Overview
This chapter is dedicated to preparing for the Pharmacy Examining Board of Canada (PEBC) pharmacology section. Pharmacodynamics describes the actions of a drug on the body. Most drugs exert effects, both beneficial and harmful, by interacting with specialized target macromolecules called receptors, which are present on or in the cell. The drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.
Fundamentals of Drug Action
1. Activation
What it Means: Activation occurs when a drug binds to a target site (like a receptor or enzyme) and stimulates a process, making it work faster or more efficiently.
Example: Caffeine is a well-known stimulant that targets the central nervous system (CNS). When you drink a cup of coffee, the caffeine molecules bind to adenosine receptors in the brain. Normally, adenosine binding to these receptors promotes sleep and relaxation. Caffeine blocks these receptors, preventing adenosine from binding and thereby increasing alertness and wakefulness.
2. Inhibition
What it Means: Inhibition is when a drug molecule binds to a target site and slows down or stops a specific biological process. This can help in reducing or preventing unwanted symptoms or disease progressions.
Example: Aspirin works by inhibiting the enzyme cyclooxygenase (COX). COX is involved in the production of prostaglandins, which are compounds in the body that cause inflammation, pain, and fever. By inhibiting COX, aspirin reduces these symptoms, acting as an anti-inflammatory, pain reliever, and fever reducer.
3. Complexation
What it Means: Complexation involves a drug forming a complex with another molecule or ion, which can deactivate or sequester (isolate) the target molecule, making it ineffective.
Example: Deferoxamine is used in the treatment of iron overload conditions, such as those that can occur from repeated blood transfusions. It works by chelating (binding to) excess iron in the body, forming a complex that can be excreted, thereby reducing iron levels in the body and preventing iron toxicity.
4. Neutralization
What it Means: Neutralization can occur through a direct chemical reaction where the drug neutralizes the harmful effects of another substance, or through a physical interaction that counteracts the substance's effects.
Examples:
Chemical Reaction: Antacids like sodium bicarbonate and magnesium hydroxide work by directly neutralizing stomach acid. When you take an antacid, it reacts with the hydrochloric acid in your stomach, reducing acidity and relieving symptoms of heartburn and indigestion.
Physical Interaction: Polyvalent antivenom is used to treat snake bites. It contains antibodies that bind to the snake venom present in the body, neutralizing its toxic effects. This interaction doesn’t involve a chemical change to the venom itself but prevents the venom from causing harm by blocking its biological activity.
The receptors are classified into four types based on the signal transduction mechanisms:
What They Are: Think of ligand-gated ion channels as special doors on the surface of cells that open or close when a specific key (the ligand) is used. These "doors" allow charged particles (ions) to enter or leave the cell.
How They Work: Each channel has a specific spot where the ligand (like a hormone or neurotransmitter) attaches. This is like a lock for our key. Normally, these channels are locked. When the right ligand comes along and binds, it's like turning the key, which opens the door, allowing ions to pass through for a short time.
Examples and Their Effects:
Nicotinic Receptors: Imagine a door that, when opened by its key (acetylcholine), lets sodium ions rush into the cell and potassium ions leave. This movement is crucial for sending signals in nerve cells and making muscles contract.
GABA_A Receptors: Another door opens with its key (GABA), but this time it lets chloride ions in. This makes the inside of the cell more negative, making it harder for the cell to send a signal. It's like putting a dampener on the cell's activity.
Why It Matters: These processes are important for how our bodies function, from how we think and feel to how we move. Some medicines work by targeting these channels, helping to treat various conditions by either blocking or enhancing their activity. These channels are important targets for medicines that help our bodies work better or relieve pain. For example, Local anesthetics like lidocaine bind to voltage-gated sodium channels and block sodium influx, preventing neuronal firing and sensation.
What GPCRs Are: G protein-coupled receptors (GPCRs), also called metabotropic receptors, are special receptors found on the cell surface. They have seven segments that pass through the cell membrane. When drugs bind to these receptors, they activate a G protein.
G proteins are made up of three subunits: alpha (α), beta (β), and gamma (γ). When these three subunits are connected with GDP, the G protein is inactive. But when GTP replaces GDP, the alpha subunit separates from the beta-gamma subunit and becomes active. The activated alpha subunit can cause one of three actions:
GPCRs are like complex switches on the surface of cells. They work with special proteins called G proteins inside the cell. These receptors can read messages from outside the cell (like hormones or drugs) and tell the inside of the cell what to do next.
How They Work: Ligand Binding: Something from outside the cell (the ligand) attaches to the GPCR. This is like turning on the switch. G Protein Activation: Inside the cell, the G protein gets activated. It's made of three parts. When the GPCR switch is turned on, the G protein parts split and go on to deliver the message further inside the cell.
Activation or Inhibition of Enzyme Adenyl Cyclase: This enzyme controls the level of a molecule called cAMP in the cell. Depending on the type of G protein involved (Gs or Gi), the alpha subunit can either activate or inhibit this enzyme. Changes in cAMP levels affect protein kinases, which then modify other molecules in the cell. For example, beta-receptors increase cAMP levels, while somatostatin decreases them.
Activation of Phospholipase C: In some cases, the activated alpha subunit activates an enzyme called phospholipase C (PLC). This enzyme converts a molecule called PIP2 into two other molecules: IP3 and DAG. This process leads to an increase in calcium levels inside the cell, which affects various cellular actions. Alpha-receptors and vasopressin V1 receptors work through this pathway.
Stimulation or Inhibition of Ion Channels: The activated alpha subunit can directly affect the activity of ion channels. For example, M2 receptors of acetylcholine (ACh) can either stimulate or inhibit ion channels.
Signal Cascade: The activated parts of the G protein can then activate other molecules inside the cell, called effectors, like enzymes or ion channels. This can create a chain reaction, producing "second messengers" that spread the signal even more.
Physiological Effects: This chain reaction can change what the cell is doing, like making it move, secrete something, or change how it works.
Real Drug Examples:
Beta-blockers (e.g., Propranolol): Beta-blockers block GPCRs for adrenaline, slowing down the heart rate. This is useful for treating high blood pressure.
Antihistamines (e.g., Cetirizine): These block GPCRs for histamine, reducing allergy symptoms.
Selective Serotonin Reuptake Inhibitors (SSRIs, e.g., Fluoxetine): While SSRIs mainly affect serotonin transport, some also modulate GPCRs related to serotonin, impacting mood and emotion.
Effector Examples and Second Messengers:
Adenylyl Cyclase: Activated by some G proteins, it produces cAMP, a second messenger that can speed up or slow down various cell functions.
Phospholipase C: Activated by other G proteins, it creates IP3 and DAG. IP3 can increase calcium inside the cell, while DAG activates other proteins. This can affect things like muscle contraction or cell growth.
In Simple Terms: Think of GPCRs as intricate message systems on cell surfaces that, when triggered by something outside the cell (like a drug), can start a series of reactions inside the cell. This can lead to big changes in how the cell behaves, influencing our health. Medicines targeting these receptors can help manage or treat various conditions by either activating these systems or blocking them to prevent certain reactions.
