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Introduction To Pharmacology
#2 of 2
September 1999
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Last updated 04/10/00 12:26 PM

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Most drugs are lipid soluble and diffuse out of the kidney's tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space.  In order to minimize this reabsorption, drugs are modified by the body to be more polar using two types of reactions:  Phase I--Involve either the addition of hydroxyl groups or the removal of blocking groups from hydroxyl, carboxyl or amino groups, or Phase II--Use conjugation with sulfate, glycine, or glucoronic acid to increase drug polarity.  The conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen.
Glomerular filtration –125ml/min. It can’t filter large proteins.  Glomerular filtration happens in the kidneys.  Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus.  Free drug (not bound to albumin) flows through the capillary slits into Bowman's space as part of the glomerular filtrate.  The filtration rate (GFR = 125 ml/min) is normally about 20% of the renal plasma flow.  Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate.
Drug that was not transferred into the glomerular filtrate leaves the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule.  Secretion primarily occurs in the tubules by 2 energy-requiring active transport systems, one for anions (weak acids) and one for cations (weak bases).  These systems can transport many compounds so there may be competition between drugs for carriers.  Note:  Premature infants and neonates have incompletely developed tubular secretory mechanism and thus may retain certain drugs.  (Tubular secretion removes bound and free drug. Proximal tubules carrier systems are active transport and can saturate. Renal clearance is the sum of filtration and secretion.)
As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space.  The drug, if uncharged, may diffuse out of the nephric lumen back into the systemic circulation.  Manipulating the pH of the urine to increased the ionized form of the drug in the lumen may be used to minimize the amount of back diffusion and hence increase the clearance of the undesirable drug.  (In the venous blood of the nephrons – can be active or passive. Things are readily reabsorbed that have high lipid solubility and a large fraction of uncharged ions at urine pH and ionized form at plasma pH)
    Bile and fecal Enterohepatic circulation:  
Brody pg. 43.  Can have biliary elimination then GI tract reabsorption and return to systemic circulation.
in general, what factors affect clearance (e.g., blood flow to organ)
 (filtration, secretion, reabsorption; These are affected by drug (or metabolite solubility molecular size, binding affinity to plasma proteins, saturation of transporter mechanisms, etc…)
Brody pg. 43.  
    Rate of elimination:  
        Half life (t1/2):  
0.693 Vd/CLtotal    Elimination of a drug usually follows the first order of kinetics, and drops its concentration exponentially with time.  The half life is the amount of time needed to clear 1/2 of the drugs concentration.  (time it takes for [] to decrease to half the values it had at the start. It is dependent of clearance and Vd)
            Half Life Graphic.  Viewable Online.
    Flow dependent elimination:  
    Area under the curve (AUC): 
Brody pg. 53.  Plasma concentration over time: IV vs oral dosing and clearance. Will depend on the availability to systemic circulation. IV=CL=dose/AUC for oral=CL=F of dose/AUC where F = bioavailability See class notes for pictures of curves.
          Area Under The Curve Graphic.    Viewable Online.
        Plasma concentration over time:  
              Drug Concentrations Graphic.    Viewable Online.  Drug Concentrations Graphic.  Viewable Online.  Drug Concentrations.  Viewable Online.
    Volume of distribution (apparent):  
Vd – is a hypothetical volume of fluid into which a drug is disseminated. Can compare distribution of drug with volume of water compartment in body. Plasma – drugs with large molecular wts bind to plasma proteins and are too large to move out – approx 6% of body wt. ECF – drugs with low molecular wts but are hydrophilic can move through slits but can’t go through cell membranes. This is the sum of plasma water and interstitial fluid and is approx 20% of body wt. Total body water – low molecular wt and are hydrophobic will move freely – approx 60%

Drug dose and clinical response curves:  See class notes and this page for pictures of curves
    Graded dose-response relationships:  
Brody pg. 31.  
also termed effective dose [], is a measure of how much drug is required to elicit a given response. The lower the dose required for a given response, the more potent the drug. The affinity of the receptor for a drug is an important factor in determining the potency.
This is the maximal response produced by a rug. It depends on the number of drug-receptor complexes formed and the efficiency with which the activated receptor produces a cellular action.
    Quantal dose-effect curves:  
effective dose at which 50% of the patients responded positively
Therapeutic dose where 50% of subjects responded therapeutically to a dose
Lethal dose in animal studies where 50% of the animals died at that dose.
                Quantal Dose-Effect Curves Graphic.  Viewable Online.
        Therapeutic index (TI):  
this is the margin of safety of a drug. It is the range of [drug] needed to produce therapeutic response and one that produces toxic response. The closer this range the less safe the drug is.
            Therapeutic Index Curve.  Viewable Online.

Volume of distribution and clearance (revisited):  

Steady-state drug concentration:  Brody pg. 58.  This occurs when the rate of drug elimination is equal to the rate of administration. Steady state [] is inversely proportional to the clearance of the drug.
    Rate of infusion:  
The sole determinant of the rate that a drug approaches steady state is the half life or drug elimination and this rate is influenced by the factors that affect half life.
    Dosing intervals:  
The plasma concentration of a drug oscillates about a mean. Using smaller doses at shorter intervals reduces the amplitude of the swings of drug [ ].
    Half life (t1/2):  

Loading dose:  Brody pg. 60.  

Maintenance dose:  Brody pg. 60.  

Drug-drug interactions:  Brody pg. 77.  A change in magnitude or duration of pharmacological response on one drug because of the presence of another drug.
    Displacement from plasma protein binding affinity:  
The example of warfarin is given. This drug is highly bound to plasma proteins with a high binding affinity. The introduction of another drug such as an NSAID, which also has a very high binding affinity to albumin, will now compete with the warfarin for binding sites on the albumin. This in turn will increase the warfarin free [] in the plasma and will cause excessive protimes and INR’s since it is free not bound.
    Changes in pharmacokinetics:  

Age-dependent changes in pharmacokinetics:  
    Rates of metabolism and elimination:  
Brody pg. 81.  The very old and the very young have either impaired or underdeveloped methods of metabolism and elimination and dosing needs to be reduced accordingly.
    Volume of distribution:  
The following factors affect apparent volume of distribution.  How might your estimation of appropriate drug dose be affected by obesity, excessive tissue edema, or changes in muscle mass (e.g., elderly)?
        Total body water content:  
        Fatty tissue content and distribution:  

Allergic reactions:  Brody pg. 80.  Is a hypersensitization or an undesirable immunological response with drugs acting as antigens.
    Immune responses:  
Type I –Immediate or anaphylactoid reaction: IgE antibodies produced by drugs binding to surface of mast cells and basophils. They cause a release of histamine, leukotriennes, serotonin, and prostaglandins which trigger rapid immune reactions and cause bronchial constriction, cap dilatation, urticaria and anaphyl. Shock if severe. Type II – cytotoxic or autoimmune response – IgG and IgM antibodies and complement bind to proteins on vascular cell, RBC or WBC or plt surface results in cytolysis and cell death. Type III – immune complex-mediated reaction – antigen-antibody complexes interact with and are deposited in tissues like vascular endothelium or cell membranes promoting acute inflam reaction, serum sickness, arteritis, urticaria, granulocytopenia. Type IV – cell-mediated response – delayed. T-lymphocytes, macrophages and neutrophils occurring on skin combines with skin proteins and cause local inflammation. Halothane induced hepatitis is an example.
Reaction by a patient who is more sensitive to a drug (mostly relating to its side effects) then the general patient population.

Idiosyncratic reactivity:  Reaction by a patient who exhibits an unexpected or unusual response. Most often they are caused by genetic differences in drug metabolism or an immune response

Developed tolerance:  After repeated dosed of a drug there may develop a state in which the magnitude of response is decreased by subsequent drug doses of the same size as the initial dose.  This dampened response is called tolerance.  Some types of tolerance may be the result of changes in the concentration of drug at the receptor site and evolve from pharmacokinetic considerations.  Brody pg 32

Tachyphylaxis:  Tolerance manifest by rapid repeated drug administration.  (Loss of response in an organ after repeated exposure to an agonist.)

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