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1. Introduction to pharmacology A drug is defined as a chemical substance of known structure which when administered to a living organism produces a biological effect. Pharmacology is the study of the effect of drugs on living systems. Pharmacokinetics is what the body does to the drug. Pharmacodynamics is what the drug does to the body.
2. Pharmacokinetics - drug uptake and elimination Drug absorption and distribution is divided into four stages that can be remembered using the acronym 'ADME'. These are:
Absorption from the site of administration Distribution within the body Metabolism Excretion
Drugs can be administered via either enteral or parenteral routes.
Enteral administration is directly into the gastrointestinal tract. Enteral routes therefore include sublingual, oral or rectal administration. Absorption of the drug then occurs along the length of the gastro-intestinal tract. In general, drugs that are absorbed rapidly have a low degree of ionisation, high lipid/water partition in the non-ionised form, relatively low molecular weight (less than 1000) and a biological affinity with transporters or for facilitated diffusion. The physiochemical properties of a drug determine whether the drug is absorbed in acidified (the stomach) or neutral/alkaline (intestine) compartments. Many drugs are weak acids or weak bases. Therefore the overall pH of the environment will affect how much of the drug is in the ionised versus neutral form, as follows: HA H+ + ABH B- + H+
Ions require specific channels or transporters to cross cell membranes, whereas neutral compounds are able to diffuse across the membrane. Drugs administered orally undergo first pass metabolism in the liver. After absorption from the gastro-intestinal tract, the liver is the first organ the drug will reach via the hepatic portal vein. In the liver, the drug will undergo oxidation and
conjugation. This will make the compound water soluble. Many drugs are inactivated and excreted in this way. In general, drugs undergo a first catabolic phase of oxidation, reduction or hydrolysis to form a drug derivative. The drug derivative then undergoes a second anabolic stage of synthetic conjugation to produce the water soluble drug.
More specifically, this can be shown as:
Parent drugs or metabolites may recycle several times before entering the systemic circulation. This occurs as the drugs follow bile salts and are excreted back into the gastro-intestinal tract to be reabsorbed and metabolised by the liver.
In this way, drugs may be very long lasting, e.g. some antibiotics. Liver enzymes act in the smooth endoplasmic reticulum of the hepatocytes. Liver enzymes act in the smooth endoplasmic reticulum of the hepatocytes. The majority of CYP enzymes are found in the liver, but some are also present in the cell wall of the intestine. Mammalian CYPs are membrane bound to the endoplasmic reticulum. CYP 3A4, CYP 2D6 and CYP 2C9 are the main enzymes involved in the metabolism of drugs in humans. Metabolites produced by drug metabolism in the liver can have several kinds of activity. Detoxification refers to routes that produce inactive drug metabolites. Metabolites may exhibit similar activity to the parent drug, often with a different potency or duration of action to the parent drug. The metabolite can also have different activity to the parent drug, or a toxic metabolite may be produced.
Parenteral routes include topical, intradermal, subcutaneous, intramuscular, intravascular and inhalation administration. The main advantage of parenteral administration is the bypassing of first pass metabolism. Topical administration can involve administering a drug to the skin or to the eye via drops. The effects are local, slow and sustained. Intradermal administration involves administering drug in between dermis and epidermis skin layers. The drug is slowly absorbed via this route. Subcutaneous administration involves administering drug below the skin layer. The drug is absorbed faster, but the fat layer may trap lipid soluble compounds.
Massaging of the administration site increases blood flow and so drug absorption. Intramuscular administration produces very fast drug absorption. Physical activity or massage of the administration site increases absorption. Intravascular administration is mostly used when the concentration of the drug in the body must be accurately controlled, for example is the drug has a narrow margin of safety between therapeutic and toxic index. The disadvantage of this type of administration is that the injected drug cannot be recalled. Slow administration is required to avoid side effects. Inhalation administration of drugs can be via gas or aerosols. This route of administration causes rapid systemic effects but is dependent on the tidal volume and, if an aerosol, the size of the aerosol particle as smaller particles are more likely to reach alveolar ducts and sacs whereas larger particles will otherwise get stacked in bronchi.
Drug excretion and elimination
The main routes of drug elimination are via the kidneys, the hepatobiliary system and the lungs for volatile compounds such as general anaesthetics. Secondary routes of elimination include in the milk of lactating animals or in the sweat. Renal excretion is affected by filtration, secretion and reabsorption of compounds. Net renal filtration is therefore the sum of filtration and secretion minus reabsorption. Filtration is influenced by glomerular filtration rate and by plasma protein binding, and can be calculated by GFR x drug plasma free fraction. If renal excretion is greater than filtration, secretion of the drug must be taking place. If renal excretion is less than filtration excretion, then net reabsorption of the drug must be taking place. The pH of the urine has a strong influence on the renal excretion of drugs. As many drugs are weak acids or weak bases, the pH of the urine will affect the level of ionisation of the drug. This in turn affects the amount of drug that can be reabsorbed or secreted, as the drug must be in the neutral form to cross the membrane.
Drug interactions can be classified as pharmaceutical, pharmacokinetic or pharmacodynamics. The result can be the action of one or more drugs is enhanced, the development of new effects, one drug is inhibitory of another or there is no change in the effects of the combined drugs. Pharmaceutical interactions occur prior to administration, and are due to chemical or physical incompatibility or interaction between drugs. For example, sodium bicarbonate and calcium administered together forms a precipitate and diazepam will bind to plastic syringes.
Pharmacokinetic interactions occur when the tissue or plasma levels of one drug are altered by another. This may be due to altered absorption of a drug, such as a change in gastric pH, alteration in bacterial flora, competition for binding sites on plasma proteins or decreased gastric emptying. Excretion can also be effected, for example if a drug changes the pH of the urine. Some drugs also reduce circulation and therefore clearance and elimination, such as alpha-2 agonists. Metabolism of a drug may also be affected via enzyme inhibition or induction. Grapefruit juice is known to inhibit certain CYP enzymes, including CYP 1A2 and CYP3A4. This leads to higher plasma concentration of drugs that are metabolised by these liver enzymes. As an opposite example, some xenobiotics are known to increase expression of CYP3A family enzymes by binding to the pregnane X receptor (PXR). This is a transcription factor for the regulation of the CYP3A gene expression. Up-regulation of CYP3A family enzymes leads to increased metabolism of the drug. This can have adverse effects, such as inflammation of the liver. Pharmacodynamic interactions occur when the action of one drug is altered by a second drug. This occurs at receptor sites. If an agonist and an antagonist are administered, the effect will be negated, for example vitamin K and coumarin anticoagulant. A harmful effect may also be produced - for example if an alpha 2 antagonist is administered with an alpha 2 agonist. Synergistic effects are when drug combinations produce a therapeutic or toxic effect greater than the sum of each drug's action. Summation is the interaction between two drugs where each drug has an independent action in the absence of the other - for example, midazolam lowers the dose of propofol needed for anaesthesia. Potentiation interaction is between two drugs where each drug has no independent action in the absence of the other - for example probenacid reduces penicillin excretion in urine and increases its effects.
3. Quantitative pharmacokinetics Quantitative pharmacokinetics measures changes in plasma or tissue drug concentration with time. Usually the only measurements that can be taken are blood or urine concentration of a drug. Parameters can be used that relate the amount of drug in the body to the blood plasma or urine concentration.
Drug absorption rate
Drug absorption rate is the amount of drug absorbed from the administration site to the measurement site per unit of time. Absorption from bolus intravenous administration would be instant. Absorption rate from intravenous infusion or transdermal infusion follow zero order kinetics. This means that the absorption rate is independent of the amount of drug, i.e. the absorption rate equals the infusion rate.
Absorption rate from diffusion administration, such as oral and intramuscular, follow first order kinetics. This means that the absorption rate is proportional to the amount of drug given.
Drug elimination rate, clearance and volume of distribution
The drug elimination rate is the amount of parent drug eliminated from the body per unit of time. This is defined with respect to irreversible removal of the parent drug, and does not include metabolites. Volume of distribution (Vd) is the volume into which a drug appears to be distributed with a concentration equal to that of plasma. An alternative definition is that volume of distribution a proportionality constant relating the blood plasma concentration of a drug to the amount of drug in the body. An analogy to understand Vd is to think of a 10L fish tank into which 100g of a contaminant is dissolved. The volume of water in the tank is analogous to the volume of blood and interstitial fluid, i.e. the total body water. This is also described as the initial volume of distribution. The contaminant is analogous to a drug dose. Once the contaminant dissolves in the water, the concentration is 10mg/L. This would be the concentration of drug in blood immediately after IV bolus administration. However, some of the contaminant sticks to the glass of the fish tank and equilibrium of contaminant in solution and contaminant attached to glass is established. The concentration of the contaminant still in solution is now analogous to the concentration of drug in blood after distribution to tissue, whilst the contaminant stuck to the glass is analogous to the drug now residing in the body tissue. At a given time: The amount of a drug in the body = Vd x blood plasma concentration
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