Cannabis and Cannabinoids PDF

Cannabis and Cannabinoids Definition Cannabis: annual herbaceous plant grown in temperate/tropical climates ○ 2 major species: c. indica and c. sativa Cannabinoid: organic compounds that bind to cannabinoid recep. In the body, including naturally occurring, synth, endogenou...

Cannabis and Cannabinoids Definition Cannabis: annual herbaceous plant grown in temperate/tropical climates ○ 2 major species: c. indica and c. sativa Cannabinoid: organic compounds that bind to cannabinoid recep. In the body, including naturally occurring, synth, endogenous substances Phytocannabinoid: cannabinoids naturally produced by plants, especially found in c. sativa ○ ∆9-THC (delta-9-tetrahydrocannabinol) ○ CBD (cannabidiol) ○ CBN (cannabinol) ○ THC is the only psychologically active phytocannabinoid Endocannabinoid: cannabinoids naturally produced in the body (autacoid––– locally active, synth. On demand, short acting duration) ○ 2-AG (2-arachidonoylglycerol) ○ Anandamide (10-arachidonoylethanolamine) ○ Thought to help reduce pain by presynaptic modulation of NT release (regulate perception of pain) Synthetic cannabinoid: lab made compounds designed to mimic the effects of naturally occurring cannabinoids ○ Mix of antagonist/agonist of CB receps. ○ Dronabinol: synthetic THC ○ Nabilone: THC analouge, selective for CB1 ○ Rimonabant: CB1 antagonist ○ Sativex: 1THC:1CBD extract (used in cancer/MS pts resistant to high dose opioids) Difficulty in accessing therapeutic use/properties of cannabis Horticultural variability: diff growing conditions and breeding leading to varied [cannabinoid] across diff strains Phytocannabinoid stability: phytocans. Are initially produced as less active acidic forms (THCA), rq processes like heating to activate them Multiple varieties/preparations: various plant strains, contain diff THC ratios, complicating uniform assessment of pharmacological effects C/C cannabis and hemp practical uses and legal regs. in Canada Cannabis: Refers to strains with higher concentrations of THC, making it psychoactive and used primarily for medicinal or recreational purposes Hemp: A variety of Cannabis sativa with low THC content, used for industrial purposes like fabric, insulation, and food products Legal Regulation: Cannabis is regulated based on THC content for psychoactive effects, while hemp is more freely cultivated under strict THC concentration limits, hemp must not 140 mmHg (increase stiffness of large arterioles) Isolated diastolic hypertension: Increased DBP: >90 mmHg (narrowing of arterioles) Systolic-diastolic hypertension: Increased SBP and increased DBP Hypertension is a major risk factor for increased mortality, atherosclerosis (injury to blood vessels and level of clots), kidney damage, heart failure, stroke, cognitive decline Essential hypertension: 80% of hypertension cases, cause unknown Secondary hypertension: d/t a medical condition (renovascular hypertension aka narrowing of kidney arteries, aldosteronism aka increase aldosterone release = Na+ retention and increase BV, pheochromocytoma aka increase E and NA release d/t tumour in adrenal medulla, gestational hypertension) Age related thickening of arteries Common causes: 1. Hypertrophy: thickening of arterial SM layer d/t high BP 2. Disruption of endothelial cell layer (diabetes, smoking) causes build up of WBC, Ca2+, fats, SM in arteriole wall (atherosclerosis) 3. Atherosclerosis causes structural damage of arterial wall (Ca2+ accumulation and increased collagen content), can cause plaque buildup in coronary artery Non-Pharmacological Management of Hypertension Weight loss, diet, physical activity, decrease alcohol, decrease glucose, increase fruits/veggies/low fat food, stress management, no smoking, low sodium diet Antihypertensive Agents for reducing BP in essential hypertension 1. Diuretics (thiazides): increase renal Na+ excretion (lower BV = lower CO), dilate arterioles (lower TPR) 2. ANG converting enzyme inhibitor (captopril): decrease ANG II aka vasoconstrictor (lower TPR) and decrease ALD (lower BV = lower CO) 3. ANG receptor antagonist (losartan): block ANG II receptor and decrease ALD 4. B-adrenoceptor antagonist (propranolol, metoprolol, b-blockers): lower CO, lower TPR via blockage of b-adrenoceptors in the heart and lowers activities of SNS and renin-ANG-ALD system 5. A-adrenoceptor antagonist (prazosin, a-blockers): decreases vasoconstriction (lowers TPR) Thiazide Diuretics (hydrochlorothiazide) Kidney made up of units (nephrons), where via glomerular filtration, maintains fluid/electrolyte balance, and removes wastes products in blood In glomerulus, plasma (20%) is filtered via semi-permeable membrane into renal tubules where 99% of Na+ and water are reabsorbed into renal tubular cells then blood Reduction in renal Na+ reabsorption/increase in renal Na+ excretion reduces Na+ in plasma = lower BV Thiazide MOA: reduce renal Na+ reabsorption = lower BP/CO/BV, dilate arterioles = lower TPR/BP Side effects ○ Reflex tachycardia: increase HR d/t barorecep. reflex-mediated increase in sympathetic discharge in response to hypertension ○ Increased urination and thirst ○ Electrolyte imbalance: disturbance of the [essential minerals] in plasma when Na+ loss is excessive Treats hypertension and edema Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Antagonist ACE inhibitors (captopril) MOA: decrease synth of ANG II (decrease TPR), decrease synth of ALD (decrease BV and CO)  ANG II antagonist (losartan) MOA: blocks effects of ANG II, decrease ALD synth (decrease TPR and CO) Used to treat hypertension, heart failure (lower BV = lower cardiac size/work, lower TPR and BP) Side effects: taste disturbance for captopril A-receptor and B-receptor antagonist SNS mediates fight or flight thru release of E and NE E and NE cause fight/flight rxns by activating, a, b1, b2 adrenoreceptors ○ Via activation of a1 adrenoceptors, NE and E constrict arterioles (increase TPR) and veins (increase venous return and CO) = increase BP ○ Via activation of B1 adrenoceptors, NE and E directly increase HR/contractility and increase SNS and increase renin-ANG-ALD system ○ Via activation of B2 adrenoceptors, E causes bronchodilation B-receptor antagonists 1. Non-selective b-blocker: propranolol 2. Selective B1- blocker: metoprolol Propranolol and metoprolol MOA: reduce BP by blocking B1-adrenoceptors ○ Suppression of cardiac contractile function, activity of SNS, activity of renin-ANG-ALD system Propranolol side effects ○ Myocardial depression (decrease HR/contractility) ○ Reduced exercise tolerance (blocking b1) ○ Bronchoconstriction (blocking b2) Metoprolol side effects ○ Myocardial depression ○ Reduced exercise tolerance A-receptor antagonists (prazosin) Prazosin MOA: decrease BP by blocking a1-adrenoreceptors. ○ Block action of E and NE on a1 receps, causing dilation of arterioles (lower TPR = lower BP) ○ Inhibits NE and E induced constriction of veins (lower venous return and CO = lower BP) Prazosin side effects ○ Reflex tachycardia (increased HR d/t baroreceptor reflex mediated increase in sympathetic discharge in response to hypertension ○ Orthostatic hypertension (low bP when standing up) and dizziness Antibiotic Pharmacology Antibiotics: substances that inhibit the growth of or kill bacteria (ex: penicillin, tetracycline, amoxicillin)  Antibacterials: substances that specifically target bacteria, preventing their growth or killing them ○ Term sometimes interchangeable w antibiotics but, antibacterials can also be non-medicinal (soap, disinfectants) Antifungals: substances that inhibit the growth of or kill fungi ○ Target fungi-specific processes like cell membrane synthesis or DNA rep Antimicrobials: broad category of agents that inhibit the growth of or kill microorganisms (bacteria, fungi, parasites, viruses) How Antibiotics Revolutionized Medicine Routine scratches and injuries no longer mean amputation or death Increased survival prognosis post-injury Penicillin: First antibiotic discovered 1928, clinical use in 1941 Prontosil: First antibiotic clinically used in 1932 (clinical trials to treatment in >4 years) Key Differences Between Mammalian and Bacterial Cells Relevant in Selective Activity of Antibiotics Diff specific agents of function ○ Diff genes that control their processes ○ Diff DNA rep enzymes––– bacteria use diff DNA rep enzymes, antibiotics can target them w/o affecting mammalian cells ○ Other proteins/enzymes––– bacteria have other proteins/enzymes that antibiotics can target (enzymes for cell wall synth. which mammals don’t have) Diff macromolecular anabolism ○ Nucleotide production––– certain antibiotics may inhibit nucleotide synth in bacteria specifically ○ Protein production––– ribosome subunits are a key diff in the structure of ribosomes, antibiotics selectively target these preventing their synthesis Diff cell structure (cell wall)––– antibiotics like penicillin target bacterial cell wall Diff size––– bacterial cells are smaller than mammalian, easier for antibiotics to access bacterial specific structures (ribosomes, cell wall) and easier to accumulate effective [antibiotics] in bacterial cells Key Differences in Cell Envelopes of Gram+ and Gram- Bacteria Composition and structure of the cell envelope directly impact the bacteria’s susceptibility to antibiotics, influencing how easily antibiotics can penetrate or disrupt the bacteria Gram+ Bacteria Thick peptidoglycan layer ○ Composed of monosaccharide subunits— glycan, linked by peptide chains— peptido, thick b/c of carbohydrate polymer backbone ○ Lipoteichoic acid––– Embedded in thick peptidoglycan layer and extends into plasma membrane, plays a role in cell structure and regulation  No outer membrane ○ Antibiotics only need to penetrate the thick peptidoglycan layer to reach the plasma membrane and disrupt bacterial processes Gram- Bacteria Thin peptidoglycan layer––– Located between inner and outer membrane Outer membrane ○ Contains liposaccharides and porin proteins which form channels that regulate entry of molecules (including antibiotics) ○ Acts as an extra barrier, making gram-negative bacteria less permeable to many antibiotics Periplasmic space ○ Between outer and inner membrane ○ contains degenerative enzymes that can breakdown antibiotics, reducing effectiveness ○ Contains transport proteins, can transport molecules in/out of cell, impacts how effectively antibiotics can penetrate Spectrum of Activity Narrow spectrum: kill/inhibit a limited range of microorganisms Broad-spectrum: kill/inhibit wide range of microorganisms MOA: Inhibition of Cell Wall Synthesis Cell wall is part of cell envelope, more present in gram+ bacteria Drugs (penicillins) that act w this MOA are targeting the assembly and stabilization of the cell wall ○ Interferes w final cross linking assembly step (peptide and glycan chain binding) Penicillin binding proteins catalyze this step Inhibit penicillin binding proteins ○ Disrupts dynamic equilibrium of cell wall growth Renders cell vulnerable to osmotic pressures, can cause cell to swell/burst leading to bacterial cell death Beta Lactam Antibiotics Penicillin, amoxicillin, cephalosporin, etc… all have beta lactam ring ○ Ring interacts most effectively with penicillin binding proteins Penicillins Naturally derived, has beta lactam ring and R group (extra structure that differentiates the antibiotics) Primarily effective against Gram + bacteria  ○ Not all gram+ are susceptible b/c some strains have natural resistance––– bacteria is capable of demolishing, deactivating, metabolizing the penicillin before it can damage the bacterial cell Most common: bacteria has beta lactamase enzymes, cleaving the beta lactam ring and makes it so penicillin can’t bind to penicillin binding proteins Penicillin Pharmacokinetics ○ Absorption–– oral bioavailability varies by compounds, come have modifications to survive gastric pH ○ Distribution–– poor CNS permeation unless inflammation has compromised BBB ○ Metabolism/Excretion––– majority is excreted unmetabolized in urine, half-life of 30 mins to 1 hour Penicillin Adverse Effects ○ Hypersensitivity Only 5% of pop have allergic rxn to penicilloic acid (breakdown of penicillin by product that triggers rxn) Rash, edema, anaphylaxis ○ Cation toxicity Drugs given as Na/K salt, large doses may upset [ ] of crucial ions Hypernatremia (dehydration), hyperkalemia (heart palps, shortness of breath, nausea) Cephalosporins structural/functional relatives of penicillins, same MOA as penicillins Classified by generation ○ Main diff between cephalosporins and penicillins are general improvements in: Effectiveness against gram- Ability to cross BBB Resistance to beta-lactams ○ Cephalosporin comparisons First Gen (most gram+ coverage) Cefazolin, cephalexin Second Gen Cefaclor, cefotetan, cefoxitin, cefuroxime Third Gen Cefixime, cefotaxime, ceftazidime, ceftriaxone Fourth Gen (most gram- coverage) cefepime MOA: Inhibition of Protein Production Interfere w bacterial ribosome activity by exploiting differences in bacterial ribosomes ○ Interact w the 50s, 30s subunits (not present in mammalian cells) Tetracyclines and aminoglycosides use this MOA Tetracyclines MOA: All inhibit protein production Ex: tetracycline, chlortetracycline, oxytetracycline, doxycycline, metacycline Block tRNA access ○ Prevents mRNA translation and results in peptide elongation ○ Blocks new nucleotides needed for the protein production from tRNA Broad-spectrum antibiotics ○ Many gram+ and gram- rings ○ Passive diffusion and active transport pathways Tetracycline: Pharmacokinetics Absorption Can be prevented by divalent cation chelation (process where a molecule, typically a chelating agent, forms multiple bonds with a divalent cation, which is a positively charged ion with a charge of +2; ex: Ca2+, Mg2+, Fe2+) ○ Avoid certain foods (ex: dairy) and medications immediately before/after Distribution Some CNS distribution - up to 10-25% of plasma concentrations Metabolism Short, medium, and long acting derivatives Half lives of 6-36 hours Tetracyclines: Adverse Effects Gastric discomfort ○ Significance factor in non-compliance, reduced efficacy if self-medicate symptoms ○ Alkaline pH/divalent cations affect absorption Effects on calcified tissue ○ Deposit in bone/teeth ○ Avoid use in pregnancy, children under 8 Permanent discoloration of teeth Temporary growth stunting Aminoglycoside Antibiotics Family members include streptomycin, neomycin, gentamicin Similar mechanism to tetracyclines Most effective against aerobic, Gram(-) bacteria ○ Oxygen-dependent transport pumps required to cross inner membrane ○ Trouble with thick peptidoglycan layer in Gram(+) bacteria Side effects (necessitate limiting long-term use): ○ Ototoxicity (accumulation in ear hearing loss, vestibular issues) ○ Nephrotoxicity (reversible irreversible) Fluoroquinolones MOA: inhibition of DNA rep Enter bacteria passively through membrane porins Inhibit bacterial replication by inhibiting two crucial enzymes ○ DNA gyrase ○ Topoisomerase IV 4 generations, generally progression towards agents with: ○ Greater systemic distribution ○ Increased effectiveness against anaerobic and Gram+ bacteria Adverse Effects: ○ Generally well tolerated, GI effects (nausea, diarrhea) arthropathy (reversible erosion of articular cartilage, avoid in preg women and children under 8) MOA: Alter nucleotide synthesis Mammal cells can’t synthesize folate (folic acid which is essential for nucleotide production), we must take in through our diet Bacterial cells must synthesize folate ○ Sulfonamide and Trimethoprim Antibiotics MOA: interferes with the synthesis of tetrahydrofolic acid from PABA Can inhibit some strains of gram +/- Can cross BBB Generally admin tgt cotrimoxazole to produce synergistic/complete inhibition of pathway Sulfonamide adverse effects ○ Acetylated metabolite can precipitate in neutral of acid pH Crystalluria, hematuria, obstruction Trimethoprim adverse effects ○ Exacerbate folic acid deficiency Factors to consider when choosing an antibiotic 1. Bacterial strain and susceptibility Identification of the bacterial species causing the infection is critical. Some antibiotics target Gram-positive bacteria, others Gram-negative, or specific strains (e.g., Streptococcus or Rickettsiae). Culturing the pathogen helps determine: ○ Whether the strain is resistant to a specific antibiotic. ○ The minimum inhibitory concentration (MIC) required to inhibit the bacterial growth 2. Site of infection The ability of an antibiotic to penetrate the infection site is crucial. For instance, drugs that cross the blood-brain barrier are necessary for central nervous system infections. 3. Patient factors Renal/Hepatic Function: ○ Impaired metabolism or excretion can affect drug clearance, potentially leading to toxicity. Age: ○ Pediatrics: Some antibiotics, like tetracyclines, are contraindicated in children due to adverse effects on bone and teeth. ○ Elderly: Altered metabolism and comorbidities require tailored dosages. Pregnancy and Lactation: ○ Risk of teratogenicity or transfer to the fetus/infant. Allergies: ○ Hypersensitivity to antibiotics like penicillins must be avoided. 4. Severity and Progression of Infection: Broad-spectrum antibiotics may be used initially in life-threatening situations to "buy time" until culture results confirm a more targeted option. 5. Cost and Accessibility Economic factors and availability in a given region may influence choice Advantages of Culturing in Antibiotic Selection 1. Identification of the Pathogen: ○ Allows precise identification of the bacterial species causing the infection. ○ Distinguishes bacterial infections from viral or fungal ones, which may require different treatments. 2. Resistance Testing: ○ Cultures can confirm if the pathogen is resistant to certain antibiotics, avoiding ineffective treatments. 3. Determination of MIC: ○ Cultures enable determination of the lowest concentration of an antibiotic needed to inhibit bacterial growth, guiding appropriate dosing. 4. Customization of Treatment: ○ Culturing ensures a more effective and targeted therapy, reducing the risk of broad-spectrum antibiotic overuse, which contributes to antimicrobial resistance. Concentration-Dependent vs. Time-Dependent Killing Feature Concentration-Dependent Time-Dependent Killing Killing Key Effectiveness depends on the Effectiveness depends on how Characteristic peak drug concentration (Cmax) long the drug concentration relative to MIC. remains above MIC (t > MIC). Pharmacodynami - Higher Cmax improves - Killing is independent of Cmax, cs bactericidal activity. provided concentration exceeds - Exhibits prolonged MIC. post-antibiotic effect (PAE). - Requires frequent dosing to maintain t > MIC. Examples - Aminoglycosides - β-lactams - Fluoroquinolones - Vancomycin Dosing Strategy - Typically, once-daily - Frequent dosing or continuous high-dose administration. infusion to maintain consistent levels. Advantages - Prolonged effects reduce the - Effective even at lower need for frequent concentrations when exposure administration. time is adequate. - Useful for severe infections. - Often safer for patients with renal/hepatic impairment.  Disadvantages - Risk of toxicity at high peak - Requires strict adherence to concentrations. dosing schedule to maintain efficacy. By carefully considering bacterial and patient factors, leveraging culture results, and understanding the pharmacodynamics of antibiotics, clinicians can optimize infection management while minimizing resistance risks and adverse effects. Describe the key differences in mammalian and fungal cell structure Both are eukaryotes Fungal cell membrane contains ergosterol, rather than cholesterol Fungal cell wall composed of chitin and B-glucan (mammals don’t have cell wall) MOA of antifungals Disruption of cell membrane through interference with ergosterol and its system and destabilization of cell membrane (both mechanisms are fungicidal) Two major classes: polyenes and azoles MOA of Polyenes vs. Azoles 1. Polyenes Bind to ergosterol, forming pores in the fungal membrane, leading to ion leakage and cell death. Examples: Nystatin (topical) and amphotericin B (systemic). Topical Use: Nystatin is limited to topical applications due to systemic toxicity. 2. Azoles Inhibit ergosterol synthesis by targeting 14-α-demethylase, destabilizing the fungal membrane. Examples: Ketoconazole (topical/systemic), fluconazole (systemic). Systemic Use: Fluconazole is effective due to high bioavailability and fewer side effects compared to imidazoles. Nystatin and Fluconazole Nystatin Nystatin is a polyene antifungal MOA: integrates into fungal membranes, forming pores by binding to ergosterol, leading to leakage of intracellular components and cell death Use: Topical treatment of Candida infections (e.g., oral thrush, skin, vaginal infections) due to systemic toxicity. Fluconazole Triazole antifungal (a subclass of azoles). MOA: Inhibits 14-α-demethylase (a CYP450 enzyme), reducing ergosterol synthesis and  disrupting membrane integrity. Use: Treats systemic and localized fungal infections (e.g., cryptococcosis, athlete’s foot). Antibiotic resistance Antibiotic resistance occurs when bacteria are no longer inhibited or killed by an antibiotic at the maximum tolerable dose for a host MRSA, and explain the differences in bacterial physiology that make it a more dangerous strain to treat MRSA––– Methicillin-Resistant Staphylococcus Aureus ○ Physiology: MRSA resists β-lactam antibiotics (penicillins, cephalosporins) by expressing altered penicillin-binding proteins. ○ Danger: Though not more virulent, MRSA is harder to treat, especially in hospitals where immunocompromised patients are at higher risk​ Healthcare-acquired and community-acquired as it pertains to bacterial infection, and how the source can influence the likelihood of experiencing multidrug-resistant strains Healthcare-acquired infections (HAIs): occur in medical settings, higher prevalence of multidrug-resistant strains d/t extensive antibiotic use Community-acquired infections (CAIs): acquired outside medical facilities, previously limited to non-resistant strains but now increasingly include resistant bacteria Mechanisms of Acquired Resistance 1. Mutation––– alters target sites, decreasing drug affinity (ex: fluoroquinolones resist altered topoisomerase) 2. Gene-transfer––– plasmid exchange of resistance genes (ex: β-lactamase genes) Mechanisms of Bacterial Resistance 1. Efflux Pumps: Bacteria expel antibiotics (e.g., tetracyclines). 2. Altered Permeability: Reduced porin proteins prevent drug entry (e.g., E. coli and β-lactams). 3. Enzymatic Inactivation: Production of β-lactamases to degrade antibiotics​ Survival of the Fittest and Suboptimal Antibiotic Use Suboptimal dosing allows partially resistant bacteria to survive and reproduce, increasing resistant populations Rational Antibiotic Use 1. Principles Use antibiotics only for bacterial infections Avoid underdosing or premature cessation of therapy Minimize prophylactic use 2. Consequences of violation  Accelerated resistance development Diminished efficacy of future therapies Economic Challenges in Antibiotic Development Low profitability discourages pharmaceutical investments Solutions: ○ Incentives for research and development ○ Focus on alternative therapies like bacteriophages and endolysins Describe the mechanisms of action of teixobactin and endolysins as possible new therapeutic drug classes Teixobactin Binds lipid precursors in Gram-positive cell walls, inhibiting peptidoglycan and teichoic acid synthesis. No observed resistance so far Endolysins Bacteriophage-derived enzymes that degrade bacterial cell walls, targeting specific pathogens. Reduced likelihood of resistance due to precise mechanisms Anti-Cancer Pharmacology Define the following terms: Cancer, Neoplasm/tumor, Benign Tumor, Malignant Tumor Cancer: Uncontrolled proliferation of cells capable of spreading throughout the body, forming abnormal masses called neoplasms (tumors) Neoplasm/Tumor: An abnormal mass of cells. It can be benign or malignant ○ Benign Tumor: A non-cancerous tumor that remains in a confined area and can usually be treated with surgery ○ Malignant Tumor: A cancerous tumor capable of invading nearby tissue and spreading to distant tissues through the bloodstream or lymphatic system (metastasis) Hallmarks of Cancer" framework 6 Hallmarks of Cancer framework helps understand tumor pathogenesis— how tumors grow, divide, spread Grow: ○ Self-sufficiency to growth signals ○ insensitivity to growth signals Divide: ○ evade apoptosis ○ sustained angiogenesis Spread: ○ limitless replicative potential  ○ tissue invasion and metastasis 3 major broad-scope therapeutic approaches to cancer treatment, and adjuvant therapy 1. Surgery: Most effective before metastasis. 2. Radiation: X-rays or High-energy radiation used to kill cancer cells, often an adjuvant therapy. 3. Pharmacological Therapy: Includes cytotoxic agents, hormonal therapy, and molecular targeting therapy. Adjuvant Therapy: treatments like radiation or pharmacological agents used in combination with surgery to destroy remaining cancer cells after the primary tumor has been removed Major side effects that may occur with anti-cancer agents Side effects commonly arise in rapidly dividing tissues gastrointestinal upset (nausea and vomiting) — lethargy/weight loss bone marrow suppression (anemia— fatigue/weakness), (neutropenia— increased risk of infections), (thrombocytopenia— increase risk of bleeding/bruising) hair loss Infertility Specific drugs can have more targeted side effects such as neurotoxicity with vincristine Describe the therapeutic mechanism of action, and identify/recognize the bolded representative drug for each of the following therapeutic anticancer classes: Cytotoxic agents MOA: Impact one key area of cell division by impairing a particular process necessary for that step Cell cycle checkpoint fails and division is halted Examples of cytotoxic agents: Alkylating agents, antimetabolites, antimitotic agents Major issue: regulated cell division is a normal part of healthy physiology Have narrow therapeutic indices, significant side effects, there is no bacterial/mammalian cell divide to leverage Cytotoxic Agent: Alkylating agents MOA: forming covalent bonds with nucleophilic macromolecules in the cell like DNA Have two active sites allowing for DNA cross-linking and breakage during replication Depress bone marrow function and cause hair loss, with infertility common with prolonged use Example: Cyclophosphamide (requires activation by CYP450 enzymes to form nucleophilic structures) Neutral pro-drug, allowing for oral admin Permanently cross links guanine nucleotides within or across strands Therefore, inability to replicate DNA leads to programmed cell death At lower doses, can be used as an immunosuppressant in rheumatoid arthritis or Crohn’s disease Teratogenic potential based on mechanism; avoid in pregnancy Cytotoxic Agent: Anti-miotics— Microtubule-influencing agents Originated from plants as alkaloids MOA: Disrupt the assembly of microtubules, crucial for cell division ○ Microtubules play a role in cell-structure, motility, and intracellular transport ○ Microtubules play key role in chromosome separation during mitosis Disruption of this can cause cell division to arrest in Metaphase Blockages in cell division lead to apoptosis Disruptions in microtubule assembly/disassembly have similar outcomes for cell viability Example: Vincristine (prevents microtubule polymerization, halting mitosis) ○ One of the earliest leukemia treatments ○ Binds to one of two key microtubule elements (β tubulin, dimerized with α tubulin), preventing polymerization (prevents microtubules from forming) ○ May also destabilize already assembled microtubules ○ Side effects: high rate or neurotoxicity Hormonal treatment Since cancers have growth regulated through endogenous hormones (ex: hormone receptor-positive breast cancer), the aim of hormone treatment is to reduce hormone signaling cascade ○ Inhibits/reduce activation of receptor ○ inhibit/reduce hormone production Only useful in hormone-responsive cancers (ex: presence of hormone receptors on tumor tissue) Ex: Tamoxifen ○ Selective Estrogen Receptor Modulator (SERM) effective in estrogen-receptor-positive breast cancer (anti-estrogenic in breast tissue) Acting as an antagonist in breast tissue Partial estrogenic activity in non-breast cancer Acting as partial agonist Complex metabolism, involving many active metabolites Leads to variability in side effects Side effects related to agonist effects elsewhere in the body (when agonist stimulates more than what is regular for day to day) Menstrual irregularities, thromboembolic events, increase risk of endometrial cancer (2-3x risk, time-dependent) Molecule Targeting Agents Refers to chemotherapeutics selective for specialized receptors modulating key elements of cell growth  Two major families of compounds: protein kinase inhibitors, monoclonal antibodies Molecule Targeting Agents: Protein Kinase Inhibitors Theory of treatment: ○ Growth factors often make use of tyrosine kinase receptor for their signal transduction— in cancerous cells, regulation of receptor/transduction activity is often impaired The phosphorylation cascade in pathogenesis of any cancer is very important ○ Common kinases may frequently appear early in cascades of multiple cancers ○ Downstream kinases are often more specific to a tissue or type of cancer Targeting these increase chance of selective effects/minimized side effects inhibit key enzymes involved in cancer growth pathways Example: Imatinib (targets kinases in chronic myeloid leukemia— CML and gastrointestinal stromal tumors) ○ Safe for oral admin ○ Half life of 18 hours but key metabolite is also biologically active Biologics (monoclonal antibodies) Use monoclonal antibodies to either stimulate the immune system or block tumor growth Acting to stimulate immune response against cancerous cells or inhibit receptor activation of cancerous cells, preventing the proliferation and promoting apoptosis Very selective for targeting specific macromolecules Most of these drugs end in ‘mab’ Example: Bevacizumab (targets VEGF to prevent angiogenesis) ○ Vascular Endothelial Growth Factor ○ VGEF is involved in angiogenesis, creating of new blood vessels Key importance in nourishing a growing tumor ○ Not suitable for oral admin IV infusion ○ Often in combo with other drugs ○ Approved in 2004 for colorectal cancers but further approvals have expanded use Mechanisms of Cancer Drug Resistance Resistance: lower than expected response to chemotherapeutic treatment ○ Primary resistance: immediately upon initiation of therapy ○ Acquired resistance: during the prescribed time course of therapy Pharmacokinetic Mechanisms: Altered drug accumulation ○ Reduced uptake of drug into cells ○ Increased drug expulsion by transport proteins Changes in rate of drug inactivation Pharmacodynamic Properties Cancer cells developing alternative pathways ○ Common with metabolites Improved proficiency in DNA repair ○ Common with alkylating agents Alterations in target molecules expression/structure ○ Ex: an enzyme mutation causing reduced affinity Combination Therapy Can be super helpful with heterogeneous tumors, more well rounded attack against cancer cells with degrees of resistance— tumors that are made up of a variety of cell types, mutations, and characteristics May allow for a lower dose of each individual agent— minimize the likelihood of severity of concentration dependent toxicities Mechanism of Action in Relation to Hallmarks of Cancer: Each representative drug targets one or more hallmarks of cancer: Cyclophosphamide affects the ability of cells to replicate DNA. Methotrexate inhibits cell proliferation by blocking nucleotide synthesis. Vincristine stops cell division by interfering with microtubule function Reproductive Pharmacology Three major sex steroids produced by the body Estrogen Progesterone Androgens Major Elements of the Menstrual Cycle Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate follicle growth ○ As follicle grows, it releases estrogen that first inhibits LH/FSH via negative feedback and later stimulate it via positive feedback LH surge stimulates ovulation at ~Day 14 of menstrual cycle After ovulation, the follicle turns into corpus luteum ○ Corpus Luteum secretes estrogen/progesterone that promotes endometrial growth and suppresses LH/FSH levels through negative feedback After the corpus luteum degenerates, the loss in progesterone production makes the endometrium unsustainable and leads to menstruation Negative Feedback and its Role in Hormonal Contraception Negative feedback refers to the process where high levels of a hormone inhibit the production of upstream hormones ○ Ex: estrogen and progesterone inhibiting FSH and LH ○ This mechanism underlies hormonal contraception by preventing ovulation Two Components of Combined Hormonal/Oral Contraception (COC) and their MOA Components: synthetic estrogen (commonly ethinyl estradiol) and synthetic progesterone (levonorgestrel or norethindrone) MOA: inhibition of FSH and LH release through negative feedback, which prevents ovulation and reduced endogenous hormone secretion Comparison of Standard and Extended Cycle COC Formulation Standard Prescription ○ 21 combination hormone tablets followed by 7 placebo tablets, allowing for a withdrawal bleeding period ○ Two variations Monophasic formulations Biphasic/triphasic formulations Extended-cycle ○ Ex: Seasonale 84 combination hormone tablets and 7 placebo, reducing the frequency of withdrawal bleeding Ex: lybrel/amethyst ○ Only combination hormone tablets, no placebo Defining features of Monophasic, Biphasic, and Triphasic COC Formations Monophasic: identical doses of estrogen and progestin throughout the cycle Biphasic: two different doses of estrogen and progestin combinations during the cycle Triphasic: three different dose combinations, mimicking natural hormone fluctuations Key Features and Mechanism of Action of Progestin-Only Contraceptives (POC) Aka the mini pill Lower doses than in COC ○ Reduced probability of negative feedback on pituitary gland Can be sources of potential anxiety that limit patient acceptance ○ Daily admin, no placebo period ○ Requirement of more consistent dosing (take at same time everyday) typically a lower dose of progestin w/o estrogen, useful for individuals where estrogen is contraindicated MOA: decreasing sperm motility through thickening the uterine mucus lining, also may suppress ovulation Comparison of POCs with COCs Indications: POCs are often used when estrogen is contraindicated, such as estrogen-responsive cancers Key features of dosing: POCs require consistent daily admin, while COCs have placebo intervals Advantages/disadvantages: POCs carry fewer risks associated w estrogen (ex: thromboembolism) but require stricter adherence to dosing schedules Key Features of Long Term Injectable and Implantable Contraceptives and Their Mechanisms Injectable Treatments  ex: Depo-Provera (medroxyprogesterone acetate) ○ Intramuscularly or subcutaneously administered every three months ○ inhibits ovulation and thickens cervical mucus Implantable devices ex: Intrauterine Devices (IUD) Progestin-releasing IUD provides 3-5 years of contraception, which thickens the cervical mucus and may prevent ovulation Copper IUDs provide 10 years of contraception Common Side Effects of Hormonal Contraception and Strategies to Address Them: Mild/moderate Adverse Effects Menstrual irregularities ○ Breakthrough (mid-cycle) bleeding ○ Lack of withdrawal bleeding Weight Gain Acne/Hirsutism ○ Some progestins are more androgenic than others Ex: more/less capable of stimulating testosterone receptor Many effects will respond to change in pill formulation (different synthetic hormone and/or change in dose Severe Adverse Effects Depression Thromboembolic disease ○ 3-fold increase (1 to 3 events per 1000 women) Cardiovascular event/stroke ○ Increased risk over age 35 Hormonal Contraception and Cancer Risk Greater concern for cancer risk with COC compared to progestin-only contraceptives May increase the risk of some cancers like cervical and breast cancer but decrease the long-term risk of other cancers like ovarian cancer and womb cancer Emergency Contraception Options Available in Canada and their Mechanisms High-dose progestins ○ ex: Plan B ○ Preventative contraception doses ○ Inhibits ovulation Antiprogestins ○ Ulipristal acetate, Mifepristone Mifepristone (Approved in Canada as Mifegmiso, a combo treatment with misoprostol (PGE1, analogue) Ulipristal is a partial agonist, mifepristone is a partial antagonist ○ (ex: Ella) Prevents fertilization by delaying ovulation as primary mechanism Copper IUD ○ induces a toxic environment for sperm and ova, sets a local inflammatory response ○ Most effective method of emergency contraception Challenges in Achieving Male Hormonal Contraception 2-3 months to achieve severe oligozoospermia (less than a million sperm in ejaculate) ○ Synthetic testosterone derivative with pregestational and androgenic activities 30/40 men over 28 days had reduced LH/LSH levels Side effects; fatigue, headache, decreased libido, mild ED, no change in depression scores Male hormonal contraception is difficult b/c testosterone derivatives need to drastically reduce sperm counts and do so without causing unacceptable side effects Underlying Physiology of Male Erection Basal sympathetic tone is reduced and increased PNA activity dilates cavernosal artery smooth muscle ○ Cavernosal artery has a complex testosterone role and is nitric oxide/prostaglandin-mediates Increased blood flow increases volume of corporal spaces Two Major Drug Classes for ED Treatment  Phosphodiesterase-5 (PDE-5) Inhibitors (ex: sildenafil, tadalafil): enhance the effects of nitric oxide, increasing blood flow to the penis Alprostadil (PGE1 analogue): directly stimulates an erection through local vasodilation Psychiatric Drugs Describe the mechanisms by which mental activity is coordinated within the brain, both within and between neurons Brain Coordination of mental abilities, consists of over 100 billion neurons Neuron ○ Nerve cell ○ Within cell: electrical transmission ○ Between cells: chemical transmission ○ Each neuron can receive input from many other neurons or send input Define neurotransmission, and explain basic elements involved in the process. Neurotransmission: a complex process involving neurotransmitter synthesis, storage and release, receptor activation, and neurotransmitter inactivation occurs by means of specific neurotransmitters at the synapse ○ NT: chemical that is released from the presynaptic neuron in response to an electrical signal ○ Synapse: junction between two neurons Define psychiatric disorder in general terms, and identify some of the contributing causes to such conditions Psychiatric disorders: a group of medical conditions characterized by alterations in thinking, mood, and/or behavior Associated with significant distress and impaired functioning over an extended period of time Have major economic impact ○ About 15.8 billion in 2015 in public and private mental health expenditure ○ Lost productivity (self and society) Causes  ○ Genetics, neurodevelopmental defects, medical conditions (infections, stroke), psychosocial experiences (emotional, physical, sexual abuse), stress, drugs (substance abuse) Psychiatric disorders - negative impact on quality of life ○ Mood disorders: Changes in emotional state (Depression, BPD) ○ Psychotic disorders: changes in thoughts and perception (schizophrenia) ○ Anxiety disorders: excessive, persistent worry/fear Describe the general properties of psychiatric drugs Used for treatment of psychiatric disorders Act in the CNS (brain), cross the BB Influence neurotransmission by modulating NT action Cause changes in perception, mood, cognition, behavior Do not "cure"––– only decrease or relieve symptoms Wide spectrum of therapeutic activity Usually slow onset of therapeutic effects––– may take weeks to improve symptoms Often many side effects Identify and explain the pharmacokinetic elements common to most psychiatric drugs Often administered orally (very lipid soluble) Most are metabolized in liver Generally eliminated from the body by renal excretion (metabolites are lipid soluble) Basic features and symptoms of depression Depression: Characterized by feelings of severe despair over an extended period of time Some ppl experience only a single episode in there lifetime, but most people experience multiple episodes Effects 8% of the population Nearly twice as prevalent in women Average age of onset is 30 years old Symptoms ○ One required from this list: depressed mood, apathy/loss of interest ○ 4 required from this list: weight/appetite changes, sleep disturbances, fatigue, guilt, executive dysfunction, suicidal ideation Drugs to Treat Depression: MOA, side effects/complications, C/C w other drug classes in terms of MOA, effectiveness, preference Antidepressants: indicated for the treatment of depression and anxiety disorders Affect serotonin and/or norepinephrine neurotransmission Theory of treatment: depression is associated with low levels of serotonin and norepinephrine in the brain Monoamine Oxidase Inhibitors (MAOIs): inhibit the enzyme monoamine oxidase which breaks down monoamines (serotonin and norepinephrine) Increase [NT] in the nerve terminal, available for neurotransmission Must avoid foods and beverages that include tyramine (cheese, red wine) ○ Avoid: dried/aged/smoked/fermented fish and poultry, broad bean pods, aged cheeses, tap/unpasteurized beers, marmite, sauerkraut  ○ Risk of hypertensive crisis d/t excessively high levels of norepinephrine Last-line treatment for depression Tricyclic Antidepressants (TCAs): prevent serotonin and norepinephrine reuptake by inhibiting the serotonin transporter (SERT) and the norepinephrine transporter (NET) Increase [NT] in synaptic cleft Not very selective (high affinity for other additional receptors) Many side effects ○ Anticholinergic effects ○ Orthostatic hypotension ○ Sedation, weight gain ○ Cardiac arrhythmia Ex: imipramine, clomipramine, doxepin, amitriptyline, nortriptyline Selective Serotonin Reuptake Inhibitors (SSRIs): prevent serotonin reuptake by selectively inhibiting SERT Increase [serotonin] in synaptic cleft Less side effects than TCAs and MAOIs, therefore safer and better tolerated Side effects: nausea, headache, drowsiness, sexual dysfunction First-line treatment for depression, some approved use in children Ex: Prozac, Paxil, Zoloft Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Prevent serotonin and norepinephrine reuptake by selective inhibiting SERT and NET Increase [NT] in synaptic cleft Side effects similar to SSRIs (nausea, headache, drowsiness, sexual dysfunction) Basic features and symptoms of BDP Bipolar Disorder: characterized by drastic mood changes–– alternating between extreme highs (mania) and extreme lows (depression) Affects 1% of the population Average age of onset is 25 years old Symptoms of BPD ○ Manic phase High energy, higher self-esteem, racing thoughts, very quick talking, impulsive behavior, irritability, reduced need for sleep ○ Depressed phased Lack of concentration, low self esteem, suicidal thoughts, helplessness, loss of interest, low energy levels Drugs to Treat BPD: MOA, side effects/complications, C/C w other drug classes in terms of MOA, effectiveness, preference Mood Stabilizers Indicated for the treatment of bipolar disorder Mechanism of action not clearly understood More effective in treating mania than depression, therefore often used in combo with antidepressants ○ Antidepressant monotherapy should be avoided in patients with bipolar disorder Lithium Small monovalent cation (+1 charge)  Relatively slow onset of action (1-3 weeks) Mechanism of action unclear ○ May alter signal transduction pathways ○ Possibly influence NTs and receptors Not metabolized, excreted through kidneys Very low therapeutic index ○ Ineffective at blood levels 1.5 mmol/L ○ Must monitor blood levels during treatment Over 80% of patients experience side effects ○ Tremor, weight gain, polyuria (increased urine), polydipsia (increased thirst), hypothyroidism, GI symptoms (vomiting, diarrhea) Effective treatment for reducing the risk of suicide in people with mood disorders Anticonvulsants Only a few anticonvulsants are approved for the treatment of BPD Specific mechanism unknown ○ Possibly act by reducing neuronal excitability ○ Ex: carbamazepine and valproate Basic features and symptoms of Schizophrenia Schizophrenia: characterized by deficits in thought processes, perceptions, and emotional responsiveness Affects 1% of population Typical onset in early adulthood (late teens to early 30s) Symptoms classified as positive or negative ○ Positive (presence of problematic behaviors) Hallucinations (illusory perceptions), especially auditory Delusions (illusory beliefs), especially persecutory Disorganized thought and nonsensical speech Bizarre behaviors ○ Negative (absence of healthy behaviors) Flat affect (no emotion showing in the face) Reduced social interaction Anhedonia (no feeling of enjoyment) Avolition (less motivation, initiative, focus on task) Alogia (speaking less) Catatonia (moving less) Drugs to Treat BPD: MOA, side effects/complications, C/C w other drug classes in terms of MOA, effectiveness, preference Antipsychotics Indicated for the treatment of schizophrenia and the manic phase of BPD Affect dopamine and/or serotonin Theory of treatment: positive symptoms of schizophrenia are associated with excess dopamine activity in the brain MOA  ○ Positive symptoms of schizophrenia are associated with excessive dopamine (DA) activity in the mesolimbic system ○ All antipsychotic (AP) act by blocking dopamine D2 receptors to reduce dopamine activity Typical Antipsychotics Aka first generation antipsychotics Effective against positive symptoms Higher risk of extrapyramidal (motor) side effects ○ Abnormal, involuntary movements Ex: chlorpromazine (thorazine) and haloperidol (haldol) Atypical Antipsychotics Aka second generation antipsychotics Dopamine D2 and serotonin 5-HT2a receptor antagonist = block serotonin and to a lesser degree, dopamine activity Effective against positive and negative symptoms Higher risk of metabolic side effects ○ Weight gain and/or insulin resistance Ex: clozapine (clozaril) and quetiapine (seroquel) Basic Features and Symptoms of Anxiety Disorders Anxiety disorders: characterized by excessive, exaggerated, irrational fear and dread Multiple variations and subclassifications ○ Panic disorder, generalized anxiety disorder, various phobias Affects 12% of pop Frequently co-occurs with depression Symptoms of anxiety Drugs to Treat Anxiety Disorders: MOA, side effects/complications, C/C w other drug classes in terms of MOA, effectiveness, preference Anxiolytics Indicated for the treatment of anxiety disorders Some affect GABA neurotransmission ○ GABA (gamma-aminobutyric acid) is major inhibitory NT in the brain  ○ Theory of treatment: increased GABA NT, since anxiety is associated with low levels of GABA in the brain Benzodiazepines (BZDs) Those used as anxiolytics have medium or long duration of action (>6 hours) Fast onset of action (