This Vivacast wanders into the realms of Adrenoceptors, Local Anaesthetics + PKAs and gets all caught up in classifying anti-arrythmics.
We open up this episode a bit more, to show the reality of practicing for the exam, no one is perfect, if you get something wrong, or fumble it and spaff out disorganised madness – repeat the question there and then with your newly intended order!
What are the classes of anti-arrhythmic drugs?
Anti-arrhythmic drugs are classified into four main classes: I (sodium channel blockers), II (beta-blockers), III (potassium channel blockers), and IV (calcium channel blockers), each affecting cardiac action potentials differently.
Article Spring Board
Adrenoceptors
Morphology
Adrenoceptors are G-Protien Coupled Receptors with 7 transmembrane domains.
They rely on intracellular secondary messenger systems to achieve their effect.
One receptor activation can trigger ~100 intracellular secondary messengers – excellent signal amplification!
Adrenoceptor Subtypes
They have a number of sub units which are particular to each receptor lead to their approximate tissue action (think heart, vasculature, lungs etc)
- Gs (stimulatory) – More Intracellular calcium
- Gi (inhibitory) – Less Intracellular calcium
- Gq (‘weird’ to me – Q has no specific meaning here) (oft hyperpolarises cell)
The Gs and Gi Subtypes
Either up or down regulate the activity of Adenyl Cyclase (AC)
AC converts ATP to cyclic AMP cAMP then activates Protein Kinase A (PKA) PKA phosphorylates down stream proteins triggering the physiological effects
Gq acts upon Phospholipase C
Converting PIP2 (phosphatidiylinositol) to DAG (DiAcyl Glycerol) and IP3 (inositol triphosphate) IP3 release Ca2+ into cytoplasm DAG activates protein kinase C
Other GPCRs
- Muscarinic Ach Receptors = Gq
- Beta Adrenoceptors
- Gs Glucagon receptor
- Gs Alpha Adrenoceptor
- Gi Opioid Receptor
- Gi Angiotensin II type 1 receptors = Gq
- Vasopressin V1=Gq (vasoconstricing effects on vasculature V2=Gs V3=Gq
Beta 1 Heart predominant Beta 2 Lung predominant
Table of Organs and Adrenoceptor Effects
| ORGAN | RECEPTORS | EFFECT |
|---|---|---|
| HEART | ALPHA BETA 1 BETA 2 | Inotropic (when infused into L coronary) Inotropic Chronotropic Vasodilates Coronaries |
| LUNG | ALPHA BETA 1 BETA 2 | Increased PVR Vasodilating Bronchial SM relaxation + vasodilate |
| VESSELS | ALPHA 1 BETA 1 BETA 2 | Vasoconstricting Vasodilatory Vasodilatory |
| BRAIN | ALPHA | Pupillary dilation Analgaesic/hypnotic |
| BLADDER | ALPHA 1 ALPHA2 BETA 1 BETA 2/3 | Increased sphincter tone Negligible Negligible Relax SM of bladder |
| PROSTATE | ALPHA 1 | SM Contraction |
| PANCREAS | ALPHA 1 ALPHA2 BETA 1 BETA 2 | 1/2? decreased insulin Insulin secretion increase |
| UTERUS | ALPHA BETA | Smooth Muscle Contraction Smooth muscle relaxation |
| Platelets | Beta 1 | Platelet Aggregation |
| Adipocytes | Beta 3 | Lipolysis |
| Liver | Alpha or Beta | Gluconeogenesis |
| Splanchnic | Alpha Beta | Constricts Dilates |
Other agents that influence adrenoceptors
- Ephedrine – Direct Beta and Some Alpha + some norad release
- Metaraminol – Indirect Norad release mostly. at very high dose Direct Alpha
- Phenylnephrine Direct Alpha 1 Agonism
- Dobutamine – B1 receptor agonism + some Alpha/beta 2
- Dopamine – D1 receptors at low ish dose, Then Beta Then Alpha
Modulation / down regulation
When a receptor is activated its terminal intracellular end (which has a COOH (carboxyl)) is phosphorylated it is able to facilitate the binding of a protein ‘B-Arrestin’ if bound then this receptor complex can be removed from the cell membrane – fewer receptors = smaller response – hence the tachyphylaxis that can be sometimes seen to these agents.
Local Anaesthetic Agents
Classification
Ester – Cocaine, procaine, Amethocaine, Tetracaine(ametop), chloroprocaine — (psuedocholinesterase metabolism plasma)
Amide – Bupivicaine, levobupivicaine, ropvicaine, lidocaine, prilocaine, — (liver metabolism)
Mechanism of Local anaesthetic Agents
Sodium channel blockade, but only on internal side of sodium channel, and only tend to bind to the receptor in its open(activated) state.
PKA is critical to Local anaesthetics
Defines the amount of unionised drug in solution that can subsequently cross the plasma membrane – re-ionise and get into the sodium channel.
The number given, is the pH at which this drug would be a 50:50 ionised:unionised mix, when this drug is at a different pH this ratio shifts depending on acidity/basicity of the drug, See the PKA episode here.
PKA Table
| Drug | PKa | Un-Ionised Fraction | Other |
|---|---|---|---|
| Bupivicaine | 8.1 | 15% | Heavy / Levo / |
| Lidocaine | 7.8 | 25% | Adrenaline, Emla |
| Prilocaine | 7.7 | 33% | Emla – methaemoglobinaemia |
| Chloroprocaine | 8.7-9.1 | 5% | v good tissue penetrance tho |
| Ropivicaine | 8.1 | 15% |
Influencing this with other agents
Bicarbonate for onset manipulation as increasing the pH of the perineural environment will increase the unionised fraction
Adrenaline 1:200k, causes vasoconstriction maintaining block for longer, and improving surgical field conditions;
Vaughan Williams Anti Arrythmic Classification
| Class | Drug | Mechanism | Effect |
|---|---|---|---|
| 1a | Quinidine | Sodium Channel Blockade | Prolong AP |
| 1b | Lidocaine | Sodium Channel Blockade | Shorten AP |
| 1c | Flecanide | Sodium Channel Blockade | Nil AP |
| 2 | Metoprolol, biso/esmo/carvedil | Beta Blockade | -ve chrontrope/inotrope |
| 3 | Amioderone / sotalol | Potassium Channel Blockade | -ve chronotropy/inotropy |
| 4 | Verapamil/Diltiazem | Calcium Channel Blockade | -ve chronotrope Also vasodilate coronoaires hence treat angina… |
| 5?? | Adenosine/digoxin/magnesium | A catch all cop out of a class | bah! |
Nb amioderone messes with Na/K/Ca and beta receptors….
Sotalol is also a beta blocker
Other Episodes to check out:
Bibliography
Ref -Peck and hill Pg 26+
Ref – Handbook of experimental pharmacology pg93+
Ref – masterpass pharmacology and crit incidents pg 3
Ref – Ox Handbook for drugs used in anaesthesia and intensive, many
ref: https://www.bjaed.org/article/S2058-5349(19)30152-0/fulltext
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Transcript Adrenoreceptors, Local Anaesthetics & Antiarrhythmics
Introduction
00:00-00:31 Hello and welcome to Gas Gas Gas, the podcast that covers the FRCA primary exam. We’re going to fit into your day and give you as much of your life back as you could possibly imagine. Listen to us on your commute, in the gym, in the shower, or when ironing your scrubs. Expect facts, concepts, model answers and the odd tangent. Check out the show notes for all the detail, and remember to follow the show so that you never miss an episode.
Pharmacology Viva: Tom’s Session
00:31-00:39 This is Tom’s pharmacology viva covering adrenoreceptors, local anaesthetics, and the Vaughan Williams antiarrhythmic classification.
Adrenoreceptors: Structure and Function
00:39-03:04
Basic Structure
Adrenoreceptors are G-protein coupled transmembrane proteins that respond to endogenous catecholamines (adrenaline and noradrenaline). They have multiple functions across different tissues with important effects on:
- Heart
- Peripheral vasculature
- Smooth muscle (including respiratory system)
⠀Beta-1 Receptors
- Location: High concentration in the heart
- Function: In presence of adrenaline, causes:
- Increased heart rate
- Increased stroke volume
- Therefore increased cardiac output via both mechanisms
⠀Alpha-1 Receptors
- Location: Peripheral vasculature
- Function: Respond to adrenaline and noradrenaline causing:
- Vasoconstriction
- Maintenance of blood pressure
⠀Beta-2 Receptors
- Location: Respiratory smooth muscle
- Function: Cause relaxation of smooth muscle in small airways
- Clinical use: Beta-2 agonists used in asthma and COPD
⠀Alpha-2 Receptors
- Location: Presynaptic membrane (negative feedback loop), particularly CNS
- Function: Alpha-2 agonists cause:
- Sedation (commonly used in intensive care)
- Hypotension
- Note: May cause transient hypertension when first administered due to cross-reactivity and feedback mechanisms
⠀Additional Effects
- Bladder: Alpha receptors in bladder neck smooth muscle increase tone; alpha antagonists can alleviate obstructive urinary symptoms
⠀Beta-3 Receptors
- Location: Pancreas
- Function: Alterations in glucose metabolism
- Clinical observation: Adrenaline administration causes rise in lactate from increased lipolysis
⠀Agents Affecting Adrenoreceptors
04:03-06:42
Direct Agonists
Phenylephrine:
- Direct alpha-1 agonist
- Causes peripheral vasoconstriction
⠀Metaraminol:
- Causes endogenous noradrenaline release
- Fairly pure alpha-1 agonism → peripheral vasoconstriction
- Some beta-1 activity and direct alpha-1 agonism
⠀Ephedrine:
- Similar mechanism but causes adrenaline release rather than noradrenaline
- Increases heart rate and stroke volume
⠀Tachyphylaxis: Both metaraminol and ephedrine suffer from tachyphylaxis (reduced efficacy with repeated use over time) due to their mechanism of causing endogenous catecholamine release.
Critical Care Agents
Dobutamine:
- Significant effects on stroke volume (particularly at lower concentrations)
- Positive chronotropic effect at high concentrations (increases heart rate)
- Causes peripheral vasodilation → “inodilator”
- Favoured in heart failure and cardiogenic shock
⠀Dopamine:
- Effects on beta-receptors and alpha-receptors
- Complex dose-dependent effects
⠀Local Anaesthetic Agents
06:47-10:16
Classification
Esters: Procaine, cocaine Amides: Bupivacaine, levobupivacaine, prilocaine, lidocaine (most commonly used clinically)
Mechanism of Action
Local anaesthetic agents work by sodium channel blockade from inside neurons. To enter cells, they must be:
- Present in non-ionised form
- Able to pass freely through cell walls as small non-ionic molecules
⠀Once within neuronal cells, they:
- Block sodium channels
- Prevent depolarisation of cell membranes
- Block action potential conduction
⠀pKa and Onset Dynamics
The proportion of drug that is non-ionised (and therefore active) depends on the drug’s pKa relative to physiological pH (7.35):
Lidocaine:
- Fast onset due to high proportion being non-ionised at pH 7.35
- pKa higher than 7.35 → approximately 25% non-ionised at physiological pH
⠀Bupivacaine:
- Much higher pKa than lidocaine
- Much smaller proportion non-ionised at body pH
- Slower onset time compared to lidocaine
⠀Modifying Onset Time
Bicarbonate addition: Adding bicarbonate to local anaesthetic mixtures raises pH, increasing the proportion of non-ionised drug and decreasing onset time.
Cardiac Effects and Antiarrhythmics
10:24-10:58 Local anaesthetics also block sodium channels in cardiac conduction system, enabling their use as antiarrhythmics. Lidocaine can be used in VF arrest situations as alternative to amiodarone and is classified as a Vaughan Williams Class IB antiarrhythmic.
Vaughan Williams Classification
10:58-15:47
Class I: Sodium Channel Blocking Agents
Subclassifications:
- Class IA: Prolongs action potential (e.g., quinidine)
- Class IB: Shortens action potential (e.g., lidocaine)
- Class IC: No effect on action potential (e.g., flecainide)
⠀Memory aid: “QUIFF” – Quinidine, lIdocaine, Flecainide
Class II: Beta-Blockers
Examples: Metoprolol, atenolol, esmolol, bisoprolol (“all the -lols”) Effect: Reduce heart rate
Class III: Potassium Channel Blockers
Primary agent: Amiodarone Effect: Prolongs action potential
Class IV: Calcium Channel Blockers
Examples: Diltiazem, verapamil Mechanism: Slows calcium influx at phase 2 Effect: Prolongs action potential (slowing any phase prolongs overall action potential duration)
Action Potential Effects Summary
Prolong action potential: Class IA, Class III, Class IV Shorten action potential: Class IB No effect on action potential: Class IC
G-Protein Coupled Receptor Details
17:04-18:37 Adrenoreceptors are G-protein coupled receptors with seven transmembrane domains and three subunits with different activities:
GI (Inhibitory): Inhibits adenylyl cyclase GS (Stimulatory): Stimulates adenylyl cyclase
GQ: Modulates phospholipase C, cleaving PIP2 into DAG and IP3
These pathways yield different effects on smooth muscle or cardiac tissue, altering inotropy or chronotropy depending on the specific adrenoreceptor subtype.
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