09 HIGH ON LIFE

Absorption is the movement of drug from its site of administration into the circulation. Not only the fraction of the administered dose that gets absorbed, but also the rate of absorption is important.  Routes of drug administration and absorption of drugs (sr: Rang and Dale's Pharmacology) Except when given intravenous, the drug has to cross biological membranes. Other factors influencing absorption are: Aqueous solubility : Drugs given in the solid form must dissolve in aqueous biophase before they are absorbed. A drug given as watery solution is absorbed faster.  Concentration : Passive diffusion depends on concentration gradient : concentrated drug solution is absorbed faster. Area of absorbing surface : Larger it is, faster the absorption. Vascularity of the absorbing surface : Blood circulation removes drug from site of absorption and maintains concentration gradient. Route of administration : Main routes include oral, sublingual, rectal, topical application, inhalation,

The body is divided into different fluid compartments & each contribute to certain amount of body weight SOURCE : shuterstock.com - Among Extracellular fluid    a)Interstitial fluid      - 14L  (0.2% of BW) b)Blood plasma         - 3.5L (0.05 % of  BW) c)Lymph                    - 1.2 L (0.01% of BW) - Intracellular fluid      -  28 L (0.57% of BW) - Transcellular fluid     - 2.5L  (0.03% of BW) - Fat                             -         (20% of BW )     Drugs entering the body are distributed in these compartments. Keeping in mind of the plasma proteins only the drugs that are in free form are able to move between the compartments.      Lipid insoluble drugs are mainly confined plasma and interstitial fluids. Lipid soluble drugs reach all the compartments and may accumulate in fat  Apparent volume of distribution is defined as the volume that would contain the total body content of the drug at a concentration equal to that present in plasma concentration, Given by the formula

  In general, the metabolism of a drug decreases its therapeutic effect.  The majority of drugs are metabolized to increase their water solubility to allow elimination in urine or bile . However some drugs are metabolized into active compounds first before subsequent metabolism to inactive compounds and be excreted. Most drugs must pass through the liver, which is the primary site for drug metabolism . Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes. Metabolism is a biotransformation process, where endogenous and exogenous compounds are converted to more polar products to facilitate their elimination from the body. The process of metabolism is divided into 3 phases. Phase I metabolism involves functionalization reactions. Phase II drug metabolism is a conjugation reaction. Phase III refers to transporter-mediated e

Modulation of the cytochrome P450 system INHIBITION - Drugs inhibit the action of these enzymes and even the isoforms have an important role to play Eg : Quinidine is a potent competitive inhibitor of CYP2D6 and Ketoconazole is a non-competitive inhibitor of CYP3A4 INDUCTION - Some drugs increase the activity of these enzymes and the conjugating systems when administered repeatedly Eg: Rifampicin   Presystemic metabolism   Also called as the First pass effect . Drugs when administered orally undergoes circulation via the hepatic-portal vein from Gut wall to the Liver where part of the drugs are metabolized and only the remaining part of the drug enters the circulation. source: https://resources.time.leeds.ac.uk/ Disadvantages of First pass effect 1) Lower bioavailability  source:https://metastatictrialtalk.org/ 2) Higher drug dosage  source: https://www.shutterstock.com 3) Individual variation source: https://www.Dreamstime.com  Bioavailability and Bioequivalence Bioavailability is

   Drug permeation is defined as the process by which drug crosses the biological membrane. Broadly divided into -Transcellular and Paracellular. Mostly drugs use the transcellular pathway. Transcellular pathway is further divide into simple diffusion and facilitated diffusion. DIFFUSION is the process by which molecules move along the concentration gradient. Movement occurs through kinetic energy of the molecules. Since no energy is involved it is referred to as passive diffusion. Net rate of permeation = P * SA * ( Cu 1-  Cu 2) where P - permeability P (micrometer/min)           SA - surface area           ( Cu 1-  Cu 2) - concentration difference Major properties that affect the passive diffusion of a drug : Size, Lipophilicity and Charge These major factors such as size and lipophilicity is considered to play a major role in BBB . Blood brain barrier exists because of tight junctions between the endothelial wallls and the highly resistant glial cells surrounding them. Charge carr

Basic terms to get things into head :- Diffusion:-                      Typically a random motion of molecules the net movement takes place from a region of high concentration to a region of low concentration. Permeability coefficient :-  Number of molecules crossing the membrane per unit area in unit time. Partition coefficient   :- The measure of lipid solubility i.e. (hydrophobicity/lipophilicity) in a drug, a high partition coefficient substance states that it is more lipophilic. Non-polar molecules which freely occurs in the lipid membrane continuously diffuse across the cell-membrane ,the number of molecules diffusing through the membrane depends on permeability coefficient(P) and also on concentration gradient. Permeant molecules must be present within the membrane in sufficient numbers and must be mobile within the membrane if rapid permeation is to occur. Two physicochemical factors contribute to P, namely solubility in the membrane  and diffusivity , which is a measure of

Mostly drug exists as a weak acid or a weak base in the body. Since the body compartments are already having their own nature which is either acidic or basic, it will certainly have an impact on the drug reaches it. pKa of a drug is defined as the pH concentration at which they exist in 50% ionized and 50% unionized forms. The relationship between pH and pKa can be given by the Henderson- Hasselbach equation as follows,   ION TRAPPING    At a steady state concentration an acidic drug will be located more on the basic side of the membrane and a basic drug will be on the acidic side of the membrane.    IN DIFFERENT MEDIUMS      A cidic drugs are a bsorbed in a cidic medium Eg: Ibuprofen is an acidic drug with pKa 4.4 ,after oral administration it reaches the  Gastric juice where pH is 2.5 ,according to the formulae 79.43%  is unionized where absorption of the drug takes place, from where it enters the blood where pH is 7.4  and gets distributed through the body and finally excreted via