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Pharmacology

Pharmacology // Concept

Receptors

Ensymes

Pharmacological Action

Potency and Efficacy

Side Effects

Pharmacodynamics

Pharmacokinetics

Bioavailability

Concept

It is the science that studies the origin and the properties of chemical molecules on living organisms; in this sense, it evaluates any therapeutical value and the toxicity potential of chemical agents on biological systems. It is the study of drugs, natural or synthetic, used in the treatment, cure, prevention or diagnostic of disease or health conditions.
The field of action encompasses the history, origin, phisico-chemical properties of drugs, associations, biochemical and physiological effects, biotransformation and excretion of drugs used for therapeutically use.

Questions in Pharmacology

  1. With which tissue receptor will the drugs interact to produce its effects, and how these receptors are related to the biological response?
  2. What are the biochemical steps and potential sites into which drugs can alter or modify cell signaling pathways.
  3. How are  the traditional or accepted mechanisms of action for a given drug, its biological effects, and, are these proposed mechanisms enough to explain all the observed drug effects?
  4. How these drugs interact with the cellular surface to modify/alter intracellular processes?
  5. How can drugs be used as selective sensor agents to discover detailed information of biochemical and physiological processes?
  6. What is the potential toxicity, effects, dosages, etc?
  7. What are the relationships governing biological activity and chemical structure of a drug molecule?
  8. Why certain chemical substances produced by animals or plants are able to act upon an organism and produce biological effects?
  9. How do organisms, organs, and individual cells develop and increase or decrease of biological sensibility of prescription/OTC drugs?

Receptors

Cellular macromolecules – they are generally proteins – are able to interact with hormones and chemicals to produce a constant response which is specific and predictable.

The receptor only biological function is to serve as a recognition site to neurotransmitters, hormones and other substances involved in the biological processes, therefore, they are sensors in the chemical communication system that coordinates the functions of all cells in the body.

The drugs act by modifying cellular processes (they stimulate or inhibit) and thus must first stimulate a cellular receptor.

Receptors have structures that allow the drug to attach to it, forming a drug-receptor complex that is responsible for the pharmacological action.

This relationship may be explained by the lock and key model where the key (drug) activates a lock (receptor). The receptor is specific for each one type of molecule, and that kind of molecule (ex. protein) binds to a family kind of drugs and has certain specificity and reversibility.

Enzymes

The receptor is specific for one type of molecule, and that kind of molecule (ex. protein) binds to a family type and drug and has some specificity and reversibility.

Besides cell receptors, other enzymes are also important targets for drug action.

Enzymes help transport vital chemicals, regulate the speed of the chemical reactions or perform other structural functions of regulatory or transport nature.

While drugs targeting receptors are classified as agonists or antagonists , agents targeting the enzymes are classified as inhibitors or activators (inductors).

Most interactions are reversible, either between or among drugs and drug receptors, and enzymes. The drug is released after a certain time and the receiver or the enzyme regain normal function. If the interaction were irreversible, drug effect persists until the body to produce more enzymes.

The selectivity of the interaction of proteins to macromolecules is related to the topological properties similar between them, and can be attributed in principle to electrostatic interactions, hydrophobic and steric interactions.

Example : Lovastatin is a drug used to lower cholesterol levels in the blood.This drug inhibits the enzyme hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is essential for producing cholesterol in the body.

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Pharmacological action

The drug does not create anything new, it only activates or inhibits what it finds.

The pharmacological action is accountable for the modifications, changes or processes that get started in the presence of a drug or a therapeutic vaccine.

They may be a biochemical process, an enzymatic reaction, a movement of electric charges, a movement of Ca2 + cations across the membranes, or an activation of the immune system, among others.

The pharmacological effect is the observable manifestation that is manifested after a pharmacological action. There is no effect without action and every action involves an effect, but it never expresses itself on a 1 to 1 basis.

It promotes the activation or inhibition of an enzyme system, producing a cascade of reactions or processes involved in the complex immune system.

The use of a drug requires that its use benefits exceed considerably the risks incurred upon. In practice, the use of any therapeutic agent involves a certain risk that must be minimized.

The pharmacological action can occur at any organizational level.The drug can bind to a cellular molecule, such as the antitumor drug that binds to DNA or it can also act on cellular structures, such as penicillin acts directly on the bacterial wall.Can also act to higher levels, for example, in the circulatory system or CNS or target over the entire body.
Example:

Salbutamol is a bronchodilator for the treatment of asthmatic problems. It binds to Beta-2 adrenergic receptors . These receptors are stimulated by adrenaline and salbutamol. Salbutamol is a mimetic agent of adrenaline. The drug-receptor coupling, launches the ion transport system that causes dilatation of the bronchi. The observable result is the bronchodilator effect.

Theophylline is an alkaloid of the methylxanthine family, the same to which also belong other molecules like caffeine and theobromine. It is a more potent CNS stimulant than caffeine and has bronchodilator properties.

It is found naturally in black tea and green tea. It acts on the permeability of Ca2 + cations and causes relaxation of smooth muscle by Ca2 + output. The observed effect is bronchodilation.

 

The above are examples of two different pharmacological actions which lead to the same effect. This explains how the pharmacological effect can come from actions and different routes.

This concept can be extrapolated to the conventional treatment of cancer where other chemotherapeutic agents, which enhance the immune system, can cooperate in a synergistic manner to enhance the overall effect.

To properly design a pharmacologically cooperative strategy, the mechanism of action of each of the members of the therapy must be known, thus eliminating or diminishing any interaction between drugs that might attenuate the desired final action.

 

Affinity and specificity of the drug to the receptor

 

  • Affinity is defined as the ability of a drug to bind to a receptor.
  • Specificity, through which a molecule can be discriminated from each other, even if they are similar.

 

Many drugs often have an affinity for the same receptor, in which case there is a phenomenon of competition.Receptors are molecules in the body that have appeared through evolution, and they were not intended to serve as receptors to drugs. They have a biological function, regardless of whether they join or not to drugs.

They are receptors to endogenous substances (hormones, neurotransmitters). If the drug binds to the receptors, it operates with structural affinity to endogenous substances for which the receptor was designed by nature and evolution.

 

Formation of drug-receptor complex

 

Generally, reversible interaction is established when links involved are ionic in nature. In this case the drug is complexed to be released after the action, metabolized and excreted. Being reversible makes the pharmacological action end.

They can also be of an irreversible nature – antibiotics that bind to the bacterial cell wall, marine origin inhibitors of phospholipase A2, etc. – .

The receptor may not necessarily be in the membrane, but in the cytoplasm or nucleus so that the drug has to pass through the membrane to act (for example, steroid hormones).

Many drugs have no specific receptor, its action is nonspecific on any component.

 

Intrinsic activity is defined as the ability of the drug to initiate its action after binding to the receptor. It is a specific property of the drug.

 

The intensity of the action of the drug is dependent to:

 

  1. The number of receptors occupied: Minimum number required to bring the action.
  2. The drug’s affinity for the receptors: By increasing the affinity, the effect is increased.

Potency and Efficacy

Potency refers to the amount of drug (usually expressed in milligrams) necessary to produce an effect, such as pain relief or decrease of blood pressure.

For example, if 5 milligrams of pain relieving drug B acts with the same efficacy as 10 milligrams of drug A, then the drug B is twice as potent as the drug A.

A more powerful drug is not necessarily better than another.

Physicians judge the relative qualities of the drug, taking into account many factors such as the profile of side effects, potential toxicity, and duration of effect, therefore the appropiate number of daily doses required, as well as its cost.

Efficacy refers to the therapeutic response, the maximum potential that can induce a drug. For example, the diuretic furosemide and eliminates much more salt water through urine chlorothiazide diuretic. So furosemide is more effective or achieves a greater therapeutic effect than chlorothiazide. Like potency, efficiency is one factor that physicians consider when selecting the most appropriate drug for a given patient.

 

Tolerance

Tolerance is a decrease in pharmacological response due to repeated or prolonged administration of some drugs.

Tolerance occurs when the body adapts to the continued presence of the drug.
Generally, there are two mechanisms responsible for tolerance:

  1. Drug metabolism is accelerated (usually because it increases the activity of the liver enzymes that metabolize the drug).
  2. Decrease the amount of receptors or their affinity for the drug.

The resistance/tolerance concept is used to describe the situation in which an organization to respond to an antibiotic, an antiviral drug or chemotherapy in the treatment of cancer.

Depending on the degree of tolerance or resistance developed, the doctor may increase the dose or select an alternative drug.

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Agonists and Antagonists

A drug is an Agonist when, besides having affinity for the receptor, has intrinsic activity leading to activate or stimulate the receptors, triggering a response that increases or decreases the cell function.

Antagonist drugs block the access or the binding of agonists to their receptors. Antagonists are used to block or reduce the cell response to agonists (usually neurotransmitters) that are normally present in the body.

Competitive antagonism occurs when two drugs compete for the same receptor.

 

Examples:

Carbachol, an agonist adhering to cholinergic receptors of the respiratory tract cause contraction of smooth muscle cells, which broad effect is producing bronchoconstriction (narrowing of the airways).

Another drug agonist salbutamol, adheres to other receptors in the respiratory tract called adrenergic receptors, causing relaxation of smooth muscle cells and producing bronchodilation (widening of the airways)..

Ipratropium bromide, a synthetic derivative of atropine, is an antagonist of cholinergic muscarinic receptors, blocking the bronchoconstrictor effect of acetylcholine, the natural transmitter pulses via cholinergic nerves.

Ipratropium is not selective for the different subtypes of muscarinic receptors, so that exerts pharmacologic actions similar to those of atropine on bronchial smooth muscle, salivary glands, the gastrointestinal tract and the heart, when administered systemically . However, given by inhalation, their effects are confined to the respiratory tract, being twice as potent as a bronchodilator than atropine. This route of administration for its systemic effects are minimized.

This is an example of the importance of understanding the most appropriate route of administration of a drug.
Drug Synergy

Drug synergy is defined as the increase in the drug action as a result of the administration of another drug.

The additive or synergistic synergy sum, occurs when the resulting action is the sum of the individual actions of both drugs.

Empowerment Synergy occurs when the resulting action is greater than the sum of individual actions.

As a result of the synergy, the physician can reduce the doses of drugs administered. Additive synergy occurs when both drugs bind to the same receptor, while potentiating synergy bind to different receptors.

Side Effects

It is defined as any noxious and undesirable response to a drug, which occurs at the usual doses for prophylaxis, diagnosis or therapy. Also referred to as a side effect, side effect or adverse reaction.

The causes of an adverse reaction may be due to exaggerated pharmacological effects, direct toxicity, immune reaction, reactive metabolites and reactive metabolites that cause an immune reaction.

The causes of an adverse reaction may be due to exaggerated pharmacological effects, direct toxicity, immune reaction, reactive metabolites and reactive metabolites that cause an immune reaction.

The characteristics of an adverse reaction are highly variable. They may occur immediately or after years of treatment.

Its time course can be acute or chronic.

Most of these effects may be reversible when the drug is withdrawn, but sometimes are irreversible. As its manifestations are similar to those of other diseases rooted by other causes, it is often difficult to diagnose.

 

  • Adverse reactions of type A (augmented) may be due to exaggerated pharmacological effects or direct toxic effects. Its occurrence is related to dose or plasma concentrations are predictable, reproducible and largely preventable.

 

  • The type B (bizarre) may be due to immunological causes and pharmacogenetics. Its appearance is not dose-related (although the genetic cause may be) and is not predictable or reproducible. Other adverse reactions are drug interactions and viral infections.

 

  • The type C (continuous) as in of drugs abuse and tardive dyskinesia by the administration of neuroleptics.

 

  • The type D (delayed) as mutagenesis, immunotoxicity, carcinogenicity and teratogenicity.

 

  • The type E (ending of use) refer to withdrawal syndromes and rebound effects by suppressing the medication abruptly.

 

Risk factors

 

Risk factors increase the likelihood of an adverse reaction to occur.

They may be attributed, for instance, to the specific pharmacokinetics of the drug, when they produce an increase in the plasma concentration of the drug which causes an adverse reaction, or to the pharmacodynamics, when they produce an increased sensitivity to the effects of the drug.

Pharmacodynamics

Pharmacodynamics is the branch of pharmacology that studies the action of drugs and their effects on the target and in the body to produce a pharmacological action.

The drugs act by modifying cellular processes (inhibition or stimulation) and thus must first stimulate a receptor.

Most drugs are incorporated into the blood, once administered orally, intravenously or subcutaneously, and circulate through the body, while having an interaction with a number of targets (tissues and organs).

According to the properties of the drug (solubility, chemical structure, physical properties, etc.) or the administration route, it can act only in a specific area of the body (for example, antacids action occurs mainly in stomach) or may act at several sites, exerting different effects.

The target interaction generally produces the desired therapeutic effect, while the interaction with other cells, tissues or organs can cause side effects (adverse drug reactions).

Some drugs are not very selective. For example, Tricyclic antidepressants are considered nonselective drugs because they act at least in five levels, two of which are related to their therapeutic action:

Therapeutic action: inhibit the reuptake of serotonin and norepinephrine.

Adverse effects:

  1. Blocking histamine receptors, causing weight gain and drowsiness,
  2. Block acetylcholine receptors causing constipation, dry mouth, blurred vision and drowsiness.
  3. Block alpha1-adrenergic receptors, causing hypotension, dizziness and drowsiness.

Other drugs are highly selective and primarily affect a single organ or system. For example, digoxin is a drug administered to individuals with heart failure; it acts mainly on the heart to improve the efficiency of the heartbeat.

Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen are relatively selective in that they act at any site where there is inflammation.

Pharmacokinetics

Pharmacokinetics is the branch of pharmacology studying the mechanism of action of drugs, that is, examines how physiological and biochemical processes in the body are affected by the presence of the drug.

Mathematically describe the science movement and time course of a drug, comprising phased release, absorption, distribution, biotransformation (metabolism), and excretion of a drug, in order to optimize pharmacotherapy in terms of safety and efficacy.

It uses several models to explain the movement of a substance in the body.

The compartment model assumes a single space in which equilibrium is established between the amount of drug that enters and the amount leaving.

Multicompartment models, despite its complexity, are most fit to reality, believing that the drug administered not only suffers absorption and elimination processes, but also the distribution to different organs.

Bioavailability

That portion of the dose of a drug or nutrient administered exogenously, which leads to the organ or tissue in which it carries out its action.

Since the determination of the concentration of xenobiotic in a tissue, is excessively invasive generally accepted value of its concentration in plasma.

This concept can be used to quantify the degree to which a substance is used by the body.


Toxicity

Toxicity indices are the toxicological used in risk assessment and are derived from dose-response studies.

Therapeutic Index

TI or therapeutic index is a measure of the margin of safety of a drug.

It is expressed numerically as a relationship between the dose of medication that causes death (lethal dose or LD) or an adverse effect on the ratio of the sample and the dose causing the desired therapeutic effect (effective dose or ED) in the same or greater proportion of the sample.

IT = LD50/ED50

where the number 50 means 50% of the population. The safety margin is greater the higher the value of the therapeutic index. It is considered very dangerous medication when IT value approaches 1