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General Pharmacology (Pharmacokinetics (Factors affecting Drug Absorption,…

- - - - Liquid > Solid
      - Lipid Soluble > water soluble
      - Ionised > Unionised
      - smaller is better
      - Disintegration and Dissolution time
      - Calcium reduces tetracycline absorption
    - - :pill:-insulin degraded in the stomach
        -gentamicin - highly polar and ionises in solution, so can't take enterally
    - - heparin (Strongly acidic)
        Aminoglycosides (Strongly basic)
        -remain ionised and are poorly absorbed
        :pill: heparin is the anti-coagulant used for pregnant woman cause it doesnt cross the placenta
    - - 1.milk decreases tetracycline absorption
        2.fatty meal increases griseofulvin absorption
    - - Gastroenteritis
        
        increased peristaltic movement - less absorption
      - Achlorhydria
        
        reduces iron absorption
      - Congestive Cardiac failure
        
        oedema in gastric mucosa - reduced absorption
  - - - aVd = 14-16L
        gentamicin
        distributed in ECF
      - aVd = 42L(TBW)
        ethanol (small water soluble molecules)
        distributed in total body water
      - aVd > TBW
        Chloroquine , digoxin
        accumulate in tissues.
        hemodialysis not useful to flush out the drug if overdosed
    - - highly lipid soluble drugs
        first go to areas with high blood supply and then get redistributed to areas of low blood supply
        example -- :pill:thiopentane (short duration general anesthetic)
        goes to the brain first and then redistributes into muscle, adipose tissue , etc.
        duration of action = 5-10 mins
    - - tetracyclines - bones and teeth
      - Chloroquine - liver and retina
    - - Blood-Brain Barrier
        Lipid soluble and unionised cross it
        --barbiturates, diazepam
        Lipid insoluble dont cross
        --dopamine
      - Placental Barrier
        stuff that crosses
        -- morphine , anaesthetics
        High molecular weight don't cross
        --insulin
    - - Acidic Drugs -- Albumin
        Basic Drugs -- a1 aminoglycoprotein
      - 1.difficult to remove incase of poisoning
        2.longer duration of action
        3.low aVd
        
        can cause displacement reactions
  - - - 1.Active drug to Inactive metabolite
        --Phenytoin to p-Hydroxyphenytoin
      - 2.Active drug to Active metabolite
        -- Codeine to Morphine
      - 3.Inactive drug to Active metabolite
        --Levodopa to Dopamine
    - - drugs need to be made water soluble so that they may be excreted and to inactivate it
        
        Phase 1
        
        Cytochrome P450
        ---CYP3A4 or CYP3A5
        metabolise 50% of the drugs
        
        non-synthetic
        they make small changes like adding small polar groups to make it more water soluble
        
        1.Oxidation -- Phenytoin
        2.Reduction -- Chloramphenicol
        3.Hydrolysis -- Lignocaine
        4.Cyclisation
        5.Decyclisation -- Phenytoin
        
        Phase 2
        
        conjugation with .... :question: to make it inactive and more water soluble
        
        Glucoronidation -- Aspirin, Morphine
        Acetylation -- Isoniazid
        Sulphation -- Paracetamol
        Methylation -- Adrenaline
        ....
        
        example -- Glucoronic acid has a lot of -OH groups and makes the metabolite water soluble
        
        Drugs can undergo only phase 1 or Phase 2 and if both phase 2 first also
        
        examples:
        Isoniazid -- Phase 2 first then Phase 1 reaction
      - missing
        microsomal and non-microsomal enzymes
        Hoffman Elimination
        understanding of phase 1 and phase 2
    - - Bioavailability -- Levodopa
      - to prolong Duration of action
        esters of phenothiazine(fluphenazine) have a longer duration of action than phenothiazine
      - Taste
        == Clindamycin is bitter but Clindamycin Palmitate is better
      - Site-Specific Drug delivery
        == Methanamine becomes Formaldehyde ( on exposure to acidic pH of urine ) ----- acts as antiseptic
    - - Rifampicin and Oral Contraceptives
      - Carbamazepine == autoinduction
      - Paracetamol and Alcohol
        -- hepatotoxicity ( toxic metabolite of paracetamol is produced more)
      - :+1::skin-tone-4: Phenobarbitone in Neonatal jaundice
        it induces glucuronyl transferase and jaundice is resolved
      - Repeated administration of certain drugs increase the production of microsomal enzymes
  - - - pH of Urine
        in passive reabsorption
        
        Salicylate (weak acid)
        is not reabsorbed as it remains unionised in acidic urine
        :pill: sodium bicarbonate makes urine basic and salicylate is excreted.. given incase of toxicity
        
        Morphine(weak base)
        remains ionized in urine normally and does not get reabsorbed
        :pill: vitamin C (ascorbic acid) will make the urine acidic and help in excretion of weak bases if the urine is alkaline
      - In Active tubular secretion
        
        probenecid :red_cross: penicillins
        competitive inhibition for active transporters
        increases duration of action of penicillins
        in the treatment of gonoccal infections, etc
      - Milk has an acidic pH
        basic drugs = morphine, chloramphenicol
        may affect the baby
    - - Steady State Concentration
        
        if drug is administered in sync with the T1/2 of a drug
        in 4-5 half-lifes the plasma conc. will reach a steady state
        amount of drug administered = amount of drug eliminated( in the dosing interval)
      - Plasma Half-Life
      - Clearence
        
        First order kinetics - almost all drugs , ethanol, omeprazole
        at equal intervals of time half the drug is eliminated
        
        Zero order kinetics -- warfarin, heparin
        at equal intervals of time same amount of drug is eliminated
        
        Mixed order kinetics - phenytoin ,aspirin
        low doses - first order kinetics
        high doses - zero order kinetics
        saturation kinetics , elimination processes get saturated at high plasma conc.
        
        volume of drug excreted in unit time
    - - Loading Dose
        
        lignocaine in ventricular arrhythmias after MI
        -- given in emergencies
      - Maintenance Dose
        
        repeated at fixed intervals to maintain target levels in plasma
      - Fixed Dose Combination
        2 or more drugs in a fixed ratio
        
        Levodopa+Carbidopa - parkinsonism
        Isoniazid+rifampicin+pyrazinamide - tuberculosis
        oestrogen + progesterone - oral contraceptives
        
        learn advantages and disadvantages :!!:
      - Therapeutic Drug Monitoring :star:
        
        Indicated in :
        
        lithium, phenytoin - narrow therapeutic index
        2.tricyclic antidepressants - wide interindividual variations
        
        aminoglycosides in renal failure - get toxic at higher conc.
        
        :question: Not required in :
        1.antihypertensives , anti diabetic agents, anticoagulants
        2.opiods - body develops tolerance
        
        omeprazole -- its affect lasts even after its cleared
      - Methods to Prolong duration of action
        
        Oral
        
        Sustained Release Preparation
        diclofenac - 12hours , sustained release diclofenac -24hours
        
        Parenteral
        
        adrenalline
        vasoconstrictor = reduced permeability = decreased excretion
        added to local anaesthetic to keep the area numb longer
        
        procaine/benzathine in penicillin G
        adding a water-insoluble compound
        
        protamine zinc insulin
        by complexing it with a protein
        
        Norplant , transdermal patch
        
        sulphadiazine - weak protein binding - 6 hours
        sulphadoxine - strong protein binding - 1 week
        
        inhibing drug metabolism
        delaying renal excretion
- - - - By physical action
        
        Osmosis
        20% mannitol in cerebral oedema
        
        Adsorption
        acitvated charcoal in poisoning
        
        Demulcent
        cough syrup soothes the larynx by coating it
        
        Radioactivity
        Iodine 131 in hyperthyroidism