Pharmacodynamics I
Pharmacodynamics
Pharmacodynamics is the study of the principles and mechanisms by which drugs interact with the body to produce therapeutic or adverse effects. Understanding the mechanisms of drug action is essential for the development and optimization of safe and effective medications.
Mechanisms of Drug Action
When we talk about the mechanisms of drug action, we often refer to the way drugs interact with their targets in the body, such as receptors and enzymes. However, there are other ways in which drugs can act, including physical and chemical mechanisms.
1. Physical Mechanisms of Drug Action
Physical mechanisms of drug action involve physical interactions between the drug and the target. For example
Bulk laxatives, such as ispaghula husk, work by increasing the bulk and water content of the stool, which stimulates bowel movements. They work by a physical mass mechanism, in which the fiber in the laxative absorbs water and swells, forming a gel-like substance that adds bulk to the stool. This increased bulk stimulates the muscles in the intestinal wall, leading to a bowel movement.
Activated charcoal is a substance that is often used in emergency medicine to treat drug overdoses and poisonings. It works by an adsorptive property mechanism, in which it binds to and adsorbs the toxic substance, preventing it from being absorbed into the bloodstream. The activated charcoal and toxic substance are then eliminated from the body together.
2. Chemical Mechanisms of Drug Action
Chemical mechanisms of drug action involve chemical reactions between the drug and the target, such as the covalent bonding of the drug to the target molecule. For example, antacids like magnesium hydroxide and aluminum hydroxide act by neutralizing stomach acid through a chemical reaction. The basic nature of these drugs allows them to neutralize the acidic environment of the stomach, which reduces the acidity of the stomach.
3. Receptor Mechanisms of Drug Action
Receptor mechanisms of drug action involve the drug binding to specific receptors in the body, such as G protein-coupled receptors or ion channels, and modulating their activity. One example of a drug that acts by a receptor mechanism is albuterol (salbutamol), a medication used to treat asthma. Albuterol acts by binding to beta-2 adrenergic receptors on the smooth muscle cells of the airways, causing them to relax and dilate, thereby increasing airflow and improving breathing.
4. Enzyme Mechanisms of Drug Action
Enzyme mechanisms of drug action involve the drug interacting with enzymes in the body and either inhibiting or enhancing their activity. An example of a drug that acts by an enzyme mechanism is statins, a class of medications used to lower cholesterol levels in the blood. Statins work by inhibiting the enzyme HMG-CoA reductase, which produces cholesterol in the liver. By inhibiting this enzyme, statins reduce cholesterol production, leading to a decrease in blood cholesterol levels.
Another example of a drug that acts by an enzyme mechanism is acetylsalicylic acid, also known as aspirin. Aspirin works by irreversibly inhibiting the enzyme cyclooxygenase (COX), which is responsible for the production of prostaglandins that cause inflammation and pain. By inhibiting COX, aspirin reduces inflammation and pain, but it also has potential side effects, such as gastrointestinal bleeding.
Most of the drugs acting through enzyme mechanisms are enzyme inhibitors.
Receptor
The idea that drugs can affect receptors in the body is often credited to a scientist named John Langley (1878). He noticed that two different drugs, atropine and pilocarpine, could both combine with a substance in the body to produce saliva. He called this substance a "receptive substance."
Another scientist, Paul Ehrlich, later introduced the term "receptor" in 1909. Ehrlich believed that a drug could only have a positive effect if it was able to attach to the right kind of receptor in the body. He described a receptor as a part of a cell that could combine with a specific drug molecule to cause changes in the body.
Proteins are the most important type of drug receptors in terms of numbers. Among them, many naturally function as receptors for endogenous ligands like hormones and neurotransmitters.
A receptor performs its tasks of binding to a ligand and transmitting a message (or signal). It implies the presence of specific functional areas within the receptor. These functional areas include a ligand-binding domain and an effector domain.
A receptor can affect the cell directly, or it can use other molecules to send signals to different parts of the cell. These molecules are called transducers. The group of the receptor, its cellular target, and any intermediary molecules are called a receptor-effector system or signal-transduction pathway.
Drug-Receptor Interaction
Drugs can bind to receptors through various types of interactions, including ionic interactions, hydrogen bonding, hydrophobic interactions, van der Waals forces, and even covalent bonding.
Drugs acting through receptors can be broadly divided into the following categories
- Agonist
- Antagonist
- Partial Agonist
- Inverse Agonist
Agonist (interacts with receptors and mimics the action of an endogenous ligand).
Antagonist (interacts with receptor and prevents the action of an endogenous ligand).
Receptor Theories
Pharmacological theories exist regarding the functioning of receptors. The receptor occupancy theory suggests that the effect of a drug depends on its ability to occupy a receptor. This theory is based on the law of mass action, which has been modified to fit experimental observations. A.J. Clark was the first to apply mathematical principles to drug action, and Ariens (1954) introduced the concept of intrinsic activity to explain the range of drug effects between full agonists and antagonists.
One theory suggests that a small proportion of receptors occupied by an agonist can result in a maximum effect. However, the response is not directly proportional to the number of receptors occupied. This concept is called efficacy, and different drugs may have varying capacities to initiate a response and occupy different proportions of receptors when producing equal responses.
Partial agonists are drugs with low efficacy that can occupy almost all the receptors and still produce a response lower than the maximum.
Another theory suggests that receptors can exist in two conformational states, active (Ra) and inactive (Ri). When in equilibrium and in the absence of a drug, the Ri state predominates, and the basal signal output is low. The drug's relative affinity for the two conformations determines the extent to which the equilibrium shifts toward the Ra state.
Inverse agonism occurs when a drug with a higher affinity for the Ri conformation decreases the physiological or biochemical response in a system where an equilibrium between the Ra and Ri states exists.
Classification of Receptors
Receptors are proteins that are located on the surface of cells or inside cells, and they are responsible for transmitting signals from the outside of the cell to the inside. Different types of receptors have different structures and functions, and drugs can be designed to interact with specific receptors to produce specific effects.
There are several different types of receptors, including G protein-coupled receptors (GPCRs), ion channel receptors, enzyme-linked receptors, and nuclear receptors.
G protein-coupled receptors (GPCRs)
G protein-coupled receptors are the largest and most diverse family of receptors, and they are involved in a wide range of physiological processes, including neurotransmission, hormone signaling, and immune responses.
GPCRs are proteins that interact with specific regulatory proteins known as G proteins. G proteins act as signal transducers, relaying information from the receptor to one or more effector proteins. These receptors activate a diverse range of effectors such as enzymes like adenylyl cyclase, phospholipase C, phosphodiesterases, and plasma membrane ion channels selective for Ca2+ and K+.
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Ion-channel Receptors
Ion-channel receptors are involved in the transmission of electrical signals, and they play a critical role in the function of the nervous system and muscles.
In the plasma membrane, several neurotransmitter receptors form channels that are selective for ions and regulated by agonists. These are known as ligand-gated ion channels or receptor-operated channels. By altering the ionic composition or membrane potential of the cell, these channels transmit their signals. Some examples of such channels include the nicotinic cholinergic receptor, the GABA A receptor, and the receptors for glutamate, aspartate, and glycine.
Enzyme-linked Receptors
Receptors with intrinsic enzymatic activity include surface protein kinases that can regulate the functions of other proteins by adding a phosphate group to them, a process called phosphorylation. This can alter the activity or interaction of the target protein with other molecules.
Protein phosphorylation is the most common reversible covalent modification of proteins that regulate their function. Most receptors that are protein kinases phosphorylate tyrosine residues in their substrates, such as insulin and various polypeptides that direct growth or differentiation, while a few receptor protein kinases phosphorylate serine or threonine residues.
Transcription Factors as Receptor
Steroid hormone receptors, thyroid hormone receptors, vitamin D receptors, and retinoid receptors are all examples of soluble DNA-binding proteins that can regulate the transcription of specific genes. By binding to specific DNA sequences known as response elements, these receptors can either activate or repress the transcription of genes, leading to changes in cellular processes and functions.
Regulation of Receptors
Receptors help control many important functions in our body and they are also controlled by various mechanisms. These mechanisms include regulating the production and breakdown of receptors, modifying them chemically, and moving them around inside the cell. Similarly, transducer and effector proteins are also regulated.
Receptors can be affected by signals from other receptors and they often regulate themselves through feedback. When cells are repeatedly exposed to drugs that activate receptors, the effect can be reduced. This is called desensitization, adaptation, refractoriness, or down-regulation. When this phenomenon occurs rapidly, it is called tachyphylaxis. It's important in treating illnesses like asthma, where patients can become less responsive to the repeated use of beta-receptor agonists as bronchodilators over time.
When receptors are not stimulated for a long time, the body can become extra sensitive to drugs that activate those receptors. This can happen when a drug that blocks a receptor has been taken for a long time and stopped, or when the nerves that control the receptors are damaged. For example, long-term administration of beta-receptor antagonists like propranolol (see Chapter 10), or following chronic denervation of a preganglionic fiber which induces an increase in neurotransmitter release per pulse, indicating postganglionic neuronal supersensitivity.
Sometimes, when the body is sick, it can create new receptors, which can also make it more sensitive to drugs. As seen in cardiac ischemia, resulting in the synthesis and recruitment of new receptors to the surface of the myocyte and causing supersensitivity.
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