CONCEPTS OF PHARMACODYNAMICS

PHARMACODYNAMICS-AN OUTLINE

It is very interesting to know about the drug which has been taken into our body how it acts against our body's physiology.

While pharmacokinetics is described in simple terms as the body vs the drug, pharmacodynamics on the contrary means simply the opposite term the drug vs. the body.

The concepts of pharmacodynamics include the theories of receptor reactions, mechanisms of therapeutic and toxic actions, and dose-response relationships.

RECEPTOR REACTIONS

Receptors are macro-molecules typically made out of proteins that interact with either an endogenous substance or an exogenous substance to mediate a pharmacological or physiological effect.
Receptors are functioning by ligand(an endogenous or exogenous substance) and activation of an effector messenger system
Effectors transduce a stimulus produced as a result of drug-receptor interactions into a physiologic effect. There are four types of effector mechanisms:-
1.Transmembrane
Some endogenous ligands such as insulin cannot enter inside the cell instead they interact with the outer component of its receptor present on the cell. This interaction produces a stimulus that is transduced into the inner component of the receptor present inside the cell that contains the enzyme tyrosine kinase to produce a physiologic effect that is the entry of glucose into the cell.
2.Ligand-Gated Ion Channels
When an active drug specialized for these kinds of receptors binds to them that makes a series of conductance of effects to open the ion gates situated by the sides of the receptors to produce powerful ion influxes and effluxes.
The best examples are benzodiazepines that make Cl- ion influx and acetylcholine that make Na+ ion influx.
3.Intracellular
In these types the ligands or substances react with the cellular receptors to form receptor complexes and enter inside the cell and interact directly on the DNA which causes changes in gene expressions. (e.g.)Thyroxine and steroid hormones.
4.Second Messenger Systems
Drugs bind to receptors that cause the activation of a second messenger system that involves G-proteins.
The second messengers the G-proteins such as Guanosine Tri Phosphates (GTP) and Guonosine Di Phosphates allow cell surface receptor signals to be converted and amplified into a physiologic cellular response.
There are three types of second messenger systems that follow below:-
1.Cyclic Guanosine Monophosphate(cGMP)
These are one of the major second messenger systems responsible for many physiologic cell responses such as ion channel conductance, glycogenolysis, and cellular apoptosis a process of older cell deaths by DNA defragmentation.
cGMP also causes vasodilation and increased blood flow. This action is well demonstrated by some erectile stimulating drugs like sildenafil(Viagra) which causes accumulation of cGMP to dilate the blood vessels of the penis to get more blood to flow into it for a perfect erection.
cGMP is produced by the enzyme guanylyl cyclase from GTP and is reconverted back into GTP by a cGMP specific Phospho Di Esterase(PDE).
2.cyclic Adenosine Mono Phosphate(cAMP)
the cAMP is a second messenger that is produced by adenylyl cyclase from ATP(adenosine triphosphate).cAMP involves many physiological effects such as glucose regulation.
3.Inositol Tri Phosphate (IP3)
This is produced by the enzyme Phospholipase-C. It is mostly used in signal transduction, and lipid signaling in biological cells.

Mechanism Of Therapeutic and Toxic Action

These mechanisms involve a drug binding to a receptor in order to stimulate or inhibit it.

A drug that binds with a receptor in order to stimulate and produce a maximum 100% biological effect is known as a Full Agonist.

A drug that binds with a  receptor in order to inhibit and block the biological effects is known as an Antagonist.
A drug that does not stimulate a receptor to a maximum extent and not to produce a 100% biological effect no matter whatever its concentration is known as Partial Agonist. 
If an antagonist binds to the same receptor site of an agonist competitively and reversibly is known as Competitive Antagonist.
If an antagonist binds to the different receptor sites of an agonist non competitively and irreversibly is known as Noncompetitive Antagonist.
A competitive antagonist can be overcome by increasing the concentration of the agonist. The high concentration of the agonist can replace the reversibly bound antagonist from the receptor site.
A non-competitive antagonist cannot be overcome by increasing the concentration of the agonist.
A drug's maximum efficacy is reduced thus by the presence of a non-competitive antagonist.

Dose-Responce Relations

Efficacy is defined as the ability of a drug to produce the expected biological response. A drug is said to be more efficacious if it produces the required biological response at a maximum level independent of the dosage quantity given.

On the contrary potency is defined as the minimum quantity of the drug to produce the required biological response. A drug is more potent if it produces the required biological response with a minimum quantity of dosage.

In simple terms, efficacy is a qualitative measurement whereas potency is a quantitative measurement

Examples can be described as follows:-

If two drugs A and be B both are claimed to reduce a person's heart rate by 35% and then we can say both are equally efficacious

If drug A requires 30mg to produce a heart rate effect of 35% while drug B requires 50mg to produce the same effect then drug A is said to be more potent than drug B.

The concentration of the drug required to occupy 50% of the receptor is known as the dissociation constant (Kd)

The concentration of the drug required to produce 50% of the maximum response is known as EC50.

 

 

 

FUNDAMENTALS OF PHARMACOKINETICS-PART-4

PHARMACOKINETICS-4

EXCRETION

The process by which a drug or its metabolite is eliminated from the body. It is the final and last part of the phenomenon of pharmacokinetics.

Excretion and Secretions are two different entirely opposite actions of the body on a drug. Excretion is a passive movement of the drug according to the concentration and pressure gradient towards its port of elimination.

Secretion needs special oxidation-reduction energy which the body gets from some oxidation-reduction process to move the drug against its concentration and pressure gradient from one compartment to another compartment. The best example is the tubular secretions of some reabsorbed blood contents like sodium, potassium, and chloride ions back into the renal tubules.

The major routes of excretions are,

1.The Kidneys by urine

2.Fecal or stools by colon and rectum

3.Lungs by respiration

4.Breast Milk 

5.Skin by sweat.

PRINCIPLES OF PHARMACOKINETICS-PART-3

PHARMACOKINETICS-3

METABOLISM

In this post we deal with the third principle of the body's action on the drug administered into it, which is Metabolism or Biotransformation.

Metabolism is the process by which the drug which is a foreign and unwanted substance to the body is biologically converted into another form either to make it inactive, or less toxic and to be eliminated easily. These processes mostly happen in the liver. But unfortunately liver may sometimes biotransform some drugs into more active and highly toxic metabolites unintentionally.

Lipophilic, fat-soluble nonpolar molecules are converted into hydrophilic, water-soluble polar molecules in order to eliminate them from the body.

Metabolism is conducted by two phases of reactions such as Phase-I and Phase-II.

In Phase-I reaction lipophilic, fat-soluble,non-polar molecules are converted into hydrophilic, water-soluble polar molecules by introducing or unmasking a polar group in it. These reactions are occurred mostly by oxidation, reduction(mostly by dehydrogenation, or deprotonation, or removal of a positive charge), and hydrolysis(addition of a water molecule or hydro group).

On the contrary in Phase-II conjugative reaction, conjugation between a functional group of the parent drug and a substrate occurred by a strong covalent bond formation.

Usually the substrate is, Glucuronate(the most common substrate), Acetic Acid, Glutathione(as with the toxic paracetamol metabolite N-acetyl-p-benzoquinone imine in order to make it into inert to save the liver) and sulfate.

Most of the metabolic process occurs in liver but some are in the cellular level. In the tissue, cell metabolism occurs in the endoplasmic reticulum(a cytoplasmic cleft present within the cytoplasm) and in the cytosol.

Factors Affecting Metabolism

Genetic Factors

There are differences between the capacities of metabolizing a drug among individuals. For example, some people are slow acetylation and therefore cannot rapidly inactivate some medicines like isoniazid, procainamide, and hydralazine.

Induction of the Cytochrome P-450 system

Rapid induction of this system increases the rate of metabolism.

and inhibition of this system may block the metabolism of some drugs.

The disease especially of the Liver

Age 

Gender

All metabolic processes are mathematically following the zero-order and first-order reactions.

First Order Kinetics

By this model a constant amount of drug is biotransformed in unit time.

For example 10% of a drug,is eliminated or metabolised in the concentration of 100mg/dL by every 2 hrs,then after 2 hours the concentration will be (100-10) 90mg/dL and after 4 hours (90-9),81mg/dL and so on.

The concentration of the drug is directly proportional to the rate of metabolism in first-order kinetics.

Zero Order Kinetics

The amount of drug elimination is a constant figure independent of is the concentration per unit time.

For example if a drug concenration 100mg/dL and the body can remove 10mg/dL in every 2 hour,then after 2 hour there will be a concentration of (100-10)=90mg/dL;and after 4 hours there will be a concentration of (90-10)=80mg/dL and so on.

Alcohol is metabolized as per the zero kinetics only.

PHARMACOKINETICS-FUNDAMENTALS-PART-2

PHARMACOKINETIC PRINCIPES-2

DISTRIBUTION

In part-1 for this subject in the last post we dealt with the beginning point of the pharmacokinetics-Absorption.

In this part-2 we will see the next aspect after absorption, the Distribution.

The process of Distribution is defined as the process in which the drug leaves the bloodstream into the tissue cells.

There are three biochemical mechanisms by which the process of absorption and distribution proceeds.

Passive Diffusion:-

Passive diffusion is governed by a concentration gradient formed across the area of absorption and distribution, which is a cell membrane of tissue. The concentration gradient pushes the drug from the area of high concentration to the area of low concentration. Many lipophilic non polar ions are absorbed and distributed by passive diffusion and it is the most common mode of drug distribution.

Active Transport

In this way some drugs move against the concentration gradient. For this a special energy is required which is derived from the conversion of Adenosine Tri Phosphate(ATP) to Adenosine Di Phosphate(ADP) by the enzyme ATP-ase. The best example is the movement of [H+]ion across the membrane of the parietal cell of the stomach by the ATP-ase pump to let out.

Transport by Special Carrier

There are some special proteins that help to distribute the drug by bounding up with them.

Factors Affecting Distribution

1.Blood Flow.

Distribution is directly proportional to blood flow similar to absorption.

2.Capillary Permeability.

Capillaries are having various thickness and permeability in its structure at various organs. For example in the brain the cells are arranged very tightly with the capillaries with very veery narrow junctions and distribution is slow as only smaller molecules are permeable through the junction between the cells. Conversely in liver and spleen the cells are not so tightened in arrangements embedding the capillaries and they joined with wider junctions so that large molecules can pass through the capillaries and distribution is high across these organs.

3.Binding with Plasma Proteins

Albumin is the common plasma protein that binds with the drugs and limits their distribution as albumins are large protein molecules difficult to cross the capillaries.

4.Drug Structure

In the drug molecular structure if they are non-polar lipophilic then they are smaller and are more rapidly distributed than the large ionized polar molecules.

 

 

PHARMACOKINETICS-FUNDAMENTALS-PART-1

PRINCIPLES OF PHARMACOKINETICS

Pharmacokinetics is better defined as the action of the body on the drug from its entry point to its exit point.

The actions of the body can be better classified as Absorption, Distribution, Biotransformation(Metabolism)

and Excretion.

Absorption

Absorption can be better explained as the rate at which the drug is moved from its site of administration into the body.

Factors Affecting Absorption

The rate and efficacy of absorption can be affected by the following factors.

1.Route of Administration:-

At the following sequences, the routes affect the absorption

Sublingual<Buccal<Oral<Dermal<Intradermal<Subcutaneous<Intramuscular and other parenteral <Intravenous.

From the above sequences we come to know that the most effective absorption happened at the intravenous route. The drug is 100% absorbed directly into the system by that route.

2.Blood Flow:-

In a highly vascularized area with heavy blood flow such as in small intestine the absorption is more.

3. Surface Area Available:-

The drug absorption is high at higher surface area available.

4.The solubility of a Drug:-

The ratio of the lipophilic to hydrophilic (Partition Coefficient) will decide whether the drug can permeate into a cell membrane. In short a drug that has higher lipophilic moiety will easily pass into the cell membrane to be absorbed.

5.Drug-Drug Interactions:-

When given in combination they may interact which can determine whether to inhibit or enhance the absorption

6.Hydrogen Ion Concentration:

H-ion concentration is usually measured by the negative logarithmic values in the pH scale. The pH of the drug which is acidic or alkaline may affect the absorption.

Many drugs are either weak acids or weak bases and their ionization is partial. Acidic drugs are uncharged when protonated as follows,

                [H+] + [A-] < > [HA] (uncharged)

Basic drugs are charged when protonated as follows

                [B]  + [H+] < > [BH+] (charged)

Generally the uncharged ions are non-polar and lipophilic and can easily pass through the lipid content of the cell membrane. 

Therefore the amount of drugs absorbed depends upon its ratio of charged to uncharged particles which in turn is determined by the ambient pH at the site of absorption and the pKa value which is the negative logarithm of the dissociation constant of the drug.

The fraction of the administered drug available for its biological effect after absorption is known as bioavailability.

The intravenously injected drug has 100% bioavailability as it is completely absorbed into the system.

The first pass hepatic metabolism and all other factors described earlier that affect absorption are also the factors that affect bioavailability.

Routes Of Drug Administration

1.Alimentary canal

2.Parenteral(Injections,infusions etc.etc.)

3.Inhalation

4.Topical (Skin)

5.Transdermal

Types of Alimentary Routes:-

1.Oral

2.Buccal

3.Sublingual

4.Rectal

Types Of Parenteral Routes:-

1.Intravenous

2.Intramuscular

3.Subcutaneous

4.Intradermal

5.Intrathecal

Many pulmonary agents are preferred for administration through inhalation.

Many drugs to be used for local skin applications are preferred by topical routes.

Many sustained-release drugs are used through the trans dermal route. 

 

 

 

NEWS UPDATE-CHOLESTEROL LINKED WITH OSTEOARTHRITIS

OSTEOARTHRITIS AND CHOLESTEROL

Osteoarthritis a painful condition especially at the joints are caused by high cholesterol which triggers mitochondrial oxidative stress within the cartilage and neuronal tissues and ganglia, a result of a new research study.

New research published in the FASEB journal online in animal models found that high cholesterol triggers mitochondrial oxidative stress on cartilage cells causing them to degrade and die leading ultimately to the development of osteoarthritis.

Antioxidants targeting mitochondrial oxidative stress can be a suitable treatment for cholesterol-induced osteoarthritis.

Indira PrasadamPh.D.a researcher from the Institute of Health and Biomedical Innovation, School of Chemistry, Physics, and Mechanical Engineering at the Queensland University of Technology in Brisbane, Australia, said that we have already started working with various dietitians to give proper public education about eating a healthy diet free from bad cholesterols in order to save them from mitochondrial oxidation of cartilage tissues.

In general the research found that bad cholesterols are not only harming the cardiovascular system but their traps extending to extra C.V systems such as neuronal and skeletal systems.

The researches used two sets of animal models for the study. The first model was a mouse model in which an altered gene called ApoE-/- was induced to induce hypercholesteremia.

The other was a rat model that was fed with controlled cholesterol food to produce diet-induced hypercholesteremia and among them some were treated with cholesterol-lowering drugs atorvastatin and some were given with antioxidants. Both the models were subjected to surgery to mimic knee injuries to produce osteoarthritis. Later they found the mouse models with altered genes and high cholesterol were developed rapidly osteoarthritis than those were given with normal controlled diet and those with cholesterol-lowering treatments and those with antioxidants. This because of the high cholesterol which triggers mitochondrial oxidation of bone cartilage cells.

Include antioxidants in our diets are always advisable especially after forty years in order to get rid of the painful osteoarthritis.

NEWS UPDATE-GENETIC THERAPY FOR ALZHEIMER DISEASE

ALZHEIMER'S-A GENETIC APPROACH

A newer treatment method to cure Alzheimer's is tested successfully. The research was published in the journal Proceedings of the National Academy of Sciences.

The research involves a treatment that delivers a virus to a gene in the brain that could be used to resolve early symptoms of Alzheimer's Disease.

Alzheimer's disease is the most common and devastating form of dementia affecting 40 million people worldwide. It involves memory loss, mood changes, confusion, and personality changes. Currently there are no cures for this.

The Centers for Disease Control(CDC) has estimated that nearly 5 million people are suffering from Alzheimer's disease in the United States itself and in 2014 at about 93541 deaths were attributed to this disease. Alzheimer's disease becomes the sixth main cause of death in the U.S.alone.

The research conducted by scientists from the Imperial College of London. They used a modified virus that delivers a gene known as PGC1-alpha to the brain cells of the mice. They found that it cures the development of Alzheimer's Disease.

The virus is called a lentivirus vector and is commonly used in gene therapy.

On the basis of the research they found that the gene stop a protein called amyloid beta-peptide from forming cells.

Amyloid plaques are sticky clumps of protein formed mainly at the cortex and the front lobe, the hippocampus of the brain during the development of Alzheimer's Disease (Ref.Alzheimer's Disease) in this blog. These amyloid plaques are causing the death of the brain cells which leads to Alzheimer's Disease.

Prof.Nicholas Mazarakis co-author of the research study explains how they can modify the way of infection by the lentivirus on the brain cells affected by the amyloid plaques for their own advantage and yield beneficiary effects. They use a modified harmless version of the virus.

The research was already used successfully in Parkinson's Disease.

Alzheimer's is developed by starting from the cortex and slowly spread to the hippocampus. The first damage may occur in 10 to 20 years before the disease becomes outwardly visible.

The cortex of the brain is associated with long term memory, reasoning, thinking, and mood. Damage may result in depression and difficulty figuring out to do familiar tasks.

The hippocampus is associated with learning and conversion of short term memories to long term memories. Hippocampus is instrumental in mental orientation.

Damage in the hippocampus may result in forgetting recent events such as a deal on the very day morning. This the main reason why an Alzheimer patient may forget his usual route such as the way to his house.