Pharmacodynamics Pharmacodynamics describe how a drug affects the body, including its mode of action: ● Drug : A chemical substance that interacts with a biological system to produce a physiologic effect. Receptors and selectivity Receptors are a primary focus of pharmacodynamics, in that the receptor is the part of the cell or organism that associates with or interacts with the drug, setting off a chain of biochemical events that are the drug’s effects. A receptor is commonly a protein molecule found on the surface of the cell or within the cell in the cytoplasm. Receptors are selective, in that they can only bind with certain complex molecules (ligands). In order for a drug to interact with a receptor, it must have a complementary chemical structure, fitting like a key into a lock. While most drugs will combine with more than one type of receptor, there are highly selective drugs that only bind to one particular receptor. Such a drug is said to be specific – that is, producing effects by specifically interacting with a single receptor. Most drugs interact with several receptors and thus have the capability to produce distinctly different pharmacologic effects. While drugs are classified according to a particular or primary function, no drugs cause only one single, specific effect. This is because drug molecules tend to bind to more than one type of receptor molecule. Even if a drug did bind to only one kind of receptor, the effects would vary because the subsequent biochemical processes would take place in different cell types with a range of biochemical functions. In the development and use of drugs, selectivity is measured by separating effects into either beneficial – or therapeutic – effects, versus toxic effects. In some case, a necessary drug (one that produces desired benefits) causes toxicity when given in dosages that produce the greatest benefits. In these cases, another drug may be prescribed that reduces the toxicity of the initial drug. In many cases, a drug produces both desirable and negative effects by acting on a single type of receptor in a variety of different tissues or two different receptors. When drugs react with receptors to form a drug-receptor complex, the binding of the receptor to the drug molecule is called coupling . Coupling efficiency refers to the completeness of coupling. In many cases, spare receptors (which are not bound) will also exist on the macromolecule. Drugs interact with receptors by bonding, a chemical force classified in one of three main ways: Covalent; electrostatic; and hydrophobic. Covalent bonds are very strong and may be irreversible, while electrostatic bonds are weaker and hydrophobic bonds are quite weak. Drugs that bind
● Receptor : The part of the complex cell or macromolecule to which a drug binds to initiate drug action. ● Ligand : An ion, molecule or molecular group, including hormones and neurotransmitters, that binds to another chemical entity to form a larger complex. through weak bonds to their receptors are typically more selective than drugs that bond very strongly. This is the case because weak bonds require a very close fit of the drug to its receptor in order for an interaction to occur. Only a small number of receptor types are likely to fit a particular drug structure precisely. Weaker noncovalent bonds require a better fit of drug to receptor binding site and are usually reversible. Very strong bonding (covalent bonds) usually involves less selectivity and irreversible reaction. Drug receptors function in the following ways: ● Receptors determine the quantity of a drug required for a specific response : Receptors tend to dictate the relationship between a dose or the concentration of a drug and its action or effects. The receptor’s affinity for binding a drug determines how much of the drug is necessary to form sufficient numbers of drug-receptor partnerships to produce specific effects, as well as to limit those effects. ● Receptors regulate chemical signaling in the body : Receptors are the reason drug action is selective: The size, shape and electrical charge of a drug determine whether and with what affinity it will bind to a specific receptor. There are many chemically different binding sites available in a cell, tissue or organism; changes in a drug’s chemical composition can significantly increase or decrease a drug’s affinities for different types of receptors, with each of these differences responsible for different therapeutic and toxic effects. ● Receptors determine the therapeutic and toxic effects of the drug in the body : Receptors regulate the actions of pharmacologic agonists and antagonists. This will be discussed in more detail later. Regulatory proteins are a class of receptors that mediate many useful drugs through the regulation of chemical signals, like neurotransmitters and hormones produced in the body. Understanding their function is necessary to a basic understanding of therapeutic and toxic drug action. While most drug receptors are proteins, some DNA and RNA molecules also function as drug-binding targets. In many cases, drugs bind to a site on a protein that normally binds to an endogenous molecule (one produced in the body, i.e., an enzyme). The following table shows examples of different types of endogenous molecules that function as receptors, or targets, of drugs (Masters & Trevor, 2012):
Drug
Use
Drug Receptor Bacterial enzyme
Molecule Type
Penicillin
Infection
Secreted bacterial protein
Digoxin
Congestive heart failure Na, K-ATPase
Protein transporter on cell surfaces
Cyclophos-phamide Cancer
DNA
Nucleic acid
Albuterol
Asthma
Neuro-transmitter receptor
Protein on cell surfaces
Lidocaine
Anesthesia
Voltage gated sodium channels Protein in channel on cell surfaces
Most drugs must bind to a receptor to cause an effect or activate the receptor. In some cases, drug binding brings about the effect directly by physically opening an ion
channel or causing an enzyme to function in a certain way. In other cases, receptors use other molecules to activate the receptor, linking one or more intervening molecules.
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Book Code: MIL1224
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