Pharmacology lectures - Introduction to pharmacology
Introduction to pharmacology
Pharmacology is a branch of basic medical science. Pharmacology is a study of interaction between the drug and the living system. What is a drug? A drug is defined as a chemical that will interact with the living biological system.
The branches of pharmacology may include pharmacokinetic, pharmacodynamic, pharmacotherapeutic and toxicology. Pharmacokinetic is a study of the action of the body towards the drug. (What the body does to the drug). Pharmacokinetic consists of absorption, distribution, metabolism/first pass metabolism and elimination.
What is absorption? Absorption is an extent and rate of drug absorption from the sites of its origin. The efficacy and rates of absorption of a drug depend on the surface area available. The surface area which is larger usually has the greatest rate of absorption. Drug to drug interaction may also influence the rate of absorption. A combination of some drugs may enhance each other absorption while some drugs may inhibit the absorption of other drugs. Intravascular route of administration of the drug has a greater rate of absorption than other forms of route of administrations. Highly vascularises organ such as small intestine has a greater absorbing ability.
The absorption of the drug also depends on the solubility of the drug. The amount/ratio of the lipophilic and hydrophilic component of the drug will determine the ability of the drug to permeate the cell membrane (partition coefficient). pH of the drug will influence the charges of the drug and it is indirectly will influence the absorption of the drug. The weak acidic drug will be uncharged when protonated while the weak base drug will be charged when protonated. The uncharged drug will pass through the membrane cell more easily. Therefore the amount of drug absorb depends on the charge to uncharged ration.
What is bioavailability? Bioavailability is a fraction of drug administered that reach the sited of action. The bioavailability of intravenous route of drug administration is 100% because all drugs will enter the systemic circulation and the bioavailability of the drug which is administered by another form of route of administration (oral, transdermal) is less than 100%. Some of the drugs will be inactive and not absorbed. The bioavailability depends on blood supply, surface area available, route of administration, solubility of drugs, the pH of the drug, drug interaction and first pass metabolism.
What is first pass metabolism? First pass metabolism or biotransformation usually occurs before the drug reaches the sites of action. Biotransformation /metabolism usually occurs in the liver. Nitroglycerin and morphine have a high first pass metabolism as 90% of the nitroglycerin become inactivated in the liver before it reaches the sites of action.
The body needs to biotransform the drug to facilitate the elimination of the drug. Most of the drug that is absorbed is lipophilic drug. The lipophilic properties will hinder the elimination of the drug. The lipophilic drug need to be biotransform /modified to become more polar. The polar drug/molecule will be easily eliminated. Sometimes biotransformation may lead to conversion and activation of the prodrug to the active drug.
The modification/biotransformation of the drug may be divided into two phases such as phase I and phase II. Phase I involved in unmasking or the introduction of the polar functional group of a particular lipophilic drug. Hydrolysis, reduction, dehydrogenation and oxidation are the types of reaction that occur in phase I. This phase I reaction usually occurs in the cytochrome -p450 system in the liver. Phase II involves conjugation reaction that leads to the formation of the covalent linkage between the polar functional group of the drug and another substrate such as glutathione , acetic acid, sulphate and glucuronate. The phase II reaction usually occurs in the cytosol of the liver. In some cases, will initially undergo phase II conjugation reaction than phase I. Generally the biotransformation reaction will begin with phase I and follow with phase II.
The factor which affects biotransformation may include induction of cytochrome p450 which will increase the biotransformation or modification of drug or inhibition of cytochrome p450 that occur when two drugs competing for the same active sites of the p450 enzyme and one of the drug will have a decrease in the biotransformation rates. Genetic differences also play a major factor in influencing the rates of biotransformation. Some patient may be slow acetylators and in this patient the rate of biotransformation of certain drugs such as hydralazine, isoniazid and procainamide are low. These drugs are not rapidly inactivated by biotransformation reaction. An individual who suffers from liver disease may also have a slow rate of biotransformation. Finally biotransformation is affected by the gender and age of the individual. Neonates for example is lacking of conjugating enzyme.
The rates of biotransformation /inactivation of the drugs are predictable and based on the chemical principles of first order kinetic and zero order kinetic. In first order kinetics , the percentage of drug metabolized is constant per unit time. For example, for a particular drug, 10% of the drug will be metabolized in 2 hours and during the first 2 hours, the concentration of the drug will be 90mg/dl (original concentration of the drug is 100mg/dl).For the next 4 hour the concentration of the drug will be 81mg/dl. The concentration of the drug will be reduced by 10% for every 2 hours. The greater the concentration of the drug, the greater absolute amount of drug biotransform or inactivated /excreted per unit time.
In zero order kinetic, the amount of drug metabolized per unit time is constant regardless of the concentration of the drug. For example for a particular drug with a concentration of 100mg/dl, 10mg of the drug will be metabolized in 2 hours and during the first 2 hours, the concentration of the drug will be 90mg/dl and the for the next 4 hours the concentration of the drug will be 80mg/dl and 6 hours later 70mg/dl. The example of drug that undergo zero order kinetic may include aspirin, ethanol and phenytoin.
The route of administration of the drug may include alimentary, parenteral, topical, inhalation and transdermal. Alimentary route of administration may include oral, sublingual, buccal and suppository. Oral route of administration is the most common. It utilizes the small intestine for its greatest absorbing ability due to its large surface area available. It is also convenient for the patient and has a great compliance. Buccal route of administration may involve the placement of the drug between the gum and the cheek. Buccal route of administration allows direct absorption into the venous circulation. Sublingual route of administration involves the placement of the drug under the tongue. Nitroglycerin is the type of drug which is sublingually administered. Sublingual route of administration allows the drug to be directly drained into the superior vena cava and bypassing the first hepatic metabolism. Suppository /rectal route of administration is performed on a patient who is vomiting or loss of consciousness. 50% of the drug will bypass the liver and absorb from the rectum.
The parenteral route of administration may include intravenous route, intramuscular route, subcutaneous route and intrathecal route of administration. In the intravenous route of administration, 100% of the drug will be absorbed into the systemic circulation .It is the most potent and rapid form of drug administration. The intramuscular routes of administration reduce the risk of intravascular injection hazard. It is a potent and rapid mode of administration than the oral route. Intrathecal route may involve direct injection of the drug into the spinal subarachnoid space and it is usually performed in spinal anaesthesia or cases of acute central nervous infection.
Inhaled drug is administered by using machine vaporization and machine aerosolization. Pulmonary agent is mostly administered by inhalation route. Transdermal route of administration is useful for nicotine replacement /patch therapy which is a sustained release drug. Topical administration of drug is useful for localized disease such as eye infection, acne or psoriasis.
In distribution drug leaves the bloodstream and enters the cells or tissues or enter the interstitium. Drugs are absorbed based on three processes such as passive diffusion, facilitated transport by a specialized carrier protein or active transport.
Passive diffusion is the most common route of administration. It is based on the principle of different concentration gradient across the membrane. The drug will move from an area of high concentration to low concentration. Active transport involves the transport of the drug against the concentration gradient which requires energy from the dephosphorylation of the adenosine triphosphate. Another form of passive diffusion is known as carrier protein transport. It is similar to passive diffusion in term of mechanism of action. However the transport process requires the use of carrier protein.
The distribution process depends on the drug structures, binding to the plasma albumin, capillary permeability and blood flow. In terms of drug structure polar molecule is less likely to distribute across the cell membrane easily than small lipophilic molecule. Any drugs which bind to plasma albumin will have a limited access across the cell membrane to the cellular component. Capillary permeability may affect the distribution process. In the spleen and liver, the junctions between the endothelial cells are wide. This will allow the excess of large molecule of the drug. In the brain, the junctions between cells are tight. The ability of large molecule of drug to pass through is limited.
Excretion is the final part of pharmacokinetic. It involves the removal of the metabolites or drug from the body. The route of excretion may include renal, faecal, respiratory, breast milk and skin. Renal is the most common route of excretion of hydrophilic molecule. Acidification of the urine will aid the elimination of the weak base and alkalinization of the urine will aid the elimination of the weak acid. Respiration involves in the removal of vapor and anaesthetic gas.
Excretion is often confused with secretion. Excretion is the removal of the metabolites or drug from the body while secretion is the active transport of drugs from one part of the body to another part of the body.
Pharmacodynamic is one of the branches of pharmacology. It is defined as what the body does to the drug. It involves the interaction between the drug and the receptor, the therapeutic effect and toxic effect of the drug as well as the study of dose response relationship.
Pharmacokinetic involves the study of the extent and how fast the drug will reach the site of action while pharmacodynamic involves the study of the physiological aspect and mechanism of action of the drug.
What is a receptor? The receptor is a macromolecule. The receptor is typically made from protein. It allows the binding of the drug and ligand which mediate the physiological and pharmacological action. Besides useful as ligands or drug binding sites, Receptor is also important in message propagation or activation of the effector mechanism. What is an effector? Effector will convert and transduce the interaction of drug- receptor into cellular effect. There are four types of effector mechanism that include intracellular, transmembrane, ligand gated ion channel and second messenger system. The intracellular component may include the binding of drug such as steroid and thyroid hormone to a nuclear receptor which later interact with the DNA and affect the expression of the gene. Transmembrane involve the presence of two receptors that are intracellular and extracellular components. Binding of the drug such as insulin into the extracellular component will activate the intracellular component which is coupled to an enzyme such as tyrosine kinase.
Enzyme such as tyrosine kinase is associated with neurotrophic factor receptor and growth factor receptor while guanylyl cyclase is associated with guanylin receptor and ANF receptor. TBF beta receptor is associated with serine/threonine kinases and tyrosine phosphatase (enzymes).
The Ligand gated ion channel is another form of effector. The binding of the ligand into the ion channel will alter the conduction of the ion through the cell membrane. Ligand gated ion channels may include benzodiazepine (GABA A receptor), nicotinic acetylcholine receptor, 5HT3 serotonin receptors, glutamate receptor and glycine receptor. It consists of multi subunit.
Second messenger system is another form of effector mechanism. The drug will bind to the receptor and activated the second messenger system that involves the presence of the G-protein. The second messenger system will transduce, convert and amplified the signal from the drug-receptor interaction into a cellular response. The three most important second messenger systems may include inositol triphosphate, (IP3). Inositol triphosphate is produced by the enzyme phospholipase C . Increase in the level of phospholipase C will lead to an increase in the sodium /hydrogen (Na+/H+ exchange).
Cyclic adenosine monophosphate (cAMP) is another form of second messenger system. It is produced by an enzyme known as adenylate cyclase. An elevated level of adenylate cyclase will increase in the flow of calcium ion while a reduction in the level of adenylate cyclase will result in increase in the flow of potassium current and decrease in the flow of calcium current.
The other second messenger system includes cyclic guanosine monophosphate (cGMP) that is produced by guanylate cyclase.
The therapeutic and toxic effect of the drug
A drug which binds and activates the receptor is known as an agonist. Agonist is divided into full agonist and partial agonist. Full agonist is a drug that binds to the receptor and produce 100% of its maximum biological effect. Partial agonist is a drug that binds to the receptor and produce less than 100% of its maximum biological effect.
A drug which binds and inhibits /inactivates the receptor is known as the antagonist. Antagonist may divide into competitive antagonist and non competitive antagonist. Competitive antagonist will compete with agonist and bind to the receptor at the active sites of an enzyme. The competitive antagonist can be overcome by increasing the concentration of the drug (agonist).
Non - competitive antagonist will bind to the receptor irreversibly at a site different from the active site of the enzyme. Increasing the concentration of the agonist will not overcome the non- competitive antagonist.
What is potency? Potency is the amount of drug required to produce its biological effect. As an example, 10mg of drug X is required to reduce the blood pressure while 5 mg of drug Y is required to reduce the blood pressure. Drug Y is more potent than drug X.
What is efficacy? Efficacy is the ability of the drug to produce its biological effect/response. As an example drug C reduces the blood pressure by 5% while drug D reduce the blood pressure by 10%. Drug C has a higher efficacy than drug D. The maximum efficacy if a drug is not affected by the presence of competitive antagonist. However the maximum efficacy of a drug will be reduced by the present of noncompetitive antagonist. What is Kd? Kd is a dissociation constant. Kd is a concentration of the drug that produce 50% occupancy of the receptor. EC50 is a concentration of a drug that produce 50% of its maximum response/potential in a graded dose response curve.
How a drug is developed
The development of drugs involves in vitro studies, animal testing, clinical testing and marketing. These steps are required to create an effective and safe drug. In in vitro studies the drug is synthesized from biological product and chemical synthesis to form the lead compound/drug.
The drug will undergo an animal testing. The efficacy, mechanism and selective properties of the drugs are studied. After animal testing, the drug manufacture will submit the investigational new drug exemption application form prior to human testing/clinical testing.
Clinical testing is divided into 4 phases which include phase 1, phase 2, phase 3 and phase 4. Phase 1 is performed to justify the safety of the drug. The pharmacokinetic aspect of the drug is studied. A small number of healthy normal human is used. Any toxic effect, from negligible, mild to severe toxicity is monitored. These acute overdose effects are monitored over a wide range of dose.
The purpose of phase 2 is to evaluate the effectiveness of the non toxic level of the drug. In phase 2 the drug is used in a moderate number of patients who present with the target disease. A placebo drug is also introduced as part of the double or single blinded study.
In phase 3, the drug is used across the country like its final intended use. In phase 3, the drug is used on a larger scale. Phase 3 is similar to phase 2. In phase 3, control drug is introduced. After completing phase 3, control drug manufacturers will complete the New Drug Application (NDA) form to be submitted to the FDA. FDA will decide on the approval of the drug.
Phase 4 only taken place after the drug hits the market. Long term effects of the drug such as toxicities are monitored.
There are 3 factors that determine the appropriate dose of a particular drug. These include the plasma concentration of the drug need to achieve efficacy, the condition of the patient (any liver disease, kidney disease, and weight of the patient) and the type of disease and infection that the patient may suffer.
Volume of distribution ( Vd) is known as the ratio of the amount of drug in the body to the plasma concentration of the drug. (The total amount of drug in the body divided by the plasma concentration of the drug). Volume of distribution is an apparent volume with no physical equivalent. Small volume of distribution (Vd) indicated that the drug binds to the plasma albumin and only a small amount of the drug diffuse from the vascular compartment. Large volume of distribution (Vd) indicates that the drug has been sequestered in some compartment and tissue. Large Vd also means that the half life is extended and the drug is not being eliminated.
Clearance is the term used to describe the volume of plasma which is clear from a drug per unit time. Clearance is calculated by dividing the rate of elimination of the drug with plasma concentration of the drug.
The maintenance dose is a dose of drug required to achieve a therapeutic plasma concentration of a drug over an extended period of time. The maintenance dose is equivalent to clearance times/ * the desired plasma concentration and divided by bioavailability.
A loading dose is another form used to describe the dose of drug required to rapidly achieve a therapeutic plasma concentration. Usually a single loading dose is injected before maintenance dose is given routinely. A loading dose is equivalent to the volume of distribution times * desired plasma concentration divided by the bioavailability.
Peak and trough concentration are useful to describe the maximum and the minimum concentration of the drug during the interval of dosing. The peak and trough concentration is affected around the steady state of plasma concentration. Steady state plasma concentration is the points where the rated of drug elimination is equal to the rates of drug available. It is calculated by plasma clearance times/* plasma level. Smaller doses of the drugs that are used more frequently will minimize any swinging in the concentration of the drug.
Half life is the time taken for the concentration of the drug to be half of its original value. It is equal to 0.693 times* Vd (volume of distribution) divided by clearance. 4 1/2 half life is required to achieve a steady state of plasma concentration.
Excretion is the rate of removal of a drug from the body. It is equivalent to clearance times * plasma concentration.
Therapeutic index is a ratio of a toxic dose of a drug to a therapeutic dose of a drug. A safe drug is a drug with a high therapeutic index.
The terms used in pharmacology.
Any drug ending with the term azepam is an anti anxiety drug such as diazepam. Any drug that end with the term -ane means halothane or general anesthetic drug. The name of a drug that end with azine such as chlorpromazine is an anti psychotic drug. Postsynaptic alpha receptor blocker drug will end with the term zosin such as terazosin. Statin is the term used to describe HmG - CoA reductase inhibitor or lipid lowering drug such as lovastatin. Opril is the term used to describe ACE inhibitor /blood pressure lowering drug such as captopril or lisinopril. Beta blocker is identified by the term olol such as propanolol. Antibiotics are identified if the terms cillin such as penicillin or cycline or doxycycline present. Bital means pheobarbital or barbiturates sedative agent.
Terms such as qds means every day, while bid means twice a day. Tid means three time a day, qid means four times a day, stat means immediately, prn means as needed, po means orally, gtt means drop and qs means quantity sufficient.
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