Bio-Pharmaceutics & Pharmacokinetics revision

 

Biopharmaceutics is the study of the relation of physical & chemical properties of a drug to its bioavailability, pharmacokinetics, pharmacodynamic & toxicologic effects.

Pharmacokinetics is the study of the time course of drug movement in the body during absorption, distribution, & elimination (excretion & biotransformation).

Pharmacodynamics is the study of the relation of drug conc. or amount at site of action (receptor) & its pharmacologic response.

Bioavailability:

• Bioavailability is a measure of the relative amount of drug that is biologically available (in the systemic circulation) compared to the amount of drug in the dosage form administered.
• The 1^ry proof of a drug’s availability is the production of its pharmacologic (clinical) effect. In order to do so, the drug must achieve adequate conc. at the site of action, e.g. an antibiotic should reach a conc. > the MIC at the site of infection (rather than in the blood).

Drug Absorption:

• Absorption requires the drug to be transported across various cell membranes. Drug molecules enter bloodstream & are transported to tissues & organs. They may cross additional membranes to enter cells, or even an intracellular membrane (nuclear membrane or endoplasmic reticulum) to reach site of action.
• Drugs given by IV route do not undergo absorption; they are readily available in systemic circulation.
• Drugs given by IM / SC / ID injection undergo absorption directly from the site of injection.
• However, drugs given by oral route must undergo certain processes before being available for absorption; a tablet must undergo disintegration prior to absorption as the surface area of the tablet is very limited & dissolution from the solid tablet is negligible (except for very soluble drugs).
• The transfer of most drugs across biological membranes occurs either through:
• Passive transport process: the transfer of drug from area of # conc. to that of $ conc. (according to conc. gradient) through semi-permeable (lipoprotein) membranes until equilibrium is reached.
  • The process does not consume energy.
  • The rate of transfer #s with the # in conc. gradient across membranes.
• Active transfer process (carrier mediated transfer): This process can work against conc. gradient & continue until all drug has been transferred, thus equilibrium does not occur. It is a continuous process.
  • As the process takes place against conc. gradient, it consumes energy.
  • The carrier (e.g. an enzyme in the membrane) aids in transporting the molecules of the drug across the membrane. This process is characterized by:
  • Chemical specificity: The process is structure specific because carriers are often very specific with respect to the drug they will transport. Carriers may be selective for certain types of drugs.
  • Limited capacity: The number of available carriers limits the capacity of the process. At high drug conc., carrier system may become saturated.

Thus, this process can become saturated. When this occurs, the active transport rate becomes a constant value (i.e. zero order kinetics) until the drug conc. is reduced.

Certain chemicals (e.g. poisons) can reduce active transport through inactivation of carriers.

The blood brain barrier: is a lipid membrane (a sheath of glial cells) surrounding the capillaries of the brain. The rate of entry of a drug is correlated with its o/w partition coefficient & its degree of ionization at the pH of plasma (pKa). Drugs that are poorly lipid soluble or extensively ionized at the pH of plasma, will penetrate the BBB very slowly.

Rates & Orders of Reactions:

The rate of a reaction: is the velocity at which the reaction occurs. It is expressed as dc/dt.

Reaction rates depend on certain conditions [reactant conc., temp, pH, solvents / additives, radiation & catalytic agents (polyvalent cations)].

The order of a reaction: is the way in which the concentration of drug (reactant) affects the rate.

• Zero-order reaction: the rate (of absorption, elimination, degradation, etc) is independent of conc. of reactants, i.e. it is constant over time. Other factors (absorption of light in photochemical reactions) determine the rate. i.e. – dc / dt = k
• 1^st-order reaction: the rate depends on the 1^st power of conc. of a single reactant.

Most drugs (in their absorption, elimination, etc) obey 1^st-order kinetics, where:

– dc / dt = k C

            where dc/dt is change of drug conc. with respect to time, k is the rate constant, C is conc. of drug

Distribution:

Plasma protein binding of drugs affects drug distribution.

• A drug bound to a protein forms a complex that is too large to cross cell membranes.
• Albumin is the major plasma protein involved in drug protein binding of acidic drugs. a₁-Glycoprotein, also found in plasma, is important for binding of such basic drugs as propranolol.
• Potent drugs (phenytoin) that are highly bound (> 90%) to plasma proteins may be displaced by other highly bound drugs. Displacement of bound drug results in more free (non-bound) drug, which rapidly reaches drug receptors & causes more intense pharmacologic response.
• Plasma protein binding leads to prolongation of t ½ & slower elimination.
• Plasma protein binding leads to decreased selectivity for target organs.

Biotransformation or Metabolism: This is always an irreversible process where by a drug is transformed into metabolites that are more polar (less lipid soluble / low O/W partition coefficient), less protein bound & are more rapidly excreted, than the parent drug.

The Rate of Metabolism or Elimination of Drugs:

• Drugs can follow zero-order kinetics in their metabolism or elimination where the rate of drug elimination / metabolism is constant & can be expressed as      – dc / dt = k     where

dc/dt is rate of change of drug conc. in blood over time, k is the zero-order rate constant of elimination.

• However, most drugs follow 1^st-order kinetics in their metabolism & elimination, where the rate changes with time depending only on the conc. of drug in the blood, thus:                  – dc / dt = k C            

where C is the conc. of the drug in the plasma.

1. 1.      The half-life (t ½): is the time required for the conc. of a drug to decrease by one-half (50%).

t ½ = 0.693 / k

• The t ½ is constant for each drug & is independent of the initial drug conc.
• In renal impairment patients, the t ½ of drugs excreted unchanged through the kidney, increases.
• Similarly, in newborns, as the kidney enzyme system is not fully developed, the t ½ increases.

In the graph, Curve 1 represents serum conc. levels of a drug given by IV injection. Curve 2 represents serum conc. levels of a drug given by IV infusion. Curve 3 represents serum conc. levels of a drug given by either oral or IM route.

Serum Conc. Time (hrs) I III II

In the IV infusion, the resulting steady state Css (plateau) is directly proportional to the infusion rate.

Time to maximum serum conc. (t_max) is independent of the rate of infusion; it is dependent on t ½ .

Urinary Excretion Data:

The kidney is the major route of elimination of many polar, low m. wt. & water soluble drugs. For such drugs, bioavailability can be evaluated using urinary excretion data, taking in consideration:

• Complete urine collection.
• The individual should have normal kidney function.

However still, bioavailability is better based on serum (blood) data rather than urine excretion data.

The presence of drug &/or its metabolite in urine is an indication of its presence in the blood, based on the assumption that a drug must 1^st be absorbed in the systemic circulation before it can appear in urine.

Weakly acidic drugs in alkaline urine are in ionized form à # excretion & $ reabsorption.

The Rate of Change of Drug Amount in the Body:

This is a function of the rate of absorption & the rate of elimination.

• If the rate of absorption is > the rate of elimination, the conc. will increase.
• If the rate of absorption is < the rate of elimination, the conc. will decrease.
• If the rate of absorption is = the rate of elimination, the conc. will not change.
• Drug absorption will continue to occur even after peak serum level has been achieved; however the rate of absorption will be < the rate of elimination.

1. 1.        The time to peak serum concentration (t _max ) gives some indication of the relative rate of absorption; the lower the t_max (the shorter the time), the faster the rate of absorption.

The difference between peak conc. & trough conc. is greatest when a drug is given at dose intervals much longer than the t ½; e.g. aminoglycosides are almost completely eliminated from the body before the next dose is given.

1. 2.        The AUC: represents the amount of drug absorbed (extent of absorption). The 2 critical factors that affect the shape & height of the curve are the rate of absorption & the rate of elimination.

Doubling the dose of a given drug will not double the height of the curve, but the AUC will be doubled (dose related).

1. 3.       For a sustained release (SR) drug: the rate limiting step for bioavailability must be the drug release from dosage form.
2. 4.       Drugs having the following properties should not be formulated in a SR form:

• Poor solubility (dissolution rate is the limiting step)
• Very long half-life.
• Very short-half life (very large amount of drug is needed).
• Very high potency (because of individual variation).
• Narrow safety margin (e.g. digitalis)

Kidney Function Tests: Several tests can be used to access the kidney function, e.g.:

• Blood Urea Nitrogen (BUN):  9 – 20 mg / dl
• Serum Creatinine (SrCr):   1 mg / L
• Creatinine Clearance (CrCl): this is a more precise way for determining the renal function than either SrCr or BUN. It is also used to measure the glomerular filtration rate (GFR).

Normal CrCl in an adult of 70 kg is 100 – 120 ml/min. Elderly patients have CrCl of 70 ml/min.

Given the SrCr, one can calculate the CrCl according to the following equations:

            Male CrCl = (140 – Age) (wt in kg) / 72 X SrCr

            Female CrCl = Male CrCl X 0.85

Clearance: is the volume of blood that is completely cleared from a drug per unit time. It is used to measure drug elimination from the body.

            Total clearance Cl _T = Drug elimination / Plasma conc.

This is useful in calculating the maintenance dose.

            Maintenance dose = Cl . CP . I / S . F                                              where

CP       = average steady state plasma conc.

I           = dosing interval

S          = the proportion of salt form which is active (aminophylline is 80-85% theophylline, S = 0.8-0.85)

F          = fraction of dose absorbed

The loading dose: is an initial dose (e.g. initial IV injection before the continuous infusion) that is given to achieve the desired steady state conc. (Css) level as rapidly as possible. To calculate the loading dose we need 1^st to calculate the volume of distribution (V_d).

                        V_d = amount of drug in the body / amount of drug in plasma =  AB / Cp

Thus knowing the V_d of a drug permits the calculation of the total amount in the body.

                        AB = V_d X Cp

The loading dose can be thus calculated as follows

Loading dose =  V_d X Cp / S X  F

Tss is the time needed to reach Css (steady state conc.) in blood under a constant rate of infusion. It is independent of the rate of infusion but is dependant on t ½ .

Models & Compartments

• A model is a mathematic description of a biologic system & is used to express quantitative relations concisely.
• A compartment is a group of tissues with similar blood flow & drug affinity. A compartment is not a real physiologic or anatomic region.
• A compartment is any body tissue (site) or fluid that appears to contain the drug & may thus be considered as a pool or compartment in a model.

The Two Compartment Model (IV bolus): this can be observed when a drug is rapidly absorbed & distributes slowly (between 2 compartments e.g. blood & tissue).

• After IV bolus injection, drug distributes & equilibrates rapidly into highly perfused tissues (central compartment) & more slowly in peripheral tissues (tissue compartment) (Figure 6-5).
• The initial rapid decline in plasma conc. is known as the distribution phase. The slower rate of decline in drug conc. after complete equilibration is achieved is known as the elimination phase.
• This does not occur in case of oral drug administration.

The Rate Process:

1. 1.      The 2 compartment open model: Describes elimination of the drug from the system. At least, it has one additional rate constant ( >2). This model does not achieve complete equilibrium. The term open indicates that some drug is lost (e.g., eliminated).
2. 2.      The 2 compartment closed model: Describes the distribution of the drug. This model has only 2 rate constants (for the transfer of drug from plasma to tissue & vice versa) & it achieves equilibrium.

Steady State Plasma Concentration:

• For drugs eliminated by 1^st-order kinetics, the time required (tss) to reach steady state plasma conc. (Css) is dependant only on the biological t ½ of the drug in a given individual. It is from 4 – 5 t ½.

                        t ss = t ½  X  4 or 5 = (0.693 / k)  X  4 or 5

• A steady state conc. is reached when the amount of drug absorbed = the amount of drug eliminated.
• A basic characteristic of 1^st-order kinetics is the rate constant (of metabolism or excretion), k, is independent of the initial drug conc. ( k = 0.693 / t ½ )
• If the rate of elimination is reduced because of impaired renal function (proven by CrCl test) the half-life (t ½ ) & the time required to reach steady state plasma levels (tss) will increase.

 

N.B:

• The value of particle size reduction to enhance absorption is limited when the absorption process is rate limited if the dissolution of the drug is in gastric fluids.
• In case of penicillin G, which is unstable in the GIT, particle size reduction will lead to increased degradation à decrease the amount absorbed.
• Drugs are generally absorbed from the GIT through capillaries to the portal vein hence to the liver (where it might undergo 1^st pass biotransformation) then to the general circulation.
• Rectal route may be preferred over the oral route to allow a drug to pass directly to the systemic circulation (through the middle & inferior hemorrhoidal veins) thus bypassing hepatic deactivation.
• ASA is hydrolyzed in the intestinal lumen & does not undergo 1^st pass biotransformation.
• Bioequivalence includes:
  • Same amount of drug absorbed (same AUC)
  • Same rate of absorption

Thus 2 different oral formulations of a given drug may give equal AUCs (deliver same total amount of drug to the body) but are not necessarily bioequivalent as they might have different absorption rates.

• Urinary tract antimicrobials to be effective they should have:
  • High activity against G –ve bacilli
  • Low level of plasma protein binding
  • Short biological t ½ (to produce rapid conc. in the urine).
  • Low volume of distribution in the body (i.e. distributes itself in the UT).
• A pro-drug is a compound that liberates the active drug in the body; e.g. Geocillin is more acid stable (will not be deactivated in the GIT) than Geopen – the active form.
• Examples of pro-drugs include: Acetaminophen, L-dopa, Enalapril, Prednisone.
• If an orally administered drug appears in the feces this might be due to incomplete absorption or excretion of the drug through the bile.
• Gastric emptying is an exponential process with a normal half-life of 20 – 60 min.
  • It is slowed by vigorous exercise, pain, hot meals & emotional stress.
  • It is accelerated by hunger, mild exercise, cold meals, dilute solutions & laying on the right side.

 

PHARMACOKINETIC   EQUATIONS

Css  =

Q Cl

Q k . Vd

=

Loading Dose  =   Vd  .  Css   =

Vd  . Cp S  .  F

Maintenance Dose  =   Cl  .  Css  .  I   =

Cl  . Cp  .  I S  .  F

log C  =

kt   2.303

log C0  –

k   =   0.693  /  t ½

t ½   =   0.693  /  k

AB  =   Vd  .  Cp

Cl  =   k  .  Vd

Total Dose  =   Loading Dose [ 1  +  ( kH )]

 

 

 

 

 

In renal impairment:

Dose Fraction  =   Normal Dose [ 1  –  { Fe  ( 1 –                Cl ) } ]

Cl Cl normal

Male CrCl  =

( 140 – Age )  .  Wt in kg 72  X  SrCr in mg / dl

t ½   =   t ½  [ 1  +  ( F .                      )

Cl Cl normal

Female CrCl  =   Male CrCl  X  0.85

1.   An aqueous solution of a drug was found to decompose according to 1^st order kinetics, if the drug conc. was 100 mg/ml & after 60 days its conc. was 99 mg/ml, then the t ½ of the drug is:

a.   4136 days                                     b.   414 days                            c.   6897 days

Solution:

t ½   =   0.693 / k     where k is the 1^st order kinetic constant.

            k     =    – 2.303  (log  C₂ – log  C₁  /  t₂ – t₁ )

                   =    – 2.303   ( log 99 – log 100  / 60 ) =   0.0001675

            t ½  = 0.693  / 0.0006175   =    4136 days

2.   The press coating of a tablet contains 200 mg of a drug for immediate release. This amount of drug will provide an adequate therapeutic level. The drug in the slow release core must sustain this therapeutic level for 12 hrs. If the elimination rate constant of this drug is 0.15 hrs, what will be the total amount of drug in each tablet?

      a.   360 mg                                                            b.   400 mg                              c.   560 mg

Solution:

      Total amount of the drug   =  Loading dose  .  [ 1 + (k H) ]

Where k is the elimination constant & H is the time in hrs.

Thus, Total amount of drug  =  200  X  [ 1 + (0.15  X  12) ]

                                             =  200  X ( 1 + 1.8)  =  200   X  2.28   =  560 mg

3.   A patient received 250 mg of aminophylline; after 1 hr the serum conc. was 720 mg, & after 4 hrs the serum conc. was 360 mg. Assuming 1^st order kinetics, the elimination constant is:

      a.   4.3 mg / hr                               b.   0.231 mg / hr                    c.   90 mg / hr

Solution:

      t ½ = 0.693 / k       thus     3 =  0.693 / k              

k =   0.693 / 3   =  0.231

4.   An ASA suspension contains 100 mg / 500 ml; t ½ of ASA in this suspension is 20 days. Calculate the amount of ASA in 15 ml of this suspension at the end of 40 days assuming a 1^st order degradation.

Solution:

      Log C  =   Log C₀ – (kt / 2.303)

      Log C = Log 100 – (k X 40 / 2.303)

      Since         t ½ = 0.693 / k             i.e.       20  = 0.693 / k

      Thus          k = 0.693  /  20  =  0. 03465

      Log C =  2  –  (0.03465 X 40 / 2.303)   =   2 – 0.6 = 1.4

      Anti log 1.4    =  25 mg / 500 ml  =  0.75 mg / 15 ml

 

A simple solution:

Given the half life is 20 days, thus the conc. of the solution after 20 days is 50 mg/500 ml & after 40 days is 25 mg / 500 ml. Thus after 40 days

            500 ml                                     25 mg

            15 ml                                       ????

The amount in 15 ml = 15  X  25 / 500 = 0.75 mg.

5.   The t ½ of a drug is 4 hrs, its blood level after 2 hrs is 200 mg, what is the conc. of the drug in blood after 6 hrs?

      t ½   =  0.693 /  k                           4  =  0.693  /  k                        k = 0.693 / 4 = 0.173

      since          Log C  =   Log C₀ – (kt / 2.303)

                                    =   Log 200 – ( 0.173 X 4 / 2.303)   =   2.3   –  0.3  = 2

      Anti log 2  = 100 mg                                                        

A much simpler solution is that after 4 hrs (1 t ½) the conc. of the drug will fall by 50%, i.e. from 200 to 100 mg.

6.  A drug degrades at a rate of 1 mg in 60 days, if the original conc. is 100 mg, what is the t ½ ?

      t ½ = 50 X 60 = 3,000 days    (zero order kinetics)

7.   A drug is mainly administered at a dose of 200 mg q 6 hrs. If the drug is administered to a patient with CrCl of 60 ml/min. (Normal CrCl is 120 ml/min) what will be the rate of administration of the drug, if the drug is excreted 50% unchanged?

Solution:

Dose fraction   =   Normal dose [ 1  –  {Fe  . ( 1 – CrCl / Cr Cl _Normal )} ]

Where Fe is the fraction excreted unchanged.

Dose fraction   =  200 [ 1 –  {0.5 ( 1 –  60 / 120)}]   =  200 [ 1 – (0.5  X  0.5) ]

                       =  200 [  1 – 0.25 ] =  200 X 0.75   =   150 mg q 6 hrs

8.   In the given graph, the apparent volume of distribution, Vd is 15 liters. What is the total amount of drug in the body at 4 hrs?

Solution:

The graph shows that, after 4 hrs, the serum conc. is 0.002 mg/ml.

Since         Vd   =  AB  /  Cp                                                                                                                (where AB is the total amount in the body & Cp is the plasma conc.)

Thus          15000  =  AB  /  0.002

                  AB =  15000 X 0.002   =  30 mg

1. A drug was found to have zero order kinetics After 6 days 100 gm   a 99 gm, how many days will it take it to reach 50%

      1 gm decrease every 6 days

      50 gm decrease every ?? Days

No of days = 6 X 50 / 1 = 300 days

NB: Zero order kinetics does not depend on the initial drug conc.

10.  Approximately 50% of a drug is excreted unchanged in urine. If the normal dosage schedule of cloxacillin is 125 mg q 6 hrs, a patient with renal function 20% of the normal should receive:                                          125 / 2 = 62.5

1.  
   1. 25 mg q 6 hrs                          c.   75 mg q 6 hrs       62.5 X 20/ 100 = 12.5
   2. 31.5 mg q 6 hrs                       d.   62.5 mg q 6 hrs     62.5 + 12.5 = 75

11.  A drug that is 44% excreted unchanged has a t ½ of 8 hrs. In a patient with 50% renal function the t ½ will be:                                         

T ½ = [ 1 + (0.44 X 0.5)] X 8

              =  1.22 X 8 = 9.76

12.  In a person with normal clearance the t ½ of a drug is 8 hrs. In a patient with 50% renal function the t ½ will be:                                         

a.   8 hrs                                   b.   12 hrs                               c.   48 hrs

( 8 + 0.5 X 8 = 12 )

13.  The rate of infusion of a drug is 500 mg q 8 hrs, Clearance is 7.3 L/hr. What is the Css:                       

R₀ = 500 / 8 = 62.5 mg / hr

C ss = R₀  / Cl   =   62.5 / 7.3  =   8.56

14.  The conc. of a drug is 64 mg after 2 hrs (t ½ = 0.7 hr). Find conc. after 7 hrs.   

a.   6                                        b.   0.00                                   c.   12

log C = log C₀ – kt / 2.303

          =  log 64 – 7 k / 2.303

15.  How many ml of I ¹³¹ should be given to a patient if the prescribed activity is 0.5 millicurie? Assay shows that I ¹³¹ activity is 14.7 millicurie / 2.6 ml 2 hrs before administration & t ½ of I ¹³¹ is 8.1 days. N.B. Radioactive decay  follows 1^st order kinetics.

T ½ = 0.693 / k

8.1 = 0.693 / k                         k = 0.693 / 8.1 = 0.0856

log C = log C₀ – kt  / 2.303                                   C0 = 14.7 / 2.6 = 5.65 millicurie / ml

log C = log 5.65 – 0.856 X 2 / 2.303  =  0.752 – 0.074 = 0.678

C  =  4.76

ml needed = 0.5 X 1 / 4.76   =   0.105 ml

16.  A 65 kg patient receives 10 mg IV of morphine (t ½ = 2 hrs & Vd = 1 L/kg) calculate the initial conc in the serum.

AB = Vd . Cp

Cp  =  AB / Vd                                  

Cp  =  10 X 1000 / 65 X 1000

= 0.153 mg / ml

17.  In the previous problem, if the patient receives another dose after 4 hrs, how much morphine remains in his  body before giving the second dose?

10 mg – 2 hrs à  5 mg – 2 hrs à 2.5 mg

PHARMACOKINETIC   QUESTIONS

1.   Smaller particles of drug show better bioavailability based on:

1.  
   1. Ionization                                c.   pH
   2. Dissolution (neyes wittney equation)
2. A drug that is completely metabolized by the liver was given to a patient with renal failure. The patient was found sensitive to the drug. A good explanation is:
   1. Accumulation of metabolite (due to renal failure)
   2. Liver hypofunction                             c.   Decreased drug clearance
3. Metabolites are usually:
   1. Less water soluble                               d.   Have low o/w partition coefficient
   2. More lipid soluble                               e.   Have high o/w partition coefficient
   3. Polar (more water soluble).
4. The rate limiting step in transdermal diffusion is:
   1. Liver metabolism                                c.   Kidney excretion
   2. Diffusion through stratum cornium (of the skin)
5. The excretion of weakly acidic drugs (i.e. pKa = 3.5) will be more rapid in alkaline urine than in acidic urine because:
   1. All drugs are excreted more rapidly in alkaline urine.
   2. The drug will exist primarily in the unionized form which cannot be easily reabsorbed
   3. The drug will exist primarily in the ionized form which cannot be easily reabsorbed
   4. Weak acids cannot be reabsorbed from kidney tubules
   5. Active transport mechanisms function best in alkaline urine
6. The rate of change in the amount of drug in the body is a function of:
   1. Rate of absorption                            d.   Rate of excretion
   2. Size of the dose administered
   3. Amount of unabsorbed drug in the GIT
7. Two oral formulations of equal doses of drug A will have equal bioavailability only if:
   1. They produce the same serum levels after ½ an hr of administration.
   2. The same total amount of drug A is absorbed in the systemic circultn. from each.
   3. They disintegrate in the GIT at the same rate.
   4. They are excreted in urine at the same rate.
   5. They are bound to plasma proteins to the same degree.
8. Which of the following formulations has the fastest rate of absorption:
   1. Capsules                                  d.    Solutions
   2. Non-coated tablets                  e.    Enteric coated tablets
   3. Suspensions
9. Which of the following formulations presents a bioavailability problem:
   1. Suspension                  c.   Uncoated tablets              
   2. Enteric coated tablets
10. Factors important for a drug to reach CSF for treatment of meningitis:
    1. O/W partition coefficient.                               d.   Dose.
    2. Plasma protein binding                                               e.   pKa
    3. All of the above
11. Drugs that can penetrate the BBB should be:
    1. Unionized.                                                      b.   Lipid soluble.

1. If a drug is 50% metabolized, what is the drug conc. after 4 t ½ :

t ½ = time for drug conc. to fall by 50%.

In 2 t ½ the conc. is à 50/2 = 25%

In 3 t ½ the conc. is à 25/2 = 12.5%

In 4 t ½ the conc. is à 12.5/2 = 6.25%

1. If the t ½ of a drug is 2 hrs, what portion of the drug will remain in the body after 4 hrs:

1.  
   1. 25%.                                                               b.   50%
   2. 12.5%.

1. One gm of drug will give peak serum level of 4 mg %. At what time will it reach a serum conc. of 12 mg% if the dose is administered every 12 hrs:
   1. 36 hrs                                                  c.   72 hrs.
   2. This conc. will not be reached.
2. 50% of an oral hypoglycemic was found to be excreted unchanged. When given with an antacid, the activity of the drug was enhanced. The drug is:
   1. A weak acid                            c.   A weak base
   2. Salt of neutral action.
3. What is true if renal clearance is increased:
   1. GFR is decreased.                               b.   GFR is increased
4. Why is there greater absorption in the small intestine than in the large intestine:

      a.   Because the small intestine has a larger surface area.

1. Which is an example of drug with tubular excretion:

1.  
   1. Penicillin                                 b.   Pro            benicid                                    c.   Carbanicillin

1. Which of the following agents increases the bioavailability of another drug:

a.   Procaine                                   c.   Probenicid

1.  
   1. Probanthine                             d.   Epinephrine

1. Which drugs are hydrolyzed in the stomach:

1.  
   1. ASA                                        b.   Penicillin G
2. The determination of the fraction of drug excreted in urine, based on the plasma protein bound drug, depends on:
   1. Ionization  ????
3. The rate equation for 1st order kinetics is:
   1. dt / dx  = KC                          c.   dt/dx  = K
   2. dt/dx = KC ^-2                          d.   None  (the correct is – dc / dt = KC)
4. A line with zero slope will be:
   1. Parallel to the X axis (abcessa)         b.   Parallel to the Y axis
5. If a patient with renal impairment is receiving a drug completely metabolized in the liver:
   1. Metabolites will accumulate ( as well as Na & K, no change in Ca).
6. In the plasma conc. vs. time curve, during the absorption phase, the slope is:
   1. Positive                                               b.   Negative
7. In the equation Cp = C₀ e ^{– kt}, the slope (e ^{– kt} ) is:      (elimination phase)
   1. Positive                                               b.   Negative
8. How are low clearance drugs affected by increased plasma protein binding:

a.   Slows excretion                                  b.   Enhances excretion.

c.   Alters protein metabolism                   d.   No effect.

1. Knowledge of drug clearance is useful in:
   1. Calculating the maintenance dose.
2. Factors affecting the absorption of topical application (percutaneous absorption):

a.   Partition coefficient of drug             e.   Surfactants

b.   Type of ointment base                      f.   Intact or injured skin

c.   Age of skin                                         g.   Passive diffusion

d.   Osmosis.

1. The nasal route:

a.   Has good blood supply

b.   Has larger surface area than the small intestine

c.   Has increased mucocilliary clearance

1. Drug absorption (efficacy) was increased in a patient taking large amounts of orange juice, when administered with an antacid drug elimination was increased. The drug is:

a.   A weak acid                                       b.   A weak base 

1. Maximum bioavailability is achieved by:

a.   IV administration                              c.   S.C. administration 

b.   IM administration

1. Tablet disintegration can be increased by:

a.   Increasing compression force              c.   Decreasing particle size

b.   Decreasing amount of disintegrant     d.   Decreasing temperature.

1. What is the best way to determine the GFR:

a.   Creatinine clearance                         c.   Serum creatinine 

b.   Inulin excretion.

1. In multiple dosing regimen, the steady state is represented by:

a.   The dosing interval                           c.   Time between C_max & therapeutic dose 

b.   A straight line

1. Which is not true about 1^st order kinetics:

a.   T ½  is independent of conc.

b.   Shelf-life is dependant on initial conc.

1. A drug has a pKa of 3, in the duodenum (pH = 6) it is almost :

a.   Completely ionized

b.   Completely unionized

1. A patient has a kidney function of 50%, if it decreases to 20% then we have to:

a.   Reduce the dose by 50% & double the dosing interval.

b.   Reduce the dose by 50%.

1. Time to reach Css is dependant on:

a.   Elimination half-life                          b.   Rate of infusion. 

1. A drug that is mainly metabolized in the liver depends on:

a.   Plasma protein binding                     c.   Blood flow

b.   Intrinsic clearance

1. – dc / dt  = kC, the equation describes:

a.   1^st order kinetics

1. A protein drug delivery system is made by conjugating a protein drug with PEG, the conjugate has:

a.   Increased renal clearance                 c.   Decreased immunity

b.   Increased proteolytic degradation

1. Addition of a SAA to a protein compound to form a conjugate will:

a.   Affect its bioavailability

1. The rate of elimination will decrease by:

a.   Increasing renal reabsorption

1. The conc. of a drug in blood is helpful to:

a.   Calculate the volume of distribution

1. The plasma conc. of a drug is determined if there is a relation between plasma conc. and:

a.   Efficacy                                  b.   Toxicity

1. The time needed to reach the Css is:

a.   Almost = to the time needed to reach C_max

1. The rate of absorption from the S.C. tissue can be decreased by:

a.   Adrenaline

1. A drug has an AUC of 0.3 at a dose of 20 mg; at a dose of 40 mg the drug has an AUC of 4. This disproportional increase is due to:

a.   Saturation of 1^st pass effect

b.   Increase in bioavailability

c.   Increase in solubility & absorption

1. Penicillin V is given one hr before meals to:

a.   Maximize its bioavailability

1. In the GIT, penicillin G is:

a.   Unstable

1. In the intestinal lumen, Asprin undergoes:

a.   Hydrolysis

1. A pycnometer is used to:

a.   Determine the weight of similar volumes of 2 liquids

 

1. Gastric emptying is:

a.   An exponential process with t ½ of 20 – 60 min.

b.   Slowed by vigorous exercise, pain, hot meals, emotional stress

c.   Increased by hunger, dilute solns, cold meals, mild exercise, & lying on the right side

1. The rate of excretion & metabolism of drugs following zero-order kinetics is given by:

a.   – dc / dt = k

1. For drugs excreted unchanged in the urine, t ½ is increased in:

a.   Patients with renal impairment

b.   New borns due to incomplete development of metabolizing enzymes

1. Bioavailability is better estimated based on:

a.   Serum data

b.   Urine excretion data

1. Why are aminoglycosides given OD:

a.   To prevent accumulation (increase peak : trough ratio)

b.   Peak conc. 16 – 20 mg / L (1hr after IM inj)

c.   Trough conc in blood before second dose is 0.5 – 1.5 mg / L

1. What is pharmaco-economics:

a.   The study of the cost of new inventory drugs

b.   The study of prices of drugs in various pharmacies