Pharmacology: Drug Action & Body Interactions

• Pharmacology is a basic science that deals with small molecules to prevent, diagnose, or treat diseases.
• Clinical pharmacology studies the use of drugs in humans, encompassing interactions between drugs and patients.
• A drug is any chemical molecule that interacts with body systems and produces an effect.

Drug-Body Interactions

• Drug-body interactions involve how the body affects the drug (pharmacokinetics) and how the drug affects the body (pharmacodynamics).
• Pharmacokinetics concerns the effect of the body on the drug involving absorption, distribution, metabolism, and excretion (ADME).
• Pharmacodynamics concerns the effect of the drug on the body, including its mechanism of action and pharmacological effects.

Pharmacodynamics (Mechanism of Drug Action)

• Pharmacodynamics defines the effect of a drug on the body and how a drug produces its effects, either through direct mechanisms or interaction with body control systems.
• Drugs interact directly with body control systems involving regulatory proteins, or with certain metabolic pathways.
• Regulatory proteins include receptors, ion channels, enzymes, and carrier molecules.

Receptors

• Receptors are protein macromolecules that, when combined with a drug, can be activated or blocked.
• A ligand is any molecule that can combine with receptors
• A ligand that activates the receptor is called an agonist
• A ligand that blocks the receptor is called an antagonist.
• Affinity defines the empathy of the receptor to the ligand and determines the number of receptors occupied by the drug.

Types of Receptors

Ion Channel-Linked Receptors (Direct Ligand-Gated Ion Channels)

• Ion channel-linked receptors consist of 5 transmembrane subunits.
• Binding of an agonist to the extracellular part of the receptor opens the channel for a specific ion.
• The response of these receptors is very fast with a very short duration.
• Nicotinic Ach receptors in the motor end-plate open ion channels for Sodium ions in response to stimulation by Acetylcholine.
• Gama aminobuteric acid (GABA) receptors in the brain open ion channels for Chloride ions in response to stimulation by GABA.

G-Protein-Linked Receptors

• G-protein-linked receptors consist of 7 membrane subunits.
• Binding of an agonist to the extracellular part of the receptor activates an intracellular G-protein.
• When the G-protein is activated, its α subunit binds to GTP to be phosphorylated, leading to a stimulatory or inhibitory response.
• The response is slower than ion channel receptors and has a longer duration.

Stimulatory G-Protein (Gs)

• Stimulatory G-proteins lead to an increase in the adenyl cyclase enzyme, increasing cAMP and activating protein kinases, as observed with B1 and B2-adrenergic receptors.

Inhibitory G-Protein (Gi)

• Inhibitory G-proteins lead to a decrease in the adenyl cyclase enzyme, decreasing cAMP and inhibiting protein kinases, as observed with α2-adrenergic and M2 muscarinic receptors.

Gq-Coupled Receptors

• Gq-coupled receptors increase inositol triphosphate (IP3) and diacylglycerol (DAG), with IP3 increasing free intracellular Calcium, as observed with α1-adrenergic, M1, and M3 muscarinic receptors.

Tyrosine Kinase (TK)-Linked Receptors

• Tyrosine Kinase (TK)-Linked Receptors consist of 2 large domains connected by a transmembrane segment: an extracellular hormone-binding domain and an intracellular TK-binding domain.
• Binding of an agonist to the hormone-binding domain activates the intracellular domain to activate TK enzyme, leading to activation of several proteins known as "signaling proteins," for example, insulin receptors

Intracellular Receptors

• Intracellular receptors are located inside the cell, either in the cytoplasm or directly on DNA.
• They regulate the transcription of genes in the nucleus or mitochondria.
• The agonist must enter inside the cell to reach them.
• They have two important features: their response is slow, requiring time for protein synthesis, and their effects persist for a long time after the agonist is removed, for examples receptors for corticosteroids, sex hormones, and thyroxin.

Types of Drug-Receptor Bonds

• Hydrogen bonds involve attraction between two hydrogen atoms and are weak and reversible.
• Ionic (electrostatic) bonds involve electrical attraction between two opposing charges and are strong and reversible.
• Covalent bonds, if formed between a drug and receptor, result in permanent blockage of the receptor and are very strong and irreversible.

Biological Response to Drug-Receptor Binding

• When a drug combines with a receptor, it may lead to an agonist or antagonist effect.
• An agonist effect means the drug combines with the receptor and gives a response.
• An antagonist effect means the drug combines with the receptor but gives no response and prevents the receptor from binding to another drug.

Types of Responses to Drugs

Graded Response

• With graded responses, the response increases proportionally to the dose of the agonist.
• Graded responses are observed for the response of the heart to adrenaline, applicable to most drugs, and can be tested in one or more animals.

Quantal Response

• With quantal responses, the response does not increase proportionally to the agonist, but is an all-or-none response - for example, the prevention of convulsions by anti-epileptic drugs.
• Quantal responses apply to few drugs and cannot be tested in one animal, requiring a group of animals.

Overview of pharmacology, including drug-body interactions. Explores pharmacokinetics (ADME) and pharmacodynamics, detailing how drugs affect the body through direct mechanisms and interactions with body control systems. Discusses the effects of drugs.