Drug-receptor interactions

• Pharmacology studies the uses, effects, and modes of action of drugs.
• A drug can be any natural, synthetic, or endogenous molecule with physiological or biochemical effects on cells, tissues, organs, or organisms.
• Drugs, also called medication or medicine, treat, cure, prevent, or diagnose diseases, and promote health and well-being.
• Traditionally, drugs came from medicinal plants, but organic synthesis is now common.

Drug Interactions

• Interactions between a drug and a biological system (the body) are bidirectional, and both interact with each other.
• There are over 350,000 approved drugs and 147 preparations of Diclofenac-sodium, and 60 of Paracetamol (Acetaminophen).
• Most drugs have a single international name but may have multiple trade names.
• Throughout history, pharmacologically active substances from plants and animals have treated diseases.
• Drugs can be synthesized (hormones, neurotransmitters like dopamine, epinephrine, acetylcholine) or not synthesized in the body (xenobiotics).
• Poisons are drugs with almost exclusively harmful effects.
• The term "pharmacology" comes from the Greek words "pharmakon" (drug or poison) and "logos" (word or discourse).
• The two main areas of pharmacology are pharmacodynamics (drug actions on the body) and pharmacokinetics (fate of drugs in the body).

Pharmacodynamics vs Pharmacokinetics

• Pharmacodynamics involves interactions between chemicals (drugs) and their biological receptors.
• Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of chemicals from biological systems.
• Pharmacology overlaps with pharmacy, the science of drug preparation.
• Clinical pharmacology/therapeutics uses drugs to treat disease.
• Toxicology studies the undesirable effects of drugs on biological processes or poisons.
• Pharmacology includes drug properties/composition, synthesis/design, molecular/cellular action mechanisms, and signal transduction/communication.
• Genomes of humans, mice, and other organisms are decoded, which opens new research and treatment approaches.
• Inherited diseases stem from heritable abnormalities in DNA, now definable at the DNA base pair level.

Gene Therapy

• Gene therapy involves inserting a "healthy" gene into somatic cells to potentially correct abnormalities.
• Genomics clarifies that increased drug sensitivity in some patients is due to genetic modifications affecting drug-eliminating enzymes.
• Pharmacogenomics (or pharmacogenetics) studies genetic variations causing individual differences in drug response.
• Discovery and development of drugs (including immunotherapy/vaccinations) has increased life span and improved life quality.
• New scientific insights and controlled clinical trials have been essential to this progress.
• "Alternative" and "complementary" treatments have been promoted, but most lack rigorous scientific validation.
• The search for "magic bullets" (agents that treat disease/produce desirable effects without harm) has driven scientific discovery for >100 years.
• Identifying, testing, approving, and using drugs that maximize efficacy but minimize toxicity is a challenge.
• The fundamental anchor of medicine is "Primum non nocere": "First do no harm".
• Governments require approval processes (focusing on safety over efficacy) before drugs can be marketed and prescribed due to past problems.

Pharmacodynamics

• Pharmacodynamics (what a drug does to the body) studies the biochemical, physiologic, and molecular effects of drugs on the body.
• Involves receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions.
• The pharmacologic response relies on the drug binding to its target.
• Drug concentration at the receptor site influences its effect.
• A drug's pharmacodynamics can be affected by physiologic changes from disease, disorder, or aging.

Disorders

• Disorders that affect pharmacodynamic responses include genetic mutations, thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson's, and some insulin-resistant diabetes.
• These disorders can change receptor-binding, alter binding protein levels, or decrease receptor sensitivity.
• Aging affects pharmacodynamic responses through receptor or postreceptor sensitivity alterations.
• Pharmacodynamic drug-drug interactions involve competition for receptor binding sites or alter postreceptor responses.

Drug Receptors

• Drugs are distributed to their site of action, often a macromolecular entity called a receptor.
• Receptors are in the target tissue or organ and are macromolecules in chemical signaling between/within cells; located on cell surface, nucleus, or cytoplasm.
• Drugs exert effects by binding to specific receptors on the surface or interior of cells.

Drug Action

• Non-specific sites exist which serve include water, hydrogen ions, metal ions, enzymes & nucleic acids
• Drug binding can be covalent, electrostatic, or hydrophobic.
• Covalent bonds are very strong and not readily broken.
• Aspirin uses a covalent mechanism of action, forming a covalent bond with its target enzyme, cyclooxygenase.
• Aspirin provides pain relief and anti-inflammation by preventing prostaglandin production, and acts as an anti-clotting agent by preventing thromboxane A2 production.
• The logic behind covalently bound drugs is their duration of action, as reversing the effects requires synthesizing new enzymes.
• Electrostatic bonds are much more common in drug-receptor interactions and weaker than covalent bonds, relatively strong in ionic linkages, weaker in hydrogen bonds occurring in polar molecules, and very weak in induced-dipole interactions
• Hydrophobic interactions: molecules avoid aqueous (water) environments.

Receptor Activation

• Activated receptors regulate cellular biochemical processes (post-receptor events, e.g., ion conductance, protein phosphorylation, DNA transcription, enzymatic activation/inhibition).
• Molecules (drugs, hormones, neurotransmitters) that bind to a receptor are called ligands.
• Ligand binding can be specific and reversible.
• A ligand may activate or inactivate a receptor, either increasing or decreasing a specific cell function and each ligand may interact with multiple receptor subtypes but have relative selectivity.
• Selectivity relates largely to physicochemical binding of the drug to cellular receptors i.e. the degree to which a drug acts on a given site relative to other sites.

Affinity and Intrinsic Efficacy

• A drug's ability to affect a receptor is related to its affinity (probability of occupying a receptor) and intrinsic efficacy or activity (degree of receptor activation and cellular response).
• A drug's chemical structure determines its affinity and activity.
• Duration of the drug-receptor complex (residence time) also determines the pharmacologic effect.
• The lifetime of the drug-receptor complex is affected by dynamic processes controlling the rate of association and dissociation from the target longer residence time, prolonged effect unless increases drug toxicity.
• Physiological functions are usually regulated by multiple receptor-mediated mechanisms.
• Multiple steps (e.g., receptor-coupling, intracellular 2nd messengers) may be interposed between drug-receptor interaction and tissue/organ response.
• External factors and intracellular regulatory mechanisms influence the ability of a drug to bind to a receptor.
• Drugs, aging, genetic mutations, and disorders can increase (upregulate) or decrease (downregulate) the number and binding affinity of receptors.
• Ligands bind to recognition sites on receptor macromolecules and binding sites may be the same as or different from that of an endogenous agonist (hormone or neurotransmitter).

Agonist Types

• Agonists that bind to an adjacent or different site on a receptor are called allosteric agonists.
• Nonspecific drug binding also occurs at sites not designated as receptors (e.g., plasma proteins).
• Drug binding to nonspecific sites inactivates it by preventing receptor binding.
• Unbound drug is available to bind to receptors and have an effect.
• Agonists activate receptors to produce the desired response. Classic agonists increase activated receptors and inverse agonists stabilize the receptor.

Antagonists

• Many hormones and neurotransmitters (acetylcholine, histamine, norepinephrine) and drugs (morphine, phenylephrine, isoproterenol, benzodiazepines, barbiturates) act as agonists.
• Antagonists prevent activation, increasing cellular function if they block the action of something that normally decreases cellular function.
• Antagonists decrease cellular function if they block the action of a substance that normally increases cellular function.

Receptor Antagonists

• Receptor antagonists are classified as reversible or irreversible.
• Reversible antagonists readily dissociate from their receptor; irreversible antagonists form a stable bond.
• Pseudo-irreversible antagonists slowly dissociate.
• In competitive antagonism, the antagonist prevents the agonist from binding.
• In non competitive antagonism, both agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the agonist's action
• In reversible competitive antagonism, agonist and antagonist form short-lasting bonds.
• A steady state is reached between agonist, antagonist and receptor.
• Such antagonism can be overcome by increasing the concentration of the agonist.

Opioid Antagonists

• Naloxone (opioid receptor antagonist structurally similar to morphine) blocks morphine's effects but competitive antagonism can be overcome by giving more morphine.
• Structural analogs of agonist molecules sometimes have agonist and antagonistproperties and are called partial/low-efficacy agonists or agonist-antagonists.
• Pentazocine activates opioid receptors but blocks their activation by other opioids, providing opioid effects but blunting the effects of another opioid.
• A drug can act as a partial agonist in one tissue but as a full agonist in another.
• Dose-response describes the change in effect on a living organism caused by different degrees of exposure to a substance or different doses of a drug.

Dose Response

• Dose-response vary depending on the individual and the period of time exposed.
• "Dose" refers to the quantity of drug administered; "exposure" refers to the time-dependent concentration.
• Dose response models determines "safe", "hazardous" and (where relevant) beneficial levels and dosages for drugs, pollutants, foods, and other substances to which humans or other organisms are exposed
• Dose-response relationships generally depend on the exposure time and exposure route (e.g., inhalation, dietary intake).
• Quantifying the response after a different exposure time or route can lead to a different relationship and different conclusions.

Dose Response Curves

• Dose-response relationships are presented in graphs called dose-response curves and its a simple X-Y that depicts the relationship with the receptor.
• The relationship that describes the relationship between the magnitude of a substance or stressor (e.g. concentration of a toxicant, amount of a drug, temperature, intensity of radiation)
• The response of the receptor is usually measured for a physiological or biochemical response, or even death (mortality).
• The data generated may be counts, ordered descriptive categories, or continuous measurements and is used to study affects.
• The measured dose is plotted on the X axis and measured effect on the Y axis
• The curves used may be milligrams, micrograms, or grams per kilogram of body-weight and the measured effect.
• Some cases use other dose units include moles per body-weight, moles per animal, and for dermal exposure, moles per square centimetre.

Potency Terminology

• A graph of the logarithm of the dose is typically S shaped, also known as sigmoidal, with the steepest portion in the middle. and a "threshold-dose."is reached.
• Biologically based models are preferred because the logarithm can visually imply a threshold.
• Measured effects are frequently recorded as maximal at time of peak effect or under steady-state conditions.
• The response to a drug may be quantified at different organisational levels.
• At higher doses, undesired side effects appear and grow stronger and the steeper the curve used, the more potent that substance.
• The Y-axis is designated often by percentages and it can be death to designate LD50 and the biologic variation also occurs.
• Dose-response curves of drugs studied under identical or standard conditions can help compare pharmacologic profiles.

Dose-Response Curves Information

• Deductions from dose-response curve information helps determine the necessary dose to achieve desired effect.
• Dose-response, which involves the principles of determines the requirements and Therapeutic Index.
• Therapeutic Index aids in safe usage and probability for both and depends on a variety of Population variables.

Pharmacokinetics vs Pharmacodynamics

• Pharmacokinetics answers what the body does to a drug or a drugs fate and helps explain the relationship between dose and response.

Routes of Administration

• Routes of administration. Determine when or where it is to be administered to get to the 1) drug Characteristics, 2) Emergency/routine use, 3) Site of action, 4) Condition of the patient 5) Age of the patient. 6) Effect of Gastric 7) Patient and Doctor choice.

Local Routes

• Provides the simplest drugs at the site of Minimal Side effects.
• Topical which its at Skin locations to create suspension (Oral Cavity Suspension via Nystatin.
• Application include skin locations, GI. Anal Canal (Enemas), Eye/Ear/Nose (Drops,ointments), Bronchi (Inhalation), Skin (ointment and Cream)
• II Intra-arterial Route
• Main uses Diagnostic use coronary issues and Cancer. III
• Administration into Deep Tissues for issues such as arthritis.

Systemic Routes

• Drugs enter the bloodstream via the Enteral Oral/Sublingual and rectal.
• (a) Oral Route; Common way in tablets, capsules, easier to store.
• (b) Sublingual Route Drugs through Buccal and directly systemic, Quick onset, spitting to terminate, 1st pass by passed.
• (c) Rectal Drugs are either solid or liquid (Can be both effects with indomethacin), for children as diaxapam.

Parenteral Routes

• Other than Enteral, is quick and Aseptic (Useful in patients with V/D), and has Irritant, high pass metabolism.
• Inhalation, for quick and localized effects w volatile gases and regulated doses and quick onset.
• Injections are painful, has a intradermal drug in the skin like BCG shots, drug is low.
• (b) a solution where the route is thigh, abdomen or arm and injected for adrenaline and insulin. (c) drugs in muscly areas w Paracetamol to volume of at time of time.
• Aseptic conditions and injections (D) IV is the Bloodstream IV.
• Solution like IV Diazepam can counter epileptic, and highly irritant drugs.
• By I.V. infusion, C can be maintained as a dopamine infection, and can create Phlebitis as a rare effect.

Absorption of Drugs

• Drug, Route/Formulation is important in the form of tablets.
• Solid and Tablets (Disintegrate and deaggregate in solution), and must also cross Several Semi Permeable Walls before it has to reach the Systems.
• High bioavaibility to a Target of Action.

Transport

• Transport uses Biological Wall Barriers for passage of molecules.
• Cross-Membrane drugs must be via passive diffusion, active transport/pinocytosis and various membrane proteins depending on its membrane permeablity. Passive Mechanism does not require energy depends on Permeability, with the use of passive transport includes: diffusion, osmosis and facilitated.
• Active is cell energy in the form of hydrogen ions pumping against a change gradient in mitochondria which requires Active-Transport.
• Active transport seems be structurally limited a specific set of small intestine drugs. : (1) Passive Diffusion: Moves gradient for high and Low concentrations in blood solubility size in proportion to the molecules which are in a liquid solution
• (2) ionized form in high water and low and is (Determined by an Envr.
• (3) Passive-Diffusion in membranes
• (4) Trans in energy with transport in ATP protein.
• (5) Exoc/pinoy cytosis and fluid the.

Transfers Across Members

• Transfers and excretions are involved in crossing membranes.
• The size and the way it moves are significant molecules for membranes.
• Plasma Membranes for protein w bilayer chain with a flexible for molecules

Passive Membrane Transport

• Cross members using transport where molecules go through (lipids).
• By diffusion and is proportional and gradient.

Week Electrolytes

• Most acids in solution for soluble solution for (Lipid and can readily be used) and gradient.

Factors

• Factors. In diffusion. (First Law) to gradients. (Direction, Flux), Do diff.
• (Viscosity
• ) of solution to (Fluid

Concept of First Pass

• If the inject it is at 100. For an IV injection for metabolism
• First Pass, availability to reach other molecules by blood, revesrivly taken Up by proteins for total amount in cells bioavaliablity of 50 - !000 Drug in peripheral, and volume D determines the concentration.

Distribution

• One drug at high concentration, distribution on vascular
• Permeability as it increases with (output)
• The ability in high concentration (fat/muscle) drugs until in the body. Volume and Vd is a body mass amount of the body
• Factors for (Drug in plasma), and Tissue

Metaboliom transformation

• Altering chemicals body more soluble and increases
• Excretion.

Transofrmation

• Drugs include
• Active drug to inactive.
• Active drug to active Inactive to Active.

Activity.

• Aliver increases

• Intestinal with

• Phases 1 II and Phase II

• 1 Oxidative, hydrolytic reactions, where (Polar molecules) Synthetic results in less molecules hydroxylating enzyme.

Classifcations

• The name implications or indentificaiton with the use of a Chemical is Developed by the (IUPAC).
• Is technical personel by atomic/atomic groups. Proprietary Name where firms make (Drug Classification) A. The ATC code is a code drugs on it.

The ability of a drug to bind to a receptor is influenced by external factors as well as by intracellular mechanisms. Agonists that bind to an adjacent site or a different site on a receptor are sometimes called allosteric agonists. Drug binding to nonspecific sites prohibits the drug from binding to the receptor.