corpus - 3\) Pedanius Dioscorides- de materia medica - 600 plants - 4\) Galen of Paragon- de compositione medicamentorum - Included exact measurement - Believed in thelias- 64 ingredient composition that could cure all - Al-Rhazi - Introduced use of mercury - Ibn-Sina- Al Qanun - 700 drug preparation - Peracelsus - Toxicologist - Championed for use of mercury - Cannabis and chamomile epilepsy treatment \*humoral theory underpinned classical islam medicine because they preserved ancient greek texts Should we replicate ancient recipes This is difficult because - Not exact measurements - Unknown required conditions - Potentially very dangerous-mercury etc Is it worth it pros cons -------------------------------------------------------------------------------- -------------------------------- fun Limited shelf life Open up research on new natural products for potentially useful trace elements Cannot be mass produced easily Cannot be transported easily Lec 3 +-----------------------------------+-----------------------------------+ | define "**pharmacokinetics**" and | Pharmacokinetics= what body does | | distinguish between | to drug | | pharmacokinetics and | | | **pharmacodynamics** | - How the drug moves through | | | the body | | | | | | - ADME | | | | | | Pharmacodynamics= what drug does | | | to body | +===================================+===================================+ | describe **the key features** of | Plasma/blood concentration time | | a **plasma concentration-time | curve achieved by volunteers | | curve** and **therapeutic | being administered drug, and | | window** of a drug and their | their blood taken incrementally | | relevance to **the beneficial and | and then the drug concentration | | harmful effects** of drugs | in the blood at different times | | | plotted | | | | | | MEC= Minimum effective | | | concentration | | | | | | - Above this line, the drug | | | works | | | | | | - safe | | | | | | MTC= Maximum toxicity | | | concentration | | | | | | - Above this line, the drug | | | concentration becomes toxic | | | | | | - dangerous | | | | | | Therapeutic window= the | | | concentration between mec and mtc | | | | | | - Where the drug is effective | | | and safe | | | | | | The width of the therapeutic | | | window indicated drug safety. | | | | | | The aim of new medicine is to | | | widen the gap | +-----------------------------------+-----------------------------------+ | describe the **four key | Absorption \*determined steepness | | pharmacokinetic** processes that | to Cmax | | control the fate of drugs in the | | | body and their defining features | - Not too big | | | | | Metabolites lose affinity to | - Greasy enough- lipophilic | | receptors than parent drug | properties allow drug to | | | cross membrane from gi to | | - Active metabolite= still able | portal blood and into | | to bind to parent drug's | circulation (for oral | | receptor and cause reaction | ingested drugs) | | | | | - Inactive metabolite= unable | - Neutral charge | | to bind to parent drug | | | receptor | - Not metabolised in gut | | | | | - Pro-drug= drug is inactive | - Not pumped back into gut by | | until metabolised | membrane transporters | | | | | | Distribution \*duration at Cmax | | | | | | - Gi tractmembranegut | | | wallportal bloodliver | | | | | | - Blood-associated drug- | | | remains mostly in blood | | | | | | - Tissue-penetrating | | | drug-remains in tissue | | | | | | Metabolism | | | | | | - Hydrophilic drug in blood | | | enters Kidney and excreted in | | | urine | | | | | | - Drug transporters take drug | | | from blood into kidney's | | | urine | | | | | | - DME (drug metabolising | | | enzymes used) | | | | | | - Urine contains the parent | | | drug/metabolite | | | | | | - Hydrophilickidneyurine | | | | | | - Lipophilic drugs are | | | dangerous as they can | | | accumulate in tissues for too | | | long | | | | | | - Metabolised in liver | | | | | | - DME adds OH group to make | | | hydrophilic metabolite in | | | oxidative metabolism | | | | | | - Further hydrophilic by | | | different enzyme adding sugar | | | molecule | | | | | | - Metabolites enter kidney then | | | excreted as urine | | | | | | - Lipophilicliverkidneyurine | | | | | | \*\*steepness of decline from | | | Cmax determines by metabolism and | | | excretion | | | | | | Excretion | | | | | | - Permanent removal | | | | | | - Kidney (urine) | | | | | | - Bile | | | | | | - Breast milk | | | | | | - Expired air | | | | | | - Not liver directly as | | | liverkidneyurine | +-----------------------------------+-----------------------------------+ | **explain** the **importance of | Metabolism and excretion | | metabolism and** **excretion** in | determine how long the drug | | controlling the **duration** of | remains in the blood | | drug effects in the human body | | | | - Half-life: the time it takes | | | for drug concentration in | | | blood to decrease half the | | | calue of Cmax | | | | | | - ∴The efficiency/speed of | | | metabolism and excretion | | | determines the half life | | | | | | - Short half-life= drug | | | metab/excreted quickly, | | | leaves body quickly ∴ more | | | frequent redoes | | | | | | - Long half-life= drug | | | metab/excreted slowly, stays | | | in body longer ∴ less | | | frequent redose | +-----------------------------------+-----------------------------------+ | describe **lipophilicity** and | - Lipophilicity allows drug to | | **hydrophilicity** as | cross lipid-membrane and into | | **determinants of the | tissue | | pharmacokinetic behaviour** of | | | drugs and the use of the | - Hydrophilic drug cannot | | **octanol-water partitioning | easily cross lipid-membrane | | method** to assess these drug | and so stays mostly in the | | properties | blood | | | | | | - Octanol-water test helps | | | determine these properties | | | | | | - Top layer octanol=lipophilic | | | drugs | | | | | | - Bottom layer water= | | | hydrophillic drug | +-----------------------------------+-----------------------------------+ | **describe** **bioavailability** | Bioavailability= fraction of | | and **reasons** for **poor | ingested drug that enters the | | bioavailability** of drugs | portal vein (not metabolised in | | | gut) | | | | | | Poor bioavailability= | | | | | | - Too large | | | | | | - Not greasy enough | | | | | | - Carries charge | | | | | | - Metabolised mostly in gut | | | | | | - Pumped back into gut by | | | membrane transporters | | | | | | Bioavailability of intravenous= | | | 100% | | | | | | Bioavailability of oral drug= | | | less than 100% | +-----------------------------------+-----------------------------------+ Liver Blood Flow \| BioNinja Lec 4 +-----------------------------------+-----------------------------------+ | distinguish between | Pharmacokinetics= what body does | | pharmacokinetics and | to drug (ADME) | | pharmacodynamics | | | | Pharmacodynamics= what drug does | | | to body | +===================================+===================================+ | describe drug and three types of | (paracetamol, Panadol) | | drug name and their | | | characteristics for a marketed | - Chemical name | | drug | | | | - Generic name- type of drug, | | | common roots or stems (ol) | | | | | | - Brand/trade name- different | | | companies but same active | | | ingredient (paracetamol, | | | Panadol\_ | +-----------------------------------+-----------------------------------+ | describe drug target and list | Drugs bind to drug targets, | | four groups of human proteins as | activates or inhibits them, to | | drug targets | cause biological response | | | | | | Drug targethuman proteins: | | | | | | - Receptors | | | | | | - Ion channels | | | | | | - Transporters | | | | | | - enzymes | +-----------------------------------+-----------------------------------+ | 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 | Receptor is a type of human | | describe the main characteristics | protein drug target, binds to and | | of four receptor superfamilies | responds to endogenous molecules | | | (molecules made by body) | | | | | | - drug (ligand)-receptor | | | relationships described as | | | agonist and antagonist | | | (others described as | | | activate/inactivate) | | | | | | Receptor superfamilies- | | | | | | - 1\) ligand-gated ion channels | | | (millisec) | | | | | | - 2\) G-protein coupled recepto | | | r | | | (second) | | | | | | - 3\) enzymatic linked receptor | | | s | | | | | | (minutes) | | | | | | - 4\) nuclear receptors | | | | | | (hours) | +-----------------------------------+-----------------------------------+ | describe agonist, antagonist, | Drug(ligand)-receptor | | affinity, efficacy, | relationships are described as | | concentration/dose-response | agonist and antagonist | | relationship, potency, and EC50 | | | in the context of ligand-receptor | Agonist | | interaction and therapeutic index | | | | - Mimics endogenous molecules | | | | | | - It binds to receptor=affinity | | | | | | - Can activate receptor to | | | create signal transduction= | | | efficacy | | | | | | Antagonist | | | | | | - blocks endogenous molecules | | | | | | - it binds to receptor= | | | affinity | | | | | | - does not activate receptor to | | | create signal transduction= | | | NO EFFICACY | | | | | | ∴both bind (affinity) but | | | antagonist do not have efficacy | | | | | | Concentration/dose-response | | | curve= amount of drug necessary | | | for desired response | | | | | | - used to find potency- dose | | | needed for defined response | | | | | | - measured by ED50/EC50- dose | | | needed to create 50% of | | | desired effect | | | | | | lower Ed50=higher potency | | | (inverse relationship) | | | | | | because less drug is needed to | | | create same response | | | | | | Toxic dose-effect curve= amount | | | of drug needed to have toxic | | | effect | | | | | | TD50= amount of drug needed to | | | cause 50% of maximum toxic effect | | | | | | Therapeutic index TI= TD50/ED50 | | | | | | A higher TI means more same | | | | | | - eg TI 10= toxic dose is 10x | | | the therapeutic dose | | | | | | - describes the distance | | | between the effective dose | | | curve and toxic curve | | | | | | Overlapping of the two curves is | | | dangerous, as increased dose | | | begins to be toxic | | | | | | ∴the two doses should be far | | | apart | +-----------------------------------+-----------------------------------+ | describe the action of morphine | - Morphine is an agonist | | in the context of | | | pharmacokinetics and | - Binds to opioid receptor | | pharmacodynamics | (type of G coupled receptor | | | | | | - Once bound, activates and | | | creates signal transduction | | | | | | - Effect= pain relief | | | | | | Morphine moleculeopioid | | | receptoractivatessignal | | | transductionchange in cell | | | activitypain relief | | | | | | Metabolism: | | | Codeinemetabolisedmorphine in | | | blood | | | | | | Excretion through breast | | | milkelevated morphine in baby | | | | | | - Baby cannot metabolise | | | morphine | | | | | | - ∴baby dies | +-----------------------------------+-----------------------------------+ Q3- - = relaxation/sedation (alcohol) Lec 5- +-----------------------------------+-----------------------------------+ | describe the basic chemistry of | Presence of OH groups | | alcohols and the processes | | | involved in the production of | Drinkable alcohol= ethanol | | ethanol by yeast | ch3-ch2-OH | | | | | | - Brewer's yeast consumes | | | glucose to generate energy in | | | a fermentation (anaerobic | | | process) which creates | | | byproduct of ethanol | | | | | | - However, excess level of the | | | byproduct (ethanol) is toxic | | | to the yeast | +===================================+===================================+ | summarise four types of alcoholic | \* | | beverages in terms of | | | **sources**, **production**, and | | | **alcohol content** | | +-----------------------------------+-----------------------------------+ | describe the pharmacokinetics of | Chemical property of alcohol | | alcohol | | | | - Polar head (hydrophilic) OH | | | end | | | | | | - Non-polar end (lipophilic) | | | | | | - ∴**amphipathic**/**aphiphilli | | | c**- | | | both water and fat loving | | | properties | | | | | | - Size- small | | | | | | **Absorption** | | | | | | - Rapid absorption reaching | | | Cmax in 30 minutes | | | | | | - Small sized molecule | | | | | | - Amphiphilic | | | | | | - Paracellular uptake due to | | | small size (goes between cell | | | instead of through) | | | | | | - Absorption site=mostly in | | | small intestine, less in | | | stomach | | | | | | - ∴eating food delays | | | absorption ∴decreased BAC as | | | metabolised in stomach | | | | | | **Distribution** | | | | | | - Crossed the GI tract through | | | paracellular uptake | | | | | | - Contributes to Total Body | | | Water (TBW) | | | | | | - Intracellular fluid | | | | | | - Extracellular fluid (incl | | | blood) | | | | | | \*difference of TBW in men and | | | women relates to different BAC | | | for same amount of consumed | | | alcohol | | | | | | - Women are smaller=less | | | TBW=Higher BAC | | | | | | - Less muscle (which contains | | | water)=less TBW= higher BAC | | | | | | - Less ethanol metabolising | | | enzymes | | | | | | **Metabolism** | | | | | | - Minor in Gut wall | | | | | | - Major in Liver (enzymes: ADH, | | | ALDH coenzyme: NAD) | | | | | | 1 ethanol molecule+ alcohol | | | dehydrogenase (ADH) + | | | 1NADacet[aldehyde]+al | | | dehyde | | | dehydrogenase (ALDH) + 1 | | | NADacetic acid | | | | | | ∴ 1 alcohol requires 2 NAD | | | | | | - Since there is a limited | | | amount of NAD in liver | | | | | | - Once all NAD are saturated, | | | alcohol metabolism occurs at | | | **fixed rate** | | | | | | \*Acetaldehyde is toxic | | | | | | \* ALDH is polymorphic, ALDH2 | | | version in asians is less | | | efficient at metabolising | | | Acetaldehyde to acetic acid | | | | | | ∴accumulation of it= flushing, | | | hangover | | | | | | Heavy drinkers | | | | | | Alternate alcholacetic acid | | | pathways (once adh/aldh pathways | | | saturated) | | | | | | - CYP450 enzyme pathway in | | | hepatocyte | | | | | | - Creates free oxygen | | | radical | | | | | | - Causes liver damage | | | | | | - Catalase enzyme pathway is | | | peroxisome organelle | | | | | | **Excretion** | | | | | | (context acetic acid enters | | | citric acid cyclewater and co2) | | | | | | ∴water=urine (kidney) | | | | | | - Co2= expired air | | | | | | - BAC correlates to | | | concentration of expired | | | air | | | | | | - Unmetabolized ethanol=urine | | | (kidney) | +-----------------------------------+-----------------------------------+ | describe the main **effects of | Alcohol is a psychoactive agent- | | alcohol** on the **brain** and | affects the CNS | | human behaviour and the | | | **disinhibition hypothesis** | - Specifically nonselective CNS | | | depressant | | | | | | - Non-selective= means it | | | can bind to multiple | | | receptors (GABAA, NMDA) | | | | | | - Depressant- calming, | | | relaxation, drowsiness, coma, | | | death | | | | | | Its effect on the brain is | | | dose-dependant | | | | | | Low dose- stimulatory | | | | | | High dose- sedation, death | | | | | |  | | | | | | Disinhibition hypothesis | | | | | | Explains why alcohol as a | | | depressant cause stimulatory | | | effect | | | | | | - Supresses the inhibitory | | | neuronal network | | | | | | - Which causes social | | | restraint- shyness | | | | | | ∴inhibiting the inhibiting | | | pathways= **disinhibition** | | | | | | Note- can also inhibit excitatory | | | pathways | +-----------------------------------+-----------------------------------+ | describe the action of two key | **1) GABA-A Receptors -- | | receptors in mediating the | inhibitory** | | effects of alcohol on the brain | | | | - GABA-A receptors are | | | **ligand-gated ion channels** | | | that open in response to the | | | binding of **GABA | | | (gamma-aminobutyric acid)**, | | | the brain's primary | | | **inhibitory | | | neurotransmitter** | | | | | | - When GABA binds to the | | | receptor, the ion channel | | | opens and **chloride ions | | | (Cl⁻)** flow into the neuron, | | | making the inside of the cell | | | more negative | | | (hyperpolarization) | | | | | | - This makes it less likely | | | that the neuron will fire an | | | action potential, reducing | | | brain activity | | | | | | - Ethanol- alcohol binds at | | | sites on the receptor that | | | are different from where GABA | | | binds, but it **enhances | | | GABA's effect**, causing more | | | chloride to enter the neuron. | | | As a result, the brain | | | becomes **more inhibited** | | | | | | **2)Glutamate receptors (NMDA)- | | | excitatory** | | | | | | - NMDA receptors are | | | **ionotropic receptors** | | | activated by **glutamate**, | | | the brain's major | | | **excitatory | | | neurotransmitter** | | | | | | - These receptors allow the | | | flow of **calcium (Ca²⁺)** | | | and **sodium (Na⁺)** ions | | | into the neuron, making it | | | more likely to fire | | | | | | - NMDA receptors play an | | | essential role in **learning, | | | memory formation** (when | | | neuron fires) | | | | | | - Alcohol **inhibits NMDA | | | receptor activity**, reducing | | | the ability of glutamate to | | | excite neurons. This leads to | | | **decreased brain activity** | | | in areas responsible for | | | cognition, memory | +-----------------------------------+-----------------------------------+ | describe alcohol use disorder and | - **Alcohol Use Disorder | | alcohol metabolism in chronic | (AUD**= compulsive heavy | | heavy drinkers | alcohol use-damaging to | | | health | | | | | | - **Tolerance**= Chronic heavy | | | drinkers develop tolerance to | | | alcohol due to increased | | | activity of CYP450 enzymes in | | | the liver | | | | | | - Heavy drinking- more reliance | | | on metabolism from **ADH** to | | | **CYP450** enzyme | | | | | | - allows individuals with AUD | | | to tolerate BAC levels that | | | would be lethal to those | | | without it | | | | | | - **Free oxygen | | | radicals**=However, the | | | CYP450-mediated metabolism of | | | ethanol generates toxic free | | | radicals that contribute to | | | liver damage. | | | | | | Other alternate metabolism for | | | heavy drinkers | | | | | | - Catalase enzyme pathway in | | | peroxisome organelle | +-----------------------------------+-----------------------------------+ | describe the relevance of | **Toxic Metabolite**: | | metabolism to alcohol toxicology | | | and name the toxic metabolite of | - **Acetaldehyde** is the toxic | | alcohol that causes DNA and | intermediate of alcohol | | protein damage | metabolism | | | | | | | | | | | | - **Acetaldehyde** causes **DNA | | | and protein damage**, leading | | | to: | | | | | | - **Liver damage** (e.g., | | | cirrhosis). | | | | | | - Increased risk of | | | **cancer** (e.g., head, | | | neck, liver). | | | | | | - In heavy drinkers, metabolism | | | through **CYP450 enzymes** | | | produces **free radicals** | | | that contribute to | | | **oxidative stress** and | | | further tissue injury. | +-----------------------------------+-----------------------------------+ \* +-----------------+-----------------+-----------------+-----------------+ | Alcohol | source | Production | content | +=================+=================+=================+=================+ | Beer | Starchy grains | - Grains | 4-6% | | | | (e.g., | | | | | barley, | | | | | wheat, | | | | | maize) are | | | | | mixed with | | | | | water and | | | | | allowed to | | | | | ferment. | | | | | | | | | | - Highest | | | | | sugar | | | | | (carb) than | | | | | most | | | | | alcohols | | | | | | | | | | - Modern | | | | | beers are | | | | | typically | | | | | clear, | | | | | carbonated, | | | | | and have a | | | | | higher | | | | | alcohol | | | | | content. | | | | | | | | | | - Ancient | | | | | beer not | | | | | carbonated, | | | | | thick | | +-----------------+-----------------+-----------------+-----------------+ | Wine | Fruits | - Fruits= | 10-14% | | | | grapes, | | | | | berries, | | | | | stone | | | | | fruits | | | | | | | | | | - Fruits | | | | | fermented | | | | | for longer | | | | | period than | | | | | beer | | | | | | | | | | - Sparkling | | | | | wine- | | | | | carbonated | | | | | (adding | | | | | co2, or | | | | | 2^nd^ | | | | | bottle | | | | | carbonation | | | | | ) | | | | | | | | | | \*Champaigne-di | | | | | strict | | | | | wine- in-bottle | | | | | carbonation | | +-----------------+-----------------+-----------------+-----------------+ | Spirits | Fermented | - Fermented | 35-50% | | | product | products | | | | | are | | | | | distilled | | | | | | | | | | - ∴ | | | | | concentrati | | | | | ng | | | | | the alcohol | | | | | | | | | | - Distillatio | | | | | n | | | | | involves | | | | | boiling the | | | | | fermented | | | | | product and | | | | | collecting | | | | | the | | | | | alcoholic | | | | | steam in a | | | | | condenser | | +-----------------+-----------------+-----------------+-----------------+ | Fortified wine | Wine | - Spirits are | 18-20% | | | | added to | | | | \+ | wine, | | | | | increasing | | | | spirits | the alcohol | | | | | content and | | | | | preventing | | | | | spoilage | | | | | | | | | | - Port, | | | | | sherry, | | | | | vermouth | | +-----------------+-----------------+-----------------+-----------------+ Lec 6 +-----------------------------------+-----------------------------------+ | Describe the **botanical | - Ancient plant | | profile** of **cannabis** | | | | - May be myopic or polytypic | | - Edibles | | | | - 3 sub-species | | - Bhang | | | | - Indica | | - Butane hash oil | | | | - Sativa | | - Rosin | | | | - Ruderalis | | - Hashish | | | | - Ruderalis is small plant, low | | - sinsemilla | yield, different flowering | | | and life cycle than others so | | | avoided by breeder | | | | | | - Smoked sativa=marijuana | | | | | | - Consumed cannabis=female | | | plants, dried flowes, | | | smallest leaves | +===================================+===================================+ | Describe **key events** in the | \* | | **cultivation** and **use** of | | | **cannabis** in the **US** and | | | **Australia** | | +-----------------------------------+-----------------------------------+ | **Describe** the basic | Cannabis is | | **pharmacodynamics** and | polypharmaceutical=made of | | **pharmacokinetics** of | multiple component | | **cannabis** | | | | - **Cannabidiol** | | | | | | - **Tetra-hydro-cannabidiol | | | (THC)** | | | | | | Body has cannabinoid | | | receptors∴endocannabinoids called | | | anandamide | | | | | | **Anandamide** known to | | | | | | - Increase appetite | | | | | | - Decrease nausea | | | | | | - Decrease pain sensitivity | | | | | | - Anti-inflammatory | | | | | | **Pharmacodynamics** | | | | | | - CB1 and CB2 receptors are g | | | protein coupled receptors | | | | | | - CB1- located in cns and pns | | | | | | - CB2- located organ system, | | | skin, skeletal muscle | | | | | | - THC has equal affinity to | | | both CB1 and CB2 receptors | | | | | | - THC cannot fully activate the | | | receptors ∴ partial agonist | | | | | | - CBD has very low affinity to | | | both | | | | | | - Cannot directly activate the | | | cb1 and cb2 receptors= so | | | antagonist | | | | | | - But can indirectly modulate | | | the receptors ability to bind | | | to endocannabinoid | | | | | | - Enhances activity of | | | anandamide | | | | | | - Indirectly modulates | | | serotonin receptors (5-t-h) | | | | | | - Indirectly modulates mew | | | receptors (opioid receptors) | | | | | | - Synthetic cannabinoid | | | | | | - Specific for receptors ∴ can | | | be antagonist or agonist | | | | | | CBD- no high, (no euphoric | | | effects) | | | | | | THC- high | | | | | | - Short term rushing of | | | dopamine (long-term dopamine | | | blunting=brain has less | | | sensitivity to dopamine) | | | | | | - Turning off of the brains | | | default mode- allows thinking | | | of past/future/daydreaming | | | | | | **Pharmacokinetics** | | | | | | Smoking= higher thc level | | | | | | Smokelungbloodbrain | | | | | | Ingesting= lower thc level | | | | | | GI tractliver (first pass | | | metabolism)blood | | | | | | THC and CBD- lipophilic and able | | | to enter and stored in fat cells | | | | | | Bioavailability of smoking | | | cannabis (10-35%) | | | | | | Effects- start within secs/mins | | | | | | Lasts- 3hrs | | | | | | - Lower in joint/doobs= because | | | of pyloric effects- burning | | | of the thc causes more | | | impurities | | | | | | - Higher in vaping= cleaner | | | vapur | | | | | | Bioavailability of edibles | | | (4-12%) | | | | | | Effects start slower | | | | | | Lasts- 6-12hrs | | | | | | - Increased risk | | | | | | - mislabelling of actual thc | | | levels | | | | | | lower bioavailability than | | | smoking because edibles undergo | | | first pass metabolism in the | | | liver before circulating in blood | | | | | | but longer lasting because- thc | | | released gradually over long | | | period of time ∴onset of effects | | | are slow | | | | | | - this can cause person to take | | | more coz cannot feel effect | | | ∴higher toxicity | | | | | | edibles also depends on | | | | | | - bmi | | | | | | - metabolism | | | | | | - gender | | | | | | - eating habits | +-----------------------------------+-----------------------------------+ | **Describe** the **benefits** | Benefits | | **and** **limitations** of | | | **cannabis** as a **medical | - treatment resistant epilepsy | | treatment**, based on current | | | evidence | - multiple sclerosis symptoms | | | | | | - nausea from cancer treatments | | | | | | \*\*however, medicine for these | | | already exist and its risky to | | | use cannabis when we don't | | | understand its bindings fully | | | | | | Limitations | | | | | | Overall: | | | | | | - ↓cognitive ability | | | | | | - ↓motivation | | | | | | - ↑ suicide | | | | | | - Psychosis, depression, | | | anxiety, addiction, violence | | | | | | - Paediatric exposure causes | | | brain development issues for | | | adolescent brains | | | | | | Smoking: | | | | | | - Carcinogen=cancer causing | | | | | | - Lung diseasespneumothorax, | | | pneumonia, pulmonary | | | haemorrhage, bronchitis, | | | emphysema | | | | | | - Cardiovascular diseases | | | | | | Prescribing cannabis | | | | | | RACGP- guidelines on how cannabis | | | should be prescribed for what | | | symptoms | | | | | | TGA- 5 category for prescription | +-----------------------------------+-----------------------------------+ \*Key Events in the US Cultivation and Use: - Hemp was grown in North American colonies from the early 17th century by slaves. - The American hemp industry peaked before 1860 and declined after the Civil War due to the loss of slave labor and the rise of industrialization. - Medicinal cannabis, imported from India via Britain, was included in the American pharmacopoeia by 1851, though its medical uses were sporadic and ill-defined. - By the early 1900s, the US government began experimenting with domestic production of drugs, including cannabis. Recreational Use: - Early reports of recreational cannabis use emerged around 1900 in the Southwest and New Orleans - The term \"marijuana,\" referring to the **smoked version of cannabis Indica,** appeared with racist fears surrounding Mexican immigrants and the drug trade. - In 1915, El Paso, Texas became the first US municipality to ban the non-medical cannabis trade due to concerns about the Mexican drug trade, with the street name for cannabis being \"muggles\" at the time. - Recreational marijuana smoking spread during the 1920s, associated with industrial hubs, the working class, youth, and Black communities. Jazz musicians like Louis Armstrong contributed to its spread across the country. Prohibition and the War on Drugs: - The 1936 film \"Reefer Madness\" fueled a moral panic around marijuana. - Cannabis use persisted through the 1950s Beatnik movement and the growing counterculture of the 1960s. - American soldiers in Vietnam were exposed to Thai and Vietnamese cannabis varieties, leading to increased importation. - By the 1970s, wild cannabis harvesting became common in the US, prompting chemical pesticide spraying by local governments. - The 1980s War on Drugs intensified law enforcement campaigns, pushing cannabis cultivation indoors into labs and hydroponic systems after 1989. Re-legalization: - California became the first state to re-legalize marijuana for medicinal use in 1996, leading to indoor growing becoming the norm. - Colorado and Washington state re-legalized adult marijuana use in 2012, focusing on regulating and prioritizing energy-intensive indoor cultivation. Key Events in Australia - Medicinal cannabis was available in colonial Australia, but there is no data on the extent of its use. - Opium, associated with Chinese immigrants, was considered a more dangerous drug. - The term \"marihuana\" appeared in Australia in 1938 due to the \"reefer madness\" panic in the US. - Medical cannabis was phased out in the 1960s, with wild crops destroyed in the 1970s. - Similar to the US, the Vietnam War and counterculture influenced cannabis use in Australia. - Current cannabis laws in Australia vary by state and territory, ranging from legal recreational use in the ACT to illegal status with varying degrees of access for medicinal purposes in other regions. - Recreational use is illegal in all states except ATC (\