Please enable JavaScript.

Coggle requires JavaScript to display documents.

Pharmacokinetics - Coggle Diagram

- - - - OS
        
        Hepatic first pass effect
        
        Much more limited in other routes
        
        Sub-lingual
        
        Rectal
        
        Inhalation
        
        Drug concentration is strongly influenced by the chosen route of administration
      - IV
        
        Directly in the bloodstream
      - Other routes focus on delivering the drug to specific sites
        
        Intra thecal = CNS
        
        Ocular and nasal
  - - - Can occur through:
        
        Carriers
        
        ex. L-DOPA
        
        Passive diffusion
        
        Depends on the chemical characteristics of the drug + district
        
        Size + MW
        
        Permeability
        
        Partition coefficient: log P = log (concentration in organic phase/ concentration in aqueous phase)
        
        Solubility in biological fluids
        
        Ionization state (depends on pH of district)
      - As a general principle, small uncharged molecules and gases can easily cross membranes, while large polar/charged molecules + ions require transporters
  - - - pH of district
      - Binding to plasma proteins
        
        Most abundant
        
        alfa-1 globulin
        
        basic drugs
        
        Albumin
        
        Acid + neutral drugs
        
        Lipophilic pocket to bind lipophilic drugs, and make them able to circulate in the bloodstream
        
        Quantity changes based on age, pregnancy, hormonal changes, liver diseases
        
        Different drugs/drugs and endogenous molecules can compete for binding
        
        Creates a deposit/reservoir of drug
        
        Increased half-life due to reduced metabolism
      - Ability to cross through biological membranes, each with distinct anatomical characteristics
        
        BBB
        
        P-glycoprotein for drug extrusion
        
        Placenta
    - - Therorical volume required to contain the whole dose of drug (Q) at the same concentration of that registered in the plasma (Cp) at the point of equilibrium
        
        VD = Q/Cp
      - Apparent volume, as it reflects the drug distribution and accumulation in the specific districts. Indeed, it assumes the concentration in the body is the same as in the plasma (C = Cp), but this is not always the case
        
        ex. Chloroquine has VD=13.000 l
  - - - Liver
      - Intestine
      - Kidneys
      - Lungs
    - - Phase 1: functionalization
        
        Makes the drug more hydrophilic
        
        CYP450
        
        Monooxygenase: catalyzes the incorporation of 1 atom of oxygen in the form of an alcohol group
      - Phase 2: conjugation
        
        Increases MW of drug
    - - Age
      - Sex
      - Enzyme polymorphisms
        
        People of Asian ethnicity commonly have a ALDH variant which makes the enzyme less active, leading to accumulation of acetaldehyde and enhanced sensitivity to alcohol
      - Hormones
      - Inflammation
      - Drug-drug/food/supplements/medical conditions interactions
        
        Examples
        
        Felodipine and grapefruit
        
        Inhibition of CYP450 activity leads to -45% metabolism of felodipine (anti-hypertensive drug), which leads to a more sustained and intense pharmacological response, leading to a strong reduction in BP
        
        L-DOPA and other amino acids for BBB/intestine crossing through transporters
        
        EtOH impairing cofactors (ex. vitamins B1, B6, B12) absorption in the GI tract
        
        Lack of B12 and B16 (involved in Met cycle, fundamental for many processed like DNA synthesis, epigenetic modifications, folate metabolism)
        
        Death of peripheral neurons, causing weakness, pain and reduced sensitivity
        
        Lack of B1
        
        Wernicke-Korsakoff Syndrome
        
        Cognitive dysfunction due to brain atrophy
        
        Can result in:
        
        Reduced metabolism = toxicity
        
        Enhanced metabolism = failure of therapy
      - Hormonal imbalances
      - Microbiota
    - - ex. Cocaine + EtOH = cocaethylene
        
        Higher cardiac toxicity compared to cocaine, leading to enhanced risk of stroke
      - ex. Acetaldehyde formation during EtOH metabolism
        
        Acetaldehyde + ROS production (by CYP450) + reduction in SAMe + increase in homoCys = ER stress
        
        In the liver, this inhibits AMPK, eventually leading to a reduction in the export of oxidized lipids, and an increase in lipogenesis
        
        Fatty liver disease
      - ex. EtOH + DA = salsolinol
        
        Can bind to MOR, inhibiting GABAergic interneurons in VTA and increasing DA levels
        
        Help explain the addictive effect of alcohol
      - ex. production of acetate from EtOH which, although not as toxic as acetaldehyde, can be used by HAT for epigenetic modification, leading to stable changes in gene expression
  - - - Kidneys, through urine
        
        Kidney excretion
        
        Glomerular filtration + secretion in the distal + proximal tube + re-absorption in the tube
        
        Only drugs which are unbound to plasma proteins can be excreted
        
        Quantified by clearance (Cl)
        
        Rate at which a solute is permanently eliminated from the organism, and the plasma is purified from it
        
        To follow the plasmatic concentration, we can use the half-life (T1/2)
        
        After 5 T1/2, Cp<5% Ci, so the effects of the drugs on the body are negligible
        
        Important to determine the intervals between doses and the duration of therapeutic benefit
        
        It's a constant and it's the product Cl=VD*Ke
        
        Ke = constant of elimination
        
        Depends on the characteristics of the drug + patient
      - Hepatic-biliary system, through feces
      - Lungs, through exhalation
      - Body fluids (sweat, tears, saliva, breast milk)
    - - ABC transporters
        
        P-glycoprotein/MDR
        
        Extrusion of a wide range of chemically dissimilar drugs, mostly large and hydrophobic