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Pharmacology (Nature of drugs (Physical properties: Solid: aspirin,…

- - - - Vd :smiley: Volume of distribution
        
        Amount of drug in body (DosexF)/ Plasma drug concentration
        
        Lipophillic drug distributes well to tissues, therefore large Vd
        
        Drug bound to plasma protein but not tissue protein", small Vd**
        
        Drug highly bound to tissue protein, large Vd
        
        Used in Dose adjustment
      - Free fraction :smiley:
        
        Free/unbound drugs needed to:
        
        Cross biological membrane
        
        Bind to receptor
        
        Undergo elimination
        
        Ratio of concentration of unbound drug to total (0-1)
        
        Affects Volume of distribution
        
        Affects half-life
        
        Affects clearance
      - Factors affecting drug distribution
        
        1. Physico-chemical properties of drug
        
        2. pH differences of biological fluids Difference of pH between ECF and ICF will matter
        
        3. Blood flow through organs Greater distribution to organ with a greater proportion of cardiac output
        
        4. Drug transporter PGP in BBB
        
        5. Extent of drug-plasma protein binding
        Only unbound drug diffuse into interstitial fluid
        
        6. Concentration of drug-binding protein
        Drug causes liver disease, albumin drops, increase unbound, increase drug effects
        
        7. Binding inhibitors
        Displaces a drug from binding site, alter conformation of binding site
    - - Types of metabolism
        
        Inactive --> Active
        
        Active --> Active
        
        Active --> Reactive
        
        Active --> Inactive
      - Major drug biotransformation reaction
        
        Phase I
        
        Oxidation, Hydroxylation, Hydrolysis
        
        Phase II
        
        Conjugation with glucorinic acid, sulphate, glutathione
        
        Conjugation with acidic group to make it more water soluble
      - Drug metabolising enzymes
        
        Microsomal Mixed Function Oxidase (MFO)
        
        Cytochrome P450 :smiley:
        
        Abundant in intestine and liver
        
        CYP3A4 the most abundant form , metabolise most of the drugs
        
        Non-specific (many iso forms) can target many drugs
        
        Different people different variation in activity
        
        May exhibit genetic polymorphism
      - Relationship between rate of drug metabolism and drug concentration
        
        V: Rate of drug biotransformation reaction
        
        [S] substrate concentration
        
        Vmax maximal rate of drug biotransformation reaction
        
        Km substrate concentration where it is at Vmax
        
        FIRST ORDER KINETICS :smiley:
        
        Rate of metabolism proportional to drug concentration
        
        Same half life
        
        Capacity limited kinetics :smiley:
        
        At upper therapeutic concentration, half life changes
        
        First order changing to zero
        
        Enzymes become limited
        
        CURVE NO LONGER STRAIGHT :warning:
      - Factors affecting metabolism
        
        Pharmacological factor: enzyme inhibition/induction
        
        Pharmacogenetic factor
        
        Age
        
        Liver disease / Renal disease
        
        Increase protein synthesis or enzyme will lead to increase in Vmax, via transcription factor
        
        Examples will be some food and some drugs phenytoin, carbamazepine, rifampicin
        
        EITHER: Decrease concentration of parent drug, decrease effect
        
        OR: Increase concentration of toxic metabolite increase toxicity
        
        Decrease protein synthesis or enzyme lead to decrease in Vmax
        
        Increase parent drug, increase effect/cause toxicity
    - - Renal excretion
        
        Polar metabolites of non-polar drugs
        
        Mechanism
        
        GFR
        
        Depends on:
        
        Protein binding
        
        Molecular size
        
        Number of functional nephrons
        
        Tubular re-absorption
        
        Depends on pH, aim is to get the ionised form to stop reabsorption
        
        Active secretion
        
        In Proximal Tubule
        
        Depends on:
        
        Affinity of drug for transport protein
        
        rate of delivery to secretory site
        
        Rate of transfer of drug across tubular membrane
        
        2 types of pumps: Acid and Basic
        
        Creatinine clearance :smiley:
        
        120ml/min
        
        100% unbound, only GFR involved
        
        Adjusting Urine pH to alter excretion rate
        
        Etc. Poisoning of acidic drug
        
        Prescribe sodium bicarbonate to make urine pH more alkaline and this will increase excretion
        
        Only if it satisfy these criteria:
        
        Unchanged via renal clearance (means not metabolised by liver)
        
        Relatively small Vd (in plasma component to be filtered)
        
        pKa sensitive enough
        
        High urine flow rate, reduce concentration, reduce reabsorption
        
        When renal function decreases, K elimination constant decreases, half life increases :smiley:
    - - Parameters
        
        Ka = RATE of absorption :smiley: Fraction of drug absorbed into systemic circulation
        
        Can use Ka to tell Cmax and Tmax
        
        Tmax opposite of Ka :smiley:
        Cmax same as Ka
        
        F = Extent of absorption :smiley: Fraction of unchanged drug into systemic circulation from a particular dose
        
        Fraction so it is 0-1
        
        Reflected by the AREA UNDER THE CURVE
        
        Always compare AUC with IV
        
        BIOEQUIVALENCE :smiley: When 2 products of the same drug have less than 20% difference in total AUC and Cmax
        
        Trapezoidal rule
        
        Tmax does not change with F :smiley:
        C max increases with F
      - Absorption mainy in small intestine
        
        Mechanism of drug transfer
        
        Passive diffusion
        Dependent on:
        
        Lipid solubility
        
        Molecular weight
        
        Degree of ionisation (favours un-ionized form)
        
        Facilitated diffusion (uses a transporter)
        
        Active transport
        
        One example will be efflux transporter: p-glycoprotein (PGP) Present in cancer cells and the gut lumen
        
        Decreases Cmax and F
        
        Another enzyme linked to PGP is CYP3A4 enzyme, it metabolises drugs in the epithelial cell and prevent absorption
        
        Decreases Cmax and F
        
        First pass effect :smiley:
        
        Loss of orally administered drug at various sites (mainly small intestine and liver) prior to reaching systemic circulation
        
        Due to GIT - Poor absorption, PGP and CYP3A4
        
        Due to Liver
        
        Due to stomach flora
        
        Factors affecting absorption
        
        1. Drug factors
        
        Physico-chemical properties
        
        Type of dosage form
        
        2. Physiological and patient factor
        
        pH of GI fluids
        
        Gastric emptying rate
        
        GIT motility (high rate, absorption poor)
        
        Difference in first pass effect
        
        Blood flow rate
        
        Disease state
        
        3. Food and drug interaction
        
        Usually food decreases absorption (but some may increase, proponalol)
        
        Formation of complexes, cannot pass cell membrane too big
        
        Any drugs that changes GIT motility
    - - Total Drug Clearance :smiley: sum of clearance by all routes (lungs, liver, kidney)
        TDC is inverse to AUC
      - Hepatic Excretion Rate :smiley:
        
        (Drug concentration going in liver - going out) / Drug concentration going in
        
        Ratio 0-1, 0 being non eliminated, 1 being all
        
        Hepatic Drug Clearance :smiley:
        
        Hepatic elimination rate/plasma concentration
        
        Hepatic high ER drugs = Flow rate dependent
        
        Hepatic low ER drugs = metabolism capacity dependent
      - K Elimination rate constant :smiley:
        Fraction of drug in body removed per unit time
        95% in 5 half-lives
        99% in 7 half-lives
        Rate constant higher, half-life lower
  - - - Derive Tmax, Thalf
      - Derive C max
      - Service Vd
      - Bioavailibity
      - Onset :smiley:
        
        Time to reach MEC
      - Intensity :smiley:
        
        Cmax minus MEC
      - Duration :smiley:
        
        Time when PDC is above MEC
  - - - Single IV Injection
        
        No steady state concentration
        
        Peak plasma at T=0
        
        Normally it is one straight line but sometimes may have 2 lines
        
        Alpha phase - Distribution: Movement of drug across membranes
        
        Beta phase - Elimination Slower decline due to metabolism and excretion
      - Single Oral dose
        
        Peak is not at T=0
        
        Parameters:
        
        Cmax
        
        Tmax
        
        MEC
        
        Onset
        
        Duration
        
        Intensity
        
        Cmax: Rate of absorption = Rate of excretion :smiley:
      - Multiple Oral dose
        
        Drug accumulation
        
        Eventual steady state plasma concentration
        
        Peak and trough concentration fluctuation around Css (average concentration)
        
        Factors affecting graph
        
        Decreasing dosing interval:
        
        NO CHANGE in half-lives
        
        Increase in steady state concentration
        
        Decreasing dose:
        
        No change in half lives
        
        Decrease in steady state concentration
- - - - Derive potency
      - Derive EC50 :smiley:
        
        Drug concentration at which 50% of Emax is reached
      - Derive MEC :smiley:
        
        Minimum dose at which effect is significant
    - - Partial or Full
  - - - Agonist
        
        Full
        
        Partial
        
        Inverse
      - Antagonist
        
        Has Affinity but NO EFFICACY
        
        Pharmacological
        
        Chemical
        
        Physiological
    - - Interacts mostly with macromolecules
      - Enzymes have an active site
        
        Relative specificity confers to selectivity
        
        Example: Atenolol and propranolol
        Atenolol is beta 1 specific but propranolol is not, so atenolol may be used to avoid asthma side effects
        
        Lock and key model
        
        Induced fit model
        
        Receptor shapes changes after ligand binds to it
      - Types of drug-receptor interaction
        
        Non-Covalent
        
        MOST DRUG USES THIS
        So that the bond is reversible
        
        There are strict structural requirements because interacting groups must come very close to one another
        
        Ionic interaction
        
        Hydrogen bonding
        
        Van der Wal forces
        
        Hydrophobic interaction
        
        Covalent
        
        High energy bonds
        Example: irreversible MAO inhibitors and organophosphate anticholinerase :warning:
        
        Spatial arrangement (stereoisomers) changes the properties
        
        Example : Thalidomide Anti-nausea drug, S isomer interferes with baby development during pregnancy :warning:
    - - Types of Receptor-effector linkage
        
        Ligand-gated ion channels
        
        Ion enter the cell
        
        Example: nicotinic
        
        Super fast reaction time, (example muscles)
        
        GPCR
        
        Example: muscarinic
        
        G protein then trigger secondary effect
        
        fast
        
        Kinase-linked receptors
        
        Several hours
        
        Example: Cytokines
        
        Nuclear receptors
      - Receptor and diseases
        
        Autoantibodies
        
        Mutations in encoding receptor, affecting signal transduction
      - Law of mass action - Rate of chemical reaction is proportional to concentration of reacting substance
        
        Affinity :smiley: occupation
        
        Measured by Kd (Concentration value where binding is 50%t), stronger the affinity, the lower the Kd
        
        In the case of one-to-one mapping of activation and coupling to response, Kd = EC50
        
        SPARE RECEPTOR RESERVE THEORY :smiley:
        
        In the presence of antagonist, when there are so many antagonist present, the last few receptor present will compete, this is the point where EC50=Kd
        
        Efficacy :smiley: activation of downstream action
    - - Graded response
        
        Response that varies in magnitude in a dose-dependent manner
      - Potency :smiley:
        
        Amount of drug needed to produce a given effect, usually use EC50 to compare
        
        Higher potency shift left, Lower potency shift right
      - Efficacy :smiley:
        
        Use Emax to compare
        
        Higher efficacy, higher Emax
    - - Response is taken by the number of people that has therapeutic/lethal outcome "All-or-non"
      - ED50 :smiley:
      - LD50 :smiley:
      - TD50 :smiley:
    - - "clockwise": Response decreases as dosage increase
        
        Usually caused by tolerance development of drug
      - "anticlockwise": Response increases as dosage increase
        
        Usually caused by sensitisation of drug
- - - - Pharmacological actions of drugs
        
        Dose related
        
        Example
        
        Sedation Anti-anxiety
        
        Hypoglycemia Insulin
        
        Bleeding Anticoagulant, anti platelet
        
        Tremor beta agonist salbutamol
        
        Respiratory depression morphine
        
        Ototoxic Toxic to sensory cells of the ear
        
        Nephrotoxicity
  - - - Idiosyncratic (linked to genetic anomalies)
      - Immunological
        
        Prior exposure, may be delayed after onset
        
        Type I: IgE mediated
        
        Type II: Drugs bind to cells, making them foreign looking, antibody attacks
        
        EXAMPLE: Thrombocytopenia:fire:
        
        Carbamazepine
        
        Ticlopedine
        
        EXAMPLE: Agranulocytosis (granulocytes disappear), neutropenia :fire:
        
        Carbamazepine
        
        Phenytoin
        
        Ganciclovir
        
        Carbimazole
        
        Type III: Reaction due to elevated antibody-antigen complexes
        
        EXAMPLE: Stevens-Johnson syndrome / Toxic epidermal necrosis :fire:
        
        Carbamazepine
        
        sulphonamides
        
        Type IV: T cells involved