Therapeutic regimen slides

Therapeutic regimen : 

Therapeutic regimen

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Therapeutic response and toxicity Constant-rate regimen Multiple- dose regimen

Therapeutic response and toxicity : 

Therapeutic response and toxicity A therapeutic dosage regimen is basically derived from those factors:- that relate both efficacy and safety of drug i.e. pharmaco dynamics and toxicology. Kinetics Clinical state of patient and his or her total therapeutic regimen Genetic difference, tolarance , and drug interaction

Determinants of a dosage regimen : 

Determinants of a dosage regimen

Information relating concentration to response is obtained at three level : 

Information relating concentration to response is obtained at three level In vitro experiments Animal studies And investigation in human volunteers and patients

Responces : 

Responces Graded :-magnitude of a response can be scaled or graded Quantal or all- or –none:- toxic response do not occur on a continuous basis e.g - death

fig 5.1 : 

fig 5.1

Fig 5.3 : 

Fig 5.3

Therapeutic window : 

Therapeutic window Is the range between the concentration of a drugs show response

Fig 5.4 : 

Fig 5.4

Representative drugs and their plsma concentration usually associated with successful therapy : 

Representative drugs and their plsma concentration usually associated with successful therapy

Therapeutics correlates : 

Therapeutics correlates Wide therapeutics window Narrow therapeutics window Fig 5.5

Additional consideration : 

Additional consideration Active metabolites:-unless active metabolite are also measured, poor correlation may exist. e.g. Alprenolol is more active as B- blocker when given as single oral dose than when administered intravenously. Drug is highly cleared by liver, so in terms of parent drugs, oral dose is poorly bioavailable. Large amounts of metabolite including an active species 4-hydroxyalprenol are formed during absorption process which explains apparent discrepancy.

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2) Chirality:- about 40% of drug contain one or more asymmetric/ chiral centers in molecule. Each anantiomers from differ in their pharmacokinetics or pharmacodynamics properties of drugs. Because of difficulty and cost if separation , majority of synthetic chiral drugs are marketed as racemic mixtures. Failure to use sterospecific chemical assay to measure individual responses lead to problem to correlate response with concentration of racemate for e.g- tough R- warfarin is less potent than S form, it can still produce full anticoagulantion.

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3)Tolerance and acquired resistance:- Effectiveness of drug can diminish with continued use. Acquired resistance:-diminished with continued use Tolerance:- Diminished pharmacologic responsiveness 4)Single dose therapy:-one dose of aspirin can often relive headache , which dies not return even elimination id complete. Other e.g-isoproterenol to relive an acute asthmatic attack, morphine to relive acute pain . In these instances of single dose therapy , correlation between effect and peak plasma concentration may exist, but beyond the peak any such correlation is unlikely

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5)Duration v/s intensity of exposure:-Response observed relates more closely to duration of dosing than actual dose or concentration produced. E.G- methotrexate 6)Time delays:-little bit time is taken for response to fully reflect given plasma concentration of drug

Constant-rate regimens : 

Constant-rate regimens To maintain a constant plasma concentration , drug and must be delivered at a constant rate by i.v Constant rate regimen can ingested or placed at a variety of body sites and which deliver drug for a period of time extending from hours to years.

Representative constant-rate devices and their application : 

Representative constant-rate devices and their application

Drug level-time relationships a)infusion b)bolus dose : 

Drug level-time relationships a)infusion b)bolus dose 100 100 Percent plateau 90 50 25 0 From infusion From boius dose Half lives 0 1 2 3 3.3 5 6

The plateau value : 

The plateau value Time during infusion , the rate of change in the amount of drug in the body (da/dt) is the difference between the rates of drug infusion and elimination. da/dt= R0 – K.A 1 constant rate of Rate of elimination infusion In terms of concentration of drug in plasma v. dc/dt = R0 - CL.C 2

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Factors governing amount of plateau are rate of infusion and the elimination rate constant. Only infusion rate and clearance control the steady state plasma concentration Ass = Ro / K 3 Amount at steady = Infusion rate/elimination rate constant state Css = Ro/K 4 Concentration at steady = infusion rate/ clearance state

Mean residence time : 

Mean residence time IT is a useful parameter to describe the sojourn of drug in the body is mean residence time. The amount of drug in the body at steady state (rate of elimination = rate of infusion) depends on the time an average molecule resides the body MRT = Ass /Ro 5 From equ 3 MRT = 1/ K As K = CL/V MRT = V/CL

Time to reach Plateau : 

Time to reach Plateau Factor controlling approach to plateau is half life as the drug attains Ass size when administered and bolus dose declines exponentially with time Amount remaining in body from = Ass.e –kt 9 bolus dose Constant infusion (Ainf)difference between amount at plateau and amount remaining in body from bolus dose.Ainf = Ass - Ass. e –kt 10

Percent by dividing through by volume of distribution. : 

Percent by dividing through by volume of distribution. Cinf = Css[1 – e –kt] 11 Percent of the plateau level reached at various times following a constant infusion of drug

Post infusion : 

Post infusion After stopping an infusion , the amount falls by one-half each half-life. E.g- theophylline

Changing dose infusion rates : 

Changing dose infusion rates Rate of infusion of drug is some times changed during therapy because of excessive toxicity or inadequate therapeutic response. If object is to effect a new plateau, then time to go from one plateau to another , whether higher or lower will depend upon half life of drug

Bolus and infusion : 

Bolus and infusion As linger time required to achieve plateau in case of drug with longer t1/2, situation sometimes demands that the plateau be reached more rapidly Amount of drug in body associated with the two modes of administration are complementary i.e gain of compensate loss of other

Plateau depends upon the infusion rate and not upon the initial bolus dose : 

Plateau depends upon the infusion rate and not upon the initial bolus dose 0 1 2 3 4 5 400 0 100 200 300 Amount of drug in body (mg) Case A infusion alone Half lives Drug infused alone and amount rises reaching plateau of 200 mg approximately 4 half lives

Case B : 

Case B Amount of drug in body Bolus dose of 200 mg immediately attain and infusion rate there after maintain plateau amount 0 1 2 3 4 5 6 0 100 200 300 400

Case c : 

Case c 0 1 2 3 4 5 6 Amount of drug in body mg 0 100 200 300 400 Bolus dose of 400mg is initially because rate of loss is more than infusion

Case d : 

Case d 0 1 2 3 4 5 6 0 100 200 300 400 Amount of drug in body Bolus = 100 mg is below plateau amount because rate of infusion now exceeds body continuously rises until same plateau as in previous case is achieved

assessment of pharmacokinetic parameters : 

assessment of pharmacokinetic parameters Plasma data alone:-By dividing infusion rate by plateau concentration can very easily be achieved this is preferred method for estimating clearance Urine data:-if renal clearance is constant, rate of excretion is proportional to plasma concentration excretion rate data cab be treated analogues to plasma data and estimates can be made of elimination half life fe = rate of execration at plateau/ rate of infusion 3. when both plasma and urine data are obtained together renal clearance can be estimated in addition to other pharmacokinetic parameters

Multiple dose regimen : 

Multiple dose regimen Although constant dose regimens posses many desirable features they are not common type. That s why most common approch to maintaince of continous dose is multiple- dose regimen

DOSING FREQUENCY CONTROLS THE DEGREE OF ACCUMULATON curve A i.v bolus administered twice every half life curve B same bolus dose once every half life : 

DOSING FREQUENCY CONTROLS THE DEGREE OF ACCUMULATON curve A i.v bolus administered twice every half life curve B same bolus dose once every half life A B 0 2 4 6 8 0 100 200 300 Time /half-life Amount of drug in body(mg)

Maxima and minima on accumulation to the plateau : 

Maxima and minima on accumulation to the plateau When drug is given successively every half life, the drug accumulates substantially . Accumulation occurs because drug from previous dieses has not been completely removed maximum amt in body after Nth dose, 1 AN, max = Dose [1-e-NKT/1e-kt] Minimum amt in body After N th dose AN, min =AN,max.e-KT 2

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Maximum amt in body at plateau Ass max Ass = Dose/ 1-e –KT 3 Minimum amount in body at plateau Ass min Ass, max e-Kt =Ass, max - Dose 4 this calculation apply only to intravascular bolus administration

Average amount and concentration at plateau : 

Average amount and concentration at plateau Average rate in must be equal to average rate out. Average rate in f.Dose , Average rate outis K.Ass a v. Ass av average amt of drug in body at plateau f.Dose/t = K . Ass,av f.Dose/t = cl . Css and css ,av = F/cl dose/t Css av =F/cl Dose/t Average amt of drug at steady state depends on rate of administration, bioavailability and Half life

Comparison of Maximum, Average and Minimum Amounts at plateau : 

Comparison of Maximum, Average and Minimum Amounts at plateau max AV min 0 1 2 3 4 5 Ratio 0 1 2 3 4 5 Half life /dosing interval

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Graph shows max, min, average amount in body Observation :-1)Average amount increase in direct proportion with frequency of administration 2)The maximum amount is not much greater than dose if drug is administered less frequently than once in every 3 half lives Fluctuation of amount of drug in body depends upon :-1) frequency of drug administration and half life. 2)rate of absorption

Relationship between initial and maintenance doses : 

Relationship between initial and maintenance doses Initial dose is the priming dose/ loading dose maintenance dose is being required to sustain therapeutic amount in body. Initial dose achieve response and subesquent dose maintain response so maintenance dose is difference between loading dose DL and amount remaining at the end of dosing intervalDL.e-KT maintenance dose = [loading dose]. [1-e-kt] If maintenance dose is known initial dose can be estimated loading dose = maintenance dose/[1-e-kt]

Maintenance of drug in the therapeutic range : 

Maintenance of drug in the therapeutic range 1)Half- lives less than 30 min:-difficult to calculate . True for drugs with low therapeutic index e.g heparin half life 30 min Such drug must be either infused or discarded unless intermittent concentration are permissible 2)Half lives between 30 min and 8 hr:-consider only therapeutic index and continence of dosing. Drug of therapeutic need only every 1-3 half live drugs with low therapeutic index must be given approximately every half life

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3)Half life between 8and 24 hrs:-Most convinent and desirable regimen dose is given every half life 4)Half life greater than 24 hr:-Drugs having half greater than one day . Administration once daily is convinent

Practical aspects of multiple dose administration : 

Practical aspects of multiple dose administration Only plasma or blood is measured not the amount of drug in the body 1)Extra vascular administration:- oral , intramuscular , buccal s.c rectal administration of drug requires on added step absorption. slowness of absorption affects degree of fluctuaion and not the value of average concentration, therapeautic impact of difference in absorption kinetics depends on their frequency of administraton 2)plasma concentration and amount in body:-during multiple dosing , plasma concentration can be calculated at any time by dividing corresponding equation defining amount by volume of distribution

Controlled release : 

Controlled release The maintenance of constant plasma concentration and relatively constant response is achieved by constsnt rate administration. Controlled release regimen is desirable for only drugs with longer half life.

Evaluation of multiple dose regimen assessment of pharmacokinetic parameter : 

Evaluation of multiple dose regimen assessment of pharmacokinetic parameter Clearance/bioavailability:-stability in this ratio CL/F on multiple dosing is given by eqn- AUCss = AUC (single) where AUCss is AUC with in dosing interval at plateau Half life:-it is difficult to estimate drying multiple dosing it cannot be when dosing interval is short . Degree of accumulation :-predictor is accumulation index. This quantity predicts the ratio of amount in the body at some time with in dosing interval at plateau same time after first dose Degree of fluctuation:- fluctuation is an important consideration of any dosing regimen. It is usually evaluated at plateau one common measure of degree of fluctuation is the ratio [css, max-css,min]/css,av

Other parameter : 

Other parameter In this relative bioavailability is worth maintained. If A and B is administered extravascularley of two dosage froms Relative bioavailability = [AUCss]B /[AUCss]A =[Dose]A/[Dose]B Also renal clerance can be estimated in dosing interval at steady state Aesst and the value of AUCss renal clerance = Aesst/ AUCss