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Half life

 

Initial Drug conc. ---------- 50% or ½ drug conc.----------- 25% or 1/4 drug conc

  • Time to half the dose of drug though elimination process or the attain steady state
  • Assume single compartment body

t1/2 = 0.7 X Vd/Cl

Drug Accumulation

  • Dose repeated before 4 half lives
    Accumulation = 1/ fraction lost or 1/ 1- fraction remaining
  • Steady state/time following first dose

Bioavailability

  • Amount of drug (unchanged) reaching systemic circulation
  • ∆: - ACU
  • I/V – 100% Bioavailability
  • Oral – ≤ 100%

1st pass metabolism

  • Extraction Ratio = ClearanceLIVER / Q (Hepatic blood flow)
  • Systemic Bioavailability (F) = f (1 – ER)

f = extent of absorption

ER = extraction ratio

 

Time Course of Drug Effect

  1. Immediate Effect
    1. If even after 7 t1/2 the conc. Of drug remains more than E50 than once a daily dose
    2. Effect is immediate & not related to plasma conc. (E.g. Enalapril)
  2. Delayed Effect
    1. Distribution time required by drug to reach sit of action
    2. E.g. Warfarin
  3. Cumulative Effect
    1. Aminoglycoside toxicity – due to continuous infusion rather intermittent dose (more peak conc. Hence more penetration causes early saturation)
    2. Anticancer drugs – extent upto will bound to DNA

Rationale of dosage regime

  1. To produce target conc.--- 1. Maintenance dose, 2 Loading dose
  2.  To replace the cleared drug from body

Maintenance dose:

Rate given = Rate eliminated

  • Dosing rate = clearance / Dose given × Target.Conc.
  • Dosing Rate (oral) = Dosing Rate/ F (systemic bioavailability)
  • Intermittent dose = Dosing Rate (oral) x dosing interval

Loading Dose

-         For long t1/2 drug – take time to reach steady state

  • Prompt dosing (LD) – conc. To Target Concentration

-         LD = Vd × Accumulation factor

  • Useful to attain steady state for drug with long t1/2

  

 

Elimination of drug: -

  • Metabolism – Enzymatic conversion of drug (Change)
  • Excretion – Removal as unchanged form

 

     

 

 

PHASE I Rx

-         Catabolic Reaction

-         Exposure of functional group / functionalization

  • Paradoxically: - More reactive / toxic/ Carcinogenic chemical from

e.g   Oxidation                  e.g. Pethidine

        Reduction                         Morphine

        Hydrolysis                        Enalapril

 

PHASE II Rx

-         Anabolic Reaction (May occur extra hepatic)

-         Addition of new functional group / Conjugation

  • Results in Inactive / less reaction product
  • / Decrease lipid solubility - Increase / Renal excretion

e.g

  • Glucoronidation By UDP-GA
  • Sulfation
  • Methyl/ Ethylation             Methyl                   S.Adenosine methionine
     
                                           Acetyl                   Acetyl CoA
  • Glutathione

CYP 450 enzyme

  1. K/S Microsomal enzyme (Smooth endoplasmic reticulum breaks into microsome on centrifugation)
  2. Stereo selective in nature (e.g. Warfarin, sotalol, cyclophosphamide)
  3. Lipophilic drug are not excreted by kidney because of tubular reabsorption

Nature

-         Haem proteins

-         CYP Superfamily denoted by Alphabets

  • CYP 1 A 1, 1A2, 2E1 etc.
  1. Differ in Amino acid sequence
  2. Substrate Specificity (Some have overlapping specificity)
  3. Regulation / Induction.

 


 

* Also known as CYP 450: - As Fe3+ Fe2+ gives peak at 450nm (but there is evident CYP 448 also)

* Biological Variation in P450Genetic polymorphism / pharmacogenomics

E.g. Isoniazid metabolism is by Fast & slow acetylators

 

Inhibition of CYP 450

  • Competitive Inhibition: - quinidine for CYPD6 (Substrate like)
  • Non Competitive Inhibition: - Ketoconazole covalently Bind with Fe3+ of CYP3A4

      ↓

In reversible fashion (covalent binding)

      ↓

CYP Regenerates after sometime


Suicide Inhibition

  1. Aspirin – COX 1 and 2
  2. Penicillin – Transpeptidase
  3. Sulbactam – lactamase
  4. Allopurinol – Xanthine Oxidase
  5. Gestodene – CYP3A4
  6. Diethylcarbamate – CYP2E1
  1. Furafylline – CYP1A2

                    ↓

In irreversible fashion (Covalent binding)

                    ↓

CYP Degenerates

 

Non P-450 Phase I Rx

  • Alcohol – Alcohol Dehydrogenase (cytoplasmic enzyme)
  • 6-Mercaptopurine – xanthine oxidase


P450 Induction

Formation of CYP450 enzyme by intranuclear Receptors (gene induction)


e.g. Rifampicin/ Ethanol / Carbamazepine

  • Poly Aromatic Hydrocarbons
  • Smoking  
  • May Cause: -       1 OCP failure
    2 PCM toxicity metabolite is toxic

First Pass Metabolism

  • Also known as pre-systemic metabolism:-
  • Bioavailability
    Marked individual variation   Disadvantageous
    dose need to be given

e.g. Calculated as Extraction Ratio

  1. Extraction Ratio = C.A – C.V/C.A

C Drug conc. In Portal vein

A arterial

V venous

  1. Clearance= Q × ER (Q- Hepatic blood flow)

Making things more Complex

E.R Also depends on * Bound / unbound fraction

                        * Intrinsic capacity of liver (CL)

  1. Extraction Ratio = ClearanceLIVER / Q (Hepatic blood flow) x Unbound Drug Fraction

Flow limited Clearance

Capacity limited Clearance

  • E.R = Cl/Q
  • When Q is limited than E.R approaches 100%               
  • Liver clearance capacity is large
  • Only factor which                limit is hepatic blood flow       
  • Drugs are: - Morphine, Lidocaine, Propanol
  • E.R = Cl/ Q
  • When Cl Hepatic intrinsic clearance capacity Q is limited rather blood flow
  • Removal of these drugs will greatly hampered by hepatic disease
  • Drugs are: - Phenytoin, Warfarin, Quinidine

 

*Third Determinant is Bound / Unbound Drug Present in portal vein

*Highly bound drug- Less clearance / Less extraction from lever.

 

Drugs with extensive 1st Pass Metabolism

(V.P Singh not a popular P.M)

 

  • Verapamil
  • Propanalol
  • Salbutamol
  • Nitroglycerine
  • Amitriptyline
  • Propoxyfene
  • Pethidine
  • Methylestosterone





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