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DRUGS AND THERAPY - Coggle Diagram

- - - - is influenced by
        
        Size
        -solubility
        -charge
        -substrate
      - WAYS OF TRANSPORT ACROSS MEMBRANE
        
        CARIER MEDIATED TRANSPORT
        
        Solute carrier transporters- OAT AND OCT
        non selective
        expressed in liver and kidney
        can influence drug elimination( blood to urine)
        
        P GLYCOPROTEINS
        
        Transmembrane efflux pump.
        ABC transporters
        -influences uptake and efflux of range of drugs
        -Usually in epithelial cells with excretory roles-> bile canaliculi,renal,git,brain
    - - what does it refer to?
        
        Where the drug gets to in the body
      - DRUGS
        
        Large drugs -> confined to circulation
        
        Polar drugs-> dosent enter cells
        
        lipophillic-> enter cells
      - FACTORS AFFECTING DISTRIBUTION
        
        How easily it moves out of vasculature, binding to plasma proteins( DP depends on D). Binding to plasma protien is dep on cocn of protein and drug.+ affinity to target.
        
        How well its delivered to tissues(blood flow)
        
        How well it binds to tissue components
    - - RENAL CLEARANCE
        
        Glomerular filtration(+), Tubular secretion(+), Reabsorbtion(-)
      - METABOLISM
        
        Makes lipophillic drugs more water soluble so the drug is not reabsorbed
        
        ENZYMATIC METABOLISM OF DRUGS
        
        Phase 1 reactions- catabolic-> redox,hydrolysis(more water soluble)
        more active
        broad spectrum( many enzy-1 drug and vice versa)
        liver enzymes in er
        p450 cytochrome
        
        Sequential reaction- Paracetamol can form suphate conjugates or NAPQI-> can either conjugate(glutathione) again or hepatotoxicity.
        
        CYTOCHROME P450
        
        May differ in substrate binding effiecinecy, aa sequence and inhibitors.
        
        For enzyme reaction, it needs molecular o2,nadph,nadph-p450 reductase-> hydroxylated product
        
        caution-> enzymes can be saturated. influenced by drugs and genetics
        
        Phase 2 reactions-anabolic-> conjugation with another molecule(water soluble)
        pharamaco-> inactive
        less lipid soluble+ excreted via urine
      - BILIARY CLEARANCE OF DRUGS+ LUNGS(GASES+VOLATILE LIQUIDS+ MILK, SWEAT,SALIVA
- - - - AMES TEST- Liver extract and suspected mutagen is added to together then placed in his negative medium. Salmonella is added. If salmonella is mutated to produce his-> growth.
  - - - Limitation is that animal to human is not predictable ( rodent( 43)+non rodent(63))-> 71%in human toxicity.
- - - - 1) Natural
        
        From trees,animals
      - 2)Serendipity
        
        -Accidentally discovering new treatments from existing drug. ex. Viagra normally used for coronary artery dilation-> sexual activity
      - 3) Rational drug design
        
        ACE causes conversion of Angiotensin 1 to 2. Captopril was designed from venom which inhibhits ACE.
        
        Other: Exploit side effect. Only select the structure which causes the side effect
        
        QSAR - Use pharmacophore -. uses structures that give important activity.
      - 4) SCREENING OF CHEMICAL LIBRARIES
        
        Screen for 1200000 different compounds
        
        HTS SCREENING - Target exposed to various compounds to get match
    - - Primary Hit candidate
        
        confirm potency/selectivity.affinity
        
        Validated Hit candidate
        
        Inhibits/activates target, has drug like features-> aromatic ring and defined novel structure
        
        After this lead compound attained
- - - - Drug candidates
        
        Animal studies- safety and efficacy of drug, genotoxicity.
        
        IN VITRO (specific target)-> ACUTE IN VIVO(several different targets+ pharmacodynamics)-> CHRONIC IN VIVO(long term effects might be different)-> human(predictive value?)
        
        VERY GOOD
        
        organ functions
        
        LESS GOOD
        
        behavioural functions
        
        NOT GOOD
        
        side effects/toxicity
- - - - i) SNP
        
        if causes unstable gene-> reduced metab, altered substrate specificity -> other metabolites
      - ii) INDELS-polymorpshisms
        
        multiplication will increase enzyme activity
      - CYP2D6(25%)
        
        no gene-> poor metab, high drug conc, high risk of adverse effects
        
        dup gene-> ultra fast, no effect
      - CYP2C9
        
        Polymorphs here can cause problems when administering Warfarin. -> inter individual variability.