Pharmacology Fundamentals

Fundamentals of Pharmacology

• Pharmacology is medicine's critical discipline focused on drug uses, effects, and actions.
• A drug is defined as a chemical altering body physiology for therapeutic purposes.
• Understanding pharmacology necessitates familiarity with cell biology, biochemistry, and pharmacodynamics.
• A drug is a chemical influencing bodily functions, including therapeutic agents, nutrients, food additives, and pollutants.
• Pharmacology incorporates cell biology, biochemistry, physiology, pathophysiology, and medicine.
• A broad scope facilitates understanding drug interactions with biological systems.
• Atropa Belladonna, a plant-sourced drug, is chemically synthesized for modern clinical use, showing the shift from natural to synthetic drug development.
• Saquinavir was developed through rational drug design based on target structures.

Drug Nomenclature and Classification

• Drugs usually have chemical, generic, and brand names.
• Generic names are vital for pharmacological discussions due to brand name variations.
• Diazepam (Valium®), a benzodiazepine, can be classified by its pharmacological effects, pharmacodynamics, and chemistry and therapeutics.
• Pharmacodynamics studies what drugs do to the body on a molecular, cellular, and tissue level.
• Pharmacokinetics studies what the body does to drugs: absorption, distribution, metabolism, and excretion (ADME).
• ADME informs bioavailability and duration of action, showing how effectively a drug reaches its target.
• Selectivity is a drug's ability to produce a specific effect, influenced by chemical properties, target receptors, administration, and patient differences.

Selectivity, Specificity, and Pharmacology's Role

• Specificity is a drug’s capacity to affect a specific function at its target site, e.g., Insulin on specific receptors versus gaseous anesthetics affecting all cell membranes.
• Risk-benefit analysis is essential during drug administration because very few drugs achieve total selectivity
• Pharmacological principles allow clinicians to choose appropriate therapies while balancing efficacy and safety.
• Drug complexities require a systematic treatment approach to optimize patient outcomes.
• Pharmacology studies drug classification and nomenclature in key concepts, including systematic, generic, and brand names, drug class, and clinical indication.
• Drug classification and nomenclature are vital for professionals in medicine and pharmaceuticals as it relates to drug identification, classification, and use.
• Systematic (IUPAC) name uses the International Union of Pure and Applied Chemistry nomenclature and provides a unique name based on structure.
• Generic names are universally used, official, and non-proprietary.
• Brand names are marketing names designated by Drug companies.
• A drug class is based on chemical structure and therapeutic effects.
• Clinical indication refers to the specific medical conditions a drug treats.
• Thorough drug classification knowledge improves safety and efficacy in pharmacotherapy, where misclassifications may cause medical errors.

Drug Examples and Conclusion

• Acetylsalicylic acid, or Aspirin, is used to treat pain and as an anti-inflammatory.
• Fluoxetine is an SSRI (selective serotonin reuptake inhibitor) used for treating depression.
• Carvedilol, a vasodilator, manages chronic health conditions.
• Grasping drug classification and nomenclature is vital in pharmacology, providing a framework for classifying drugs based on systematic, generic, and brand names, along with clinical indications.
• Mastery is indispensable for healthcare professionals to ensure safe practice and informed patient care.
• Comprehensive pharmacological knowledge improves drug safety and efficacy.
• Accurate drug classification enables correct pharmacotherapy.

Fundamentals of Pharmacology and Drug Therapy

• The four key therapy processes are pharmaceutical, pharmacokinetic, pharmacodynamic, and therapeutic.
• They affect the entirety of the drug effects from its formulation to its eventual therapeutic outcome.
• Propranolol, a hypertension medication, demonstrates these processes.
• The Pharmaceutical process addresses the drug's successful delivery to the patient after it is administered.
• Propranolol is available in tablets (10 mg), oral solutions (5 mg/5 ml), and injections (1 mg/1 ml).
• Bioavailability refers to the extent and rate at which an active ingredient is absorbed, and formulation and chemical properties significantly influence absorption.
• Pharmacokinetic concerns include a question of "Is the drug getting to its site of action?"
• Distribution involves extracellular fluids, with about 90% protein binding in the blood.
• There's extensive hepatic metabolism, in which about 4% is excreted unchanged in urine and 10% as metabolites.
• Binding to plasma proteins affects bioavailability, rate of elimination, duration of action, and may modify therapeutic outcomes.

Pharmacodynamics and Therapeutic Outcomes

• Pharmacodynamics raises the question of, "Is the drug producing the required pharmacological effect?"
• As an antagonist, Propranolol targets specific Beta 1 and Beta 2 adrenoceptors within the heart, kidneys, and central nervous system (CNS).
• Effects are linked to plasma concentration, dictating its selectivity/specificity in interacting with molecular targets.
• The therapeutic process key objective is "Is the pharmacological effect being translated into a therapeutic effect?"
• Propranolol effectively reduces heart rate and blood pressure, reducing the risk of cardiovascular events like stroke, heart attacks, and renal failure, although there are potential overdose risks.

Real-World Drug Action

• Propranolol has a well-documented track record as a hypertension treatment.
• The journey from formulation to therapy illustrates complexities and factors that influence successful outcomes.
• The drug's pharmacokinetics and pharmacodynamics offer insights not only into its workings, but also into how other medications can be evaluated.

Core Concepts in Drug Action

• Drug therapy illustrates the complex patient outcome mechanisms.
• Grasping formulation, distribution, effects, and efficacy enables informed treatment.
• Drug absorption, metabolism, and action connect to tangible health benefits or risks, affecting medication such as propranolol.

Drug Targets and Effects

• Drugs act on molecular, cellular, tissue, and systemic levels.
• The site of action is where the drug exerts its effects, operating at multiple levels, from cell to whole body.
• Non-specific drugs (e.g., gaseous anesthetics) act on all cell membranes.
• Highly specific drugs (e.g., insulin) target specific receptors.
• Classes of drug targets include receptors, ion channels, G-protein coupled receptors (GPCRs), enzymes, and transporters.
• An agonist binds to a receptor and triggers a biological response through direct action or transduction mechanisms.
• Direct action causes ion channel opening/closing or enzyme activation/inhibition.
• Transduction mechanisms activate intracellular signal pathways, influencing ion flow or DNA transcription.

Receptor Binding and Action

• An antagonist binds to a receptor without activating it, preventing natural mediators from binding.
• No cellular response results from an antagonist binding.
• Agonists activate receptors to trigger a response.
• Antagonists block receptors, preventing the normal function of endogenous molecules.
• Transduction mechanisms enable long-term effects via gene expression changes.
• Type 1: Ligand-Gated Ion Channels are fast-acting receptors that open when a ligand binds and allow ions to flow directly into the cell.

Receptor Examples

• Nicotinic Acetylcholine Receptor (nAChR) is activated by acetylcholine (Ach).
• GABA-A Receptor is activated by GABA, which allows Cl- entry (inhibitory effect).
• NMDA (Glutamate) Receptor controls Ca2+ entry, important in learning/memory.
• Type 2: G-Protein Coupled Receptors (Metabotropic Receptors) are slower-acting receptors that trigger a signaling cascade inside the cell mediated by G-proteins.

Comparison Between Ionotropic & Metabotropic Receptors

• Structure: One membrane-spanning subunit versus four-five subunits.
• G-protein coupling domain is on the inside (intracellular).
• Activated receptors send signals to second messengers like cAMP and IP3.
• Beta-Adrenergic Receptors respond to adrenaline for fight-or-flight.
• Dopamine Receptors (e.g. D1, D2) are vital in mood and movement.
• Muscarinic Acetylcholine Receptors (mAChR) are in the heart, smooth muscle, and brain.

Receptor Summary

• G-protein action is slower and affects many cellular processes.
• Type 1 receptors have fast action, whereas type 2 receptors have a slow action
• Type 1 receptors have direct ion flow, and type 2 receptors activate second messengers.
• nAChR, GABA-A, and NMDA are examples of lonotropic receptors, while B-Adrenergic, Dopamine, and mAChR are metabotropic receptors.
• Ion channels regulate ion flow for cell membrane potential and excitability
• They can be opened and closed, which allows drug control.
• Activated Nicotinic Acetylcholine Receptors trigger muscle contraction.
• d-Tubocurarine is an antagonist at nAChR and is a muscle relaxant used in surgery.

GPCRs and Cell Signaling

• G-Protein Coupled Receptors activate intracellular signaling pathways without ion pores.
• G-protein components include alpha, beta, and gamma subunits
• Beta-Adrenergic Receptors (B-AR) are found in the heart, lungs, and nervous system.
• Adrenaline increases heart rate/force.
• β-blockers, like Propranolol, lower heart rate.
• Receptors Linked to Cell Signaling include Enzyme-linked receptors (e.g., Insulin receptor), Nuclear receptors (e.g., Steroid receptors), and GPCRs (e.g., Adrenoceptors).
• Ion channels provide fast response, GPCRs provide medium response, and Nuclear receptors provide long-tern effects

Dose Response Notes

• A drug's reversibly binds to receptors.
• The binding process follows a dynamic equilibrium between free drug ([D]), free receptor ([R]), and drug-receptor complex ([DR]).
• KA = k-1 / k+1 = [D][R] / [DR]
• Lower value means better binding.
• Real world measurement of dose response relationships can be don with organ bath assays.
• Dose Repsonse Curve graph dose response and concentration.
• Full agonists activate a receptor and have an intrinsic efficacy of 1.
• Parital Agonists have an efficacy less than on and have fewer activated receptors

Key Values

• KA is dissociation, and binds to the receptor.
• EC50 is depends on multiple factors like receptor reserve.
• Some drugs need higher dose to achieve effects. -Dose-response curve measures functional response.
• Buprenorphine treats opioid addiction.

Humane Experimentation

• Home Office (HO) oversees regulations in the UK
• A project license justifies animal use.
• Legal animal testing has requirements.
• Reduce- animal numbers reduce suffering.
• In Vitro assays use small compounds.
• Skin tests use artifical skin modes. _ Testing has gone through evoluation
• A discussion of why animal testing.
• In silico apporaches- computer.

In Silico

• CAD helps discover new drugs.
• Discovery was inefficient
• APOLLO simulates.
• CAD helps design drugs.
• Gleevec is a breakthrough.
• Computer game is a bio tool!

Pharmacokinetics

• Body affects drugs.
• Absorption and metabolism are important.
• Unionised drugs cross.
• pH plays a factor
• A higher Vd means more extensive tissue distribution
• Low Vd = remains in the blood.
• Liver reduces bio.
• Catabolic metabolism affects the bod\
• Drugs may get filtered in the kidney.
• More water the better.
• More disease is bad
• Rate that body gets metabolized
• Kinetics- enzymes and stuff.

The Autonomic NS

• The main fxn of the brain and body is to talk with eachother and coordinate everything
• Visceral organs communicate in the involuntary functions
• Somatic nervous is direct
• 2 vs 1 neuron control.
• Cholinergic releases and affects what its sending
• Fight or flight and parasympathetic.
• Beta blockers and adrenline control.
• Autocomic does everything so its important.
• Acetylcholine transmits both and nore is just the one.