What is the difference between a drug and a medicine?

A medicine is any substance that is designed to prevent or treat diseases and a drug is designed to produce a specific reaction inside the body. While there is considerable overlap between the two types of substances, these differences are also quite important.

Most of the medicines that are also drugs are considered "controlled substances." This means that there are laws governing their use and that using them in ways contrary to those laws can lead to criminal charges. Antidepressants like Lexapro are drugs, in that they are designed to help alleviate the physical symptoms of depression. However, they are also used in the treatment of the chemical imbalance that leads to depression, so Lexapro is also a medicine. Cocaine, on the other hand, is a drug designed to create a specific mental reaction that leads to a "high" for the user. However, the medical establishment does not recognize any medical benefits for cocaine at this time. Over-the-counter anti-inflammatory medicines such as Advil are designed to treat pain, but they do not have a strong enough effect to fit into a controlled substance classification, unlike stronger pain relievers. This means that these are medicines rather than drugs. Understanding the similarities and differences between drugs and medicines is an important part of medical and pharmaceutical training.

Multiple Dosage Regimen

Drug kinetics after multiple dosing

Pharmacokinetics of multiple dose

•     The purpose of the multiple dosing is to maintain a desired plasma level of drugs for long periods of time.

•     The plasma level obtained from each succeeding dose is always higher than those obtained from the previous dose since some drug remains in the plasma when repeated doses are administered. • Since the rate of elimination is proportional to the amount of drug in the body, it increases with the increasing amount of drug until it approaches the rate of input (rate of input=rate of output). • At this point the amount reaches a plateau in the body. (Rate of input=rate of output).

•     The main difference is the fluctuation in the plasma concentration due to multiple dosing.

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•              Dosage regimen: – size of the drug dose – frequency of drug administration, i.e. time interval between doses (τ: tau) •              Pharmacokinetic parameters obtained from single dose administration are used to predict drug plasma levels during a multiple-dosage regimen. • The principle of superposition assumes that early doses of drug do not affect the pharmacokinetics of the subsequent doses. 11/3/2015                                                                                                                                            5

•     AUC0-∞= AUC0-τ

•     If the drug is administered at a fixed dose and fixed dosing interval (τ), the amount of the drug in the body will increase and then plateau to a mean plasma level higher than the peak Cp obtained from the first dose.

•     This is known as “steady state”, at which the plasma drug levels fluctuate between Cpss^max and Cpss^min

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•  The average Cpssav is calculated by dividing the AUC for a dosing interval (AUC0-τ) by τ, at steady state •  Regardless of the route of administration: Cpssav = F×D0 = F×D0 = AUCss0−τ = AUC0−∞                   CL×τ Vd×kd×τ      τ           τ •  Accumulation factor (R): Cpssmax  Cpssmin      =    max = min =            C1 C1      1−e 11/3/2015                                                                                                                                            7

•  The maximum accumulation of drug in the body can be given in terms of the administered dose as: 1.44 t           X/Xo =  =   1/2    , where: X: is the maximum drug accumulation Xo: is the amount after first dose                                                                                                                                                                                                                    : dosing interval •  Therefore, when the dosing interval is equal to the half-life of the drug, the maximum accumulation will be 1.44 times the administered dose. 8

•     As the frequency of dosing increases the accumulation level also increases.

•     For example:

If the dosing interval is one-fourth the half-life, the maximum accumulation is 5.76 times the administered dose.

•     Therefore, a desired plateau level can be achieved either by:

– Selecting a dosing interval and adjusting the dose or – By changing the dosing interval to give a fixed dose

•     Drug accumulation is not a phenomenon that depends on the property of a drug.

•     Accumulation is the result of the frequency of administration relative to half-life.

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•   Some fluctuation is always present and the percentage of fluctuation is given by:                                %       =                        ( − ) •   This means that the fluctuation in the plasma concentration is only a . function of the drug half life ( . = ) or the dosing interval. •   Since the half life of drug is constant, the adjustment in the dosing interval is required to achieve desired fluctuation. •   If a drug is administered more frequently (smaller τ), the fluctuation decreases and reaches a limit of (0) percent fluctuation when the dosing interval is zero as in the case of constant intravenous infusion.       11/3/2015                                                                                                                                            11
•	For a given drug in multiple-doses, the time required to reach steady state is dependent on the t1/2 of the drug and is independent of the size of the dose, length of τ, and number of doses.
•	For a drug given at the same dosing rate (e.g. 20 mg/h: 120 mg/6h, 240 mg/12h, or 480 mg/24h), the Cpssav will be the same, but fluctuation between Cpssmax and Cpssmin will vary. 12

•  The rate with which the plateau level is reached is dependent only on the elimination half-life. •  It will therefore take one half-life to reach 50% of the plateau level (Cpss), and 3.3 half-lives to reach 90% of the maximum level.                               × = × (1 − ×) tss (90%) = ‒ ln(0.1)/ k = 3.3 t1/2 11/3/2015                                                                                                                                          13

•  At steady state: Rate in (input) = Rate out (output) F×D/τ= CL×Cpss •  Regardless of the route of administration: Cpssav = F×D = F×D = AUC0−τ = AUC0−∞                 CL×τ Vd×kd×τ     τ          τ 14

•   Following multiple dosing, the plasma concentration can be estimated by using the following equation: = D 0 1− e− nkτ × −kt      Cp t                ( − −kτ ) e                     Vd  1   e , where: n = number of doses given, and t = time after nth dose •   As the number of doses (n) approaches infinity (∞), a plateau (steady state) is reached at which the plasma concentration at any time t (post dose) can be estimated by the following equation:                        D   1 Cpss = 0 ( − −kτ )×e−kt Vd 1 e 11/3/2015                                                                                                                                          15

D                                 Cp   0 Cpssmax= −0kτ ;Cpssmax = −eVd−kτ                             1−e 1 Cpssmin = Cp−0kτ ×e−kτ =Cpssmax ×e−kτ 1−e 16

•  For a continuous i.v. infusion: Cpt = R (1−e−kt )= R            (1−e−kt ) CL    Vd×kd •  After one or more short i.v. infusions: D Cp t =  (1 − e−kt )      (modified from above) tinf ×Vd × kd •  After the infusion is stopped: Cp t = C stop ×e− kt 11/3/2015                                                                                                                                          17

• For multiple oral dose regimen: –  Before reaching the steady state:             t F×ka×D0 ⎢⎡ 1−−ee−−nkakaττ ×e−kat −(11−−ee−−nkkττ)×e−kt ⎤⎥⎦      Cp =             (       ) Vd(k−ka) ⎣ 1 –  At steady state: Cpss= F×(ka×D)0 ⎡⎢⎣(1−1e−kτ)×e−kt −(1−1e−kaτ)×e−kat ⎤⎦⎥ Vd ka−k 18

Cpssmax = F×D0 ( 1−kτ )×e−ktp                                 Vd 1−e Cpssmin = ka×F×D0 ( 1−kτ )×e−kτ Vd(ka−k) 1−e 11/3/2015                                                                                                                                          19

•  Following a single oral dose: tmax = 2.3 ×log ka ka −k       k •  At steady state: tp(tmax, ss) = 1 ×ln⎡⎢ka×(1−e−−kakττ)⎤⎥ ka−k ⎢⎣k×(1−e )⎥⎦ 20

Loading dose (Priming dose) •              It is the dose that provides an effective concentration in the plasma instantaneously • The main objective of the loading dose is to achieve the desired (therapeutic) concentration as quickly as possible. •              Oral DL can be calculated as follows:                        DL0 = ka −e k )                          D (1−e      )(1 11/3/2015                                                                                                                                          21

Loading dose •  For extremely rapid absorption or in the case of IV infusion:                                   DL = 1−kτ                                    D0   (1−e    ) •  As a general rule, the dose ratio should be equal to 2 if the selected dosage interval τ = t1/2 D Dose ratio = L D0 22

• A rapid approximation of DL may be estimated from the following equation: = Vd ×Cpssav     Loading dose (DL) (S)(F) ,where: S: fraction of the administered dose which is the active form of the drug F: bioavailability of the drug 11/3/2015                                                                                                                                          23

•  After multiple dosing, the maintenance dose required is based on CL, Cpss, dosing interval (τ): CL×Cpssav ×τ Maintenance Dose (D0) = (S)(F) ,where: S: fraction of the administered dose which is the active form of the drug F: bioavailability of the drug •  When Cpss & τ are fixed, a drug with a smaller CL would require a smaller maintenance dose. 11/3/2015                                                                                                                                          25

3- Check your calculations: By         applying    these equations	to	find	the
corresponding Cpssmin & Cpssav 11/3/2015			27
• Factors that should be considered in designing a dosage regimen: 1.  Activity and toxicity: ¾ Minimum therapeutic dose ¾ Toxic dose ¾ Therapeutic index (Therapeutic window) ¾ Side effects ¾ Dose-response relationships 2.  Pharmacokinetic processes of drugs which can be influenced by dosage form: ¾ Absorption ¾ Distribution (ADME) ¾ Metabolism ¾ Excretion 3.  Clinical state of patients: ¾ Age, Weight, Urine pH, Condition being treated, Existence of other diseases. 4.  Other factors: ¾ Tolerance ¾ dependence ¾ Drug interactions 11/3/2015			28

Reference • Applied Biopharmaceutics & Pharmacokinetics by Leon Shargel, Susanna Wu-Pong (4th edition): Chapters 15 & 17 11/3/2015                                                                                                                                            29