Week 1: Workshop
# Workshop Notes: FARM30003 - Therapeutics Introduction
Main Takeaway: This workshop introduces core pharmacological principles (pharmacodynamics, pharmacokinetics) using adrenaline as a case study, emphasizing critical thinking about drug action, receptor selectivity, dose-response relationships, and the benefits and risks of drug use in real-life clinical scenarios. Understanding how drugs interact with the body, its systems, and other medications is crucial for safe and effective therapeutic application.
## 1. Introduction to Workshop (FARM30003)
* Speaker: James Yogus (Coordinator for initial workshops).
* Purpose:
* Grow interest in current and potential therapeutics.
Provide insight into how drugs affect living things (pharmacology*).
* Expand scientific and medical vocabulary.
* Encourage thinking like a pharmacologist.
* Key Concepts Reinforced:
* Pharmacodynamics (PD): What drugs do to the body (targets, receptors, ion channels, enzymes, genes).
* Pharmacokinetics (PK): What the body does to drugs (absorption, distribution, metabolism, excretion - ADME).
* Informed conversations about drug properties and system effects.
Importance of dose-response curves*.
Always consider benefits and risks* of drugs.
* Learning Strategy (Ebbinghaus Forgetting Curve): Workshops revisit lecture content and prior knowledge to reinforce learning and aid retention.
* Learning Objectives (First two workshops): Apply pharmacodynamic and pharmacokinetic principles for safe and effective drug use, particularly in given scenarios.
## 2. How Drugs Work: Principles of Pharmacology (Adapted from Simon Maxwell)
* Normal (Healthy) State:
* Chemical Signalling: Cells communicate via chemical mediators.
* Neurotransmitters: Released from nerves (wired, cell-to-cell).
* Hormones: Circulate in bloodstream (broadcast widely).
* Local Mediators: Local actions.
* Molecular Targets: Chemical mediators interact with specific targets to contribute to normal function.
* Receptors
* Ion channels
* Carriers
* Enzymes
* Cellular Contact/Recognition: Cells can also have surface molecules (e.g., viral spike proteins) that mediate contact-dependent actions.
* Disease State:
* Identify pathological process.
* Determine which molecular targets are affected/can be targeted.
* Utilize drugs (agonists/antagonists) to restore abnormal function (increase or decrease activity).
* Treatment Goal: Restore molecular target function (directly or indirectly).
* Unwanted Actions: Drugs can interfere with other chemical systems (neurotransmitters, hormones), leading to side effects.
* Drug Action Hierarchy & Predictability:
* Molecular Level: Drug binding to target; most predictable.
* Cellular Level: Changes cell activity.
* Tissue Level: Changes activity of tissues containing those cells.
* Whole Body Level: Least predictable due to integrated, self-regulating systems and physiological reflexes (e.g., drug-induced hypotension can trigger reflex tachycardia).
* Context Matters for Drug Effects:
* Agonists: Elicit a response at the molecular level.
* Antagonists: Inhibit the action of an agonist; may do "nothing" on their own at the molecular level.
* PK influence: A drug effective in an in vitro organ bath might be ineffective in vivo if it doesn't reach its target (e.g., poor absorption, rapid metabolism).
* System Activation: Antagonists only show a measurable response in the body if the target system is already activated by an endogenous agonist.
## 3. Workshop Activity: Adrenaline (Epinephrine) Case Study
* Video Content: Use of adrenaline/epinephrine in emergency clinical situations.
* Focus Points for Video: Why, how, how much, how often, agonists/antagonists, selectivity, route of administration.
* Key Discussion Points:
* Another Name for Adrenaline: Epinephrine (commonly used in USA; EpiPen trade name derived from this).
* Adrenaline Receptors & Location: Adrenaline is a "promiscuous molecule," acting on multiple adrenergic receptors.
* Alpha 1 ($\alpha_1$) Receptors: Located on smooth muscle of blood vessels (vasoconstriction), gut, GI tract sphincters, eye pupil constrictor muscle.
* Beta 1 ($\beta_1$) Receptors: Located in the heart (increase heart rate and contractility), and kidneys (release renin).
* Beta 2 ($\beta_2$) Receptors: Located in airways (bronchodilation), and skeletal muscle blood vessels (vasodilation).
* Relative Selectivity of Adrenaline:
Tends to show beta effects* more prominently at lower, circulating doses (as a hormone).
* Has good affinity for all major adrenergic receptors.
* Available Doses & Use in Emergency Care:
* Formulations: Liquid ampules (1 mg/mL and 0.1 mg/mL); Auto-injectors (e.g., EpiPen, 0.3 mg/0.3 mL for adults).
* Route of Administration:
* Intravenous (IV): Allows for precise dose control, loading doses, and continuous infusion, bypassing absorption issues seen with other routes.
* Intramuscular (IM)/Subcutaneous (SC): Less predictable absorption.
* Emergency Uses:
* Anaphylaxis: Utilizes both $\alpha_1$ effects (vasoconstriction $\rightarrow$ reduces hypotension and edema) and $\beta_2$ effects (bronchodilation $\rightarrow$ eases breathing).
* Cardiac Arrest: Utilizes $\alpha_1$ effects (vasoconstriction $\rightarrow$ improves coronary perfusion) and $\beta_1$ effects (increases heart rate and contractility).
## 4. Workshop Activity: Other Endogenous Molecules & Selectivity
* Endogenous Molecules that Activate Adrenoceptors: Adrenaline, Noradrenaline, Dopamine.
* Noradrenaline (Norepinephrine):
Primarily acts as a neurotransmitter*, released locally by sympathetic nerves.
* Higher selectivity for $\alpha_1$ receptors (vasoconstriction) and $\beta_1$ receptors (cardiac effects).
* Rarely accesses $\beta_2$ receptors due to local release and rapid inactivation in the bloodstream.
* No significant respiratory or anaphylaxis applications in emergency care.
* Dopamine:
* Slightly better at $\beta_1$ receptors than $\alpha_1$.
* Used in emergency care for acute hypotension (shock) and certain bradycardias (slow heart rate).
* Its effects are mainly on cardiovascular function; no mention of respiratory effects.
## 5. Scenario Application: Case Studies
### 5.1 Scenario 1: EpiPen failure in obese, hypertensive patient with asthma and anaphylaxis
* Case: Obese, hypertensive patient with asthma and known anaphylaxis to peanuts uses EpiPen but remains hypotensive.
* Pharmacokinetic Explanation (Drug Getting to Target):
* Obesity & EpiPen Administration: EpiPen needs to be given intramuscularly. In an obese patient, excess adipose tissue may prevent the drug from reliably reaching the muscle, leading to poor absorption and ineffective drug delivery.
* Route Unreliability: IM/SC routes are less reliable than IV.
* Pharmacodynamic Explanations (Drug Action at Target):
* Drug-Drug Interaction: The patient is hypertensive, possibly on beta-blockers. Beta-blockers (antagonists) block adrenaline's action at $\beta_1$ and $\beta_2$ receptors, counteracting its beneficial effects in anaphylaxis (e.g., reducing cardiac support and bronchodilation). Non-selective beta-blockers were common in the 1980s.
* Receptor Desensitization: Chronic use of short-acting beta-agonists (SABAs) for asthma could lead to desensitization of $\beta_2$ receptors. This would reduce adrenaline's effectiveness in causing bronchodilation.
### 5.2 Scenario 2: Fatal cardiac arrest after IV adrenaline in patient with chest injury
* Case: A patient with severe chest trauma receives iodine contrast media, develops an anaphylactic reaction, and receives a large intravenous dose of adrenaline, leading to fatal cardiac arrest.
* Pharmacodynamic Explanation:
* Underlying Cardiac Damage: The prior severe chest trauma might have caused myocardial damage, increasing the heart's sensitivity to stimuli. Adrenaline, a potent agonist, particularly at high doses, can cause cardiac arrhythmias. In a compromised heart, this could push the patient into a fatal arrhythmia or cardiac arrest.
* Adrenaline Side Effects: Even life-saving adrenaline can cause side effects like cardiac arrhythmias if sensitivity is altered or dose is too high.
* Pharmacokinetic Explanation:
* Dose Error: In emergency situations, stress can lead to errors. Emergency care physicians have high (1 mg/mL) and low (0.1 mg/mL) adrenaline formulations. If the high dose was used undiluted via IV when a diluted dose was intended, it could result in a 10-fold overdose, leading to severe adverse effects.
## 6. Historical Context & Drug Evolution
* Early Concepts (1970s): Initial formulation of alpha/beta receptor concepts and selectivity.
* Receptor Localization: Understanding $\alpha_1, \beta_1, \beta_2$ receptor locations is fundamental. Later discoveries included $\alpha_2$ and $\beta_3$ subtypes, adding complexity.
* Selectivity & Utility: The selectivity of endogenous molecules and therapeutic drugs for these receptor subtypes determines their clinical utility.
* Drug Development:
* Isoprenaline: Early non-selective $\beta$-agonist, caused cardiac activation due to $\beta_1$ effects.
* Propranolol (James Black, Nobel Prize): Original non-selective $\beta$-antagonist, problematic for asthmatics due to $\beta_2$ blockade.
* Evolution: Led to the development of selective $\beta_2$ agonists (for asthma, avoiding cardiac side effects) and cardio-selective $\beta_1$ antagonists (for hypertension, safer for asthmatics).
* Modern Pharmacology (21st Century): Advanced understanding of genetic lineage and discrete functions of adrenergic receptor subtypes ($\alpha_1, \alpha_2, \beta_1, \beta_2, \beta_3$ and their further subtypes). This allows for highly selective drug design.
* Overall Principle: Drug choice (agonist vs. antagonist) depends on whether the pathological condition involves an increase or decrease in receptor activity.