Summary of Pharmacy Chapters of Licensed Pharmacists Examination in 2006 (16)

Section 1 Overview

I. Concept of Pharmacokinetics

Pharmacokinetics is a science that studies the changes of drug dosage with time in vivo.

Pharmacokinetics plays an important role in guiding the design of new drugs, optimizing the administration scheme, improving the dosage form, and providing pharmaceutical preparations with high efficiency, quick effect (or slow release) and low toxicity (or low side effects).

Second, the relationship between blood drug concentration and pharmacological action

Because there is a parallel relationship between the plasma concentration of most drugs and their pharmacological effects, it is extremely important to study the change law of plasma concentration to understand the change of pharmacological action intensity, which is also the central issue of pharmacokinetic research.

Third, several important basic concepts

(A) compartment model

The in vivo process of drugs generally includes absorption, distribution, metabolism (biotransformation) and excretion. In order to quantitatively study the changes of drugs in the above process, the mathematical model established by simulating the process of drugs in vivo by mathematical methods is called pharmacokinetic model.

The transport of drugs in vivo can be regarded as the transport of drugs between compartments, which is called compartment model theory.

The concept of atrioventricular is abstract and has no physiological or anatomical significance. However, the division of compartments is not arbitrary, but determined according to the tissues, organs, blood supply and the speed of drug distribution and transportation.

1. Single cell model

That is, after drugs enter the systemic circulation, they quickly distribute in various tissues, organs and body fluids, and immediately reach a dynamic balance in distribution, becoming a so-called "homogeneous" state in dynamics, so it is called a single-chamber model or a single-chamber model.

2. Two-compartment model

The two-compartment model regards the body as a system consisting of two units with different drug distribution speeds, one called the central chamber and the other called the peripheral chamber. The central cavity is composed of tissues and organs rich in blood and blood flow, and the distribution of drugs between blood and these tissues is balanced. The peripheral cavity (external cavity) is composed of tissues and organs with poor blood supply, and the distribution of drugs in the body to these tissues is slow, and it takes a long time to reach the distribution balance.

3. Multi-compartment model A model with more than two compartments is called a multi-compartment model, which regards an organism as a system consisting of multiple units with different drug distribution speeds.

(B) to eliminate the speed constant

Elimination refers to the irreversible loss of drugs in the body, mainly including metabolism and excretion. The defecation constant k between speed and dose is called apparent first-order elimination speed constant, which is called elimination speed constant for short. Its unit is the reciprocal of time, and the value of k can measure the speed at which drugs are eliminated from the body.

The ways of drug excretion from the body are: liver metabolism, kidney excretion, bile excretion and lung respiratory excretion. Therefore, the drug elimination rate constant k is equal to the sum of the rate constants of each metabolism and excretion process, that is:

K=Kb+Ke+Kbi+Klu+……

The elimination rate constants are additive, so the drug elimination score of each route can be obtained according to the ratio of the rate constant of each route to k.

(3) Biological half-life

Half-life is referred to as half-life, that is, the time required for the drug dosage or blood drug concentration in vivo to drop by half, which is expressed by t 1/2 and the unit is time. The relationship between the biological half-life of drugs and the elimination rate constant is as follows:

Therefore, t 1/2 is also one of the important parameters to measure the drug elimination speed. Drugs have a long biological half-life, that is to say, they are slowly eliminated in the body and have a long retention time.

Generally speaking, the drug half-life of normal people is basically the same. If the biological half-life of the drug changes, it indicates that the function of eliminating organs of the individual has changed. For example, in patients with low renal function and liver function, the biological half-life of drugs will be significantly prolonged. It is of great application value to determine the biological half-life of drugs, especially to determine the interval between multiple doses of drugs and to adjust the dosage regimen when liver and kidney organs are diseased.

According to the length of half-life, drugs can generally be divided into: t 1/22 in 1~4 hours, called short half-life drugs; T 1/2 is 4~8 hours, which is called a medium half-life drug; T 1/2 within 8~24 hours is called a long half-life drug; T 1/2 >24 hours is called a very long half-life drug.

(4) Closing rate

The drug elimination rate of the whole body (or some organs and tissues in the body) refers to how much volume of drugs flowing through the blood is eliminated by the body (or some organs and tissues in the body) in a unit time.

Cl=(-dX-dt)/C=KV

From this formula, it can be seen that the clearance rate of drugs in vivo (or organs to be eliminated) is the product of the elimination speed constant and the distribution volume, so the clearance rate Cl is a parameter that includes both speed and volume. At the same time, it has clear physiological significance.

2. Intravenous administration of single-compartment model

1. Pharmacokinetic analysis by plasma concentration method.

(A) the establishment of pharmacokinetic agenda

After intravenous administration, because the in vivo process of the drug is only elimination, and the elimination process is carried out according to the first-order speed process, the elimination speed of the drug is proportional to the first-order power of the drug in the body.

dX/dt=-KX

Integral equation 16-4.

X=X0e-Kt

logX=(-K/2.303)t +logX0

The relationship between in vivo dose and time after single-dose intravenous injection in a single room,

logC=(-K/2.303)t+logC0

From this, the value of k can be obtained, and then the biological half-life (also called elimination half-life) can be obtained from the formula (16-2). T 1/2 = 0.693/K 2. The pharmacokinetics was analyzed by urine drug data method.

The kinetic parameters are calculated by urine drug data method, provided that most drugs are excreted from the kidney as prototype drugs, and the renal excretion process of drugs conforms to the first-order speed process.

1. Urine drug excretion rate method

log(dXu/dt)=(-K/2.303)t+log kex 0

K value can be obtained from blood drug concentration and urine drug excretion data. The renal excretion rate constant k can be obtained from the intercept of a straight line.

2. Total Reduction Method The total reduction method is also called deficit method.

Xu=KeX0( 1-e-Kt)/K

log(X∞u-Xu)=(-K/2.303)t+logX∞u

Both the total reduction method and the urine drug velocity method can be used to calculate the kinetic parameters k and Ke. The advantage of the speed method is that the urine collection time does not need to be as long as that of the total reduction method, and it does not affect the loss of one or two urine samples. The disadvantage is that it is sensitive to error factors, the experimental data fluctuates greatly, and it is sometimes difficult to estimate parameters. The total reduction method is just the opposite, which needs to obtain the total urine dose, so the experiment time is long, with 7 biological half-lives and at least 5 biological half-lives. The kinetic parameters estimated by total reduction method are more accurate than those estimated by urine drug velocity method.

3.

Intravenous drip administration of single-chamber model

1. the pharmacokinetic equation was established by plasma concentration method.

The change speed of drug dosage in vivo during constant-speed intravenous drip is as follows:

dX/dt=K0-KX

X=K0( 1-e-Kt)/K

The relationship between the dose and time of constant-speed intravenous drip in the single-chamber model is expressed by the blood concentration as follows:

C=K0( 1-e-Kt)/VK

Second, the steady-state blood drug concentration

That is, the dropping speed is equal to the elimination speed, and the blood concentration at this time is called the steady blood concentration or the plateau concentration.

Css=K0/VK

With the increase of infusion speed, the steady-state blood drug concentration also increases, so in order to obtain the ideal steady-state blood drug concentration in clinic, it is necessary to control the infusion speed, that is, to control the dose and infusion time.

The time from the start of intravenous drip to the steady-state blood drug concentration depends on the value of drug elimination speed k (or the length of biological half-life).

Xss=K0/K

In the steady state, the blood drug concentration and drug dose in the body remain unchanged.

Three, steady-state blood drug concentration score [medical education network collection]

The ratio of plasma concentration to steady-state plasma concentration at time t is called fractional fss of steady-state plasma concentration, namely:

fss=C/Css

n =-3.323 log( 1-FSS)www.med66.com

The blood concentration is equivalent to the steady-state fraction, or the time required for infusion to reach a certain fraction of the steady-state blood concentration. But no matter which drug, the half-life required to achieve the same steady-state score is the same.

Fourthly, calculate the kinetic parameters after the static drop stops.

(1) Stop dropping after the steady state.

At this time, the change of blood drug concentration is equivalent to the change after rapid intravenous injection, and the time-history equation of blood drug concentration is:

logC=(-K/2.303)t+log(K0/VK)

(2) Stop dropping before steady state.

Stop intravenous drip before reaching steady state, and the change of blood drug concentration in vivo is similar to that after stopping intravenous drip.

Five, intravenous drip and intravenous injection combined medication

The effective plasma concentration of many drugs is at a steady state level, so drugs with a half-life of more than 1 hour may take effect too slowly, and intravenous administration alone is of little significance. In order to overcome this shortcoming, it is usually to inject a large dose intravenously to make the blood concentration C reach the steady-state blood concentration Css immediately, and then drip intravenously at a constant speed to maintain the steady-state concentration. This larger dose is usually called the first dose or loading dose.

X=K0/K

Before intravenous drip, the load dose of intravenous injection reached a steady state, so the dose in the body was constant during the whole process.

4. Extravascular administration of single-compartment model

1. the pharmacokinetic method was established by plasma concentration method.

The difference between extravascular administration of single-chamber model is:

dX/dt=KaXa-KX

C=KaFX0 (e-Kt-e-Kat)/ V(Ka-K)

(a) Eliminating the calculation of velocity constant k

(2) Calculate the absorption rate constant by residue method.

(3) Calculation of peak time and blood drug concentration

After extravascular administration, the plasma concentration-time curve is a single peak curve, and the absorption phase is on the left side of the peak, and its absorption rate is greater than the elimination rate. The right side of the peak is the late absorption stage (also known as the elimination period, which is mainly elimination), and its elimination speed is greater than the absorption speed. At the moment when it reaches the peak, its absorption speed is just equal to its elimination speed.

(4) Calculation of area under curve

The area AUC under the plasma concentration-time curve is an important parameter of pharmacokinetics.

AUC=FX0/KV 5。 Multi-dose administration

6. Intravenous injection of single-chamber model

Second, the plasma concentration-time relationship after reaching steady state

Third, the steady-state average blood drug concentration

In the case of multi-dose administration, the steady-state average blood drug concentration is a very useful parameter. The so-called average value is not the arithmetic average of the steady-state plasma concentration (C∞)max and the steady-state minimum plasma concentration (C∞)max, but the ratio of the area under the plasma concentration curve to the dose interval τ in a steady-state dose interval (that is, from 0 to τ).

(1) single-chamber intravenous injection model

In the single-chamber model, when the drug intravenous injection reaches a steady state, the steady-state average blood concentration is

It can also be seen from the formula that because V and K are specific constants of the drugs used, the ideal steady-state average blood drug concentration can only be obtained by adjusting the dose X0 and the administration time τ.

(2) Extravascular administration of single-compartment model

According to the definition of steady-state average blood drug concentration, the steady-state average blood drug concentration of extravascular administration in single-chamber model is:

Verb (abbreviation for verb) first dose and maintenance dose

When taking multiple doses, it takes a long time to reach a steady state, so it is hoped that a larger dose will be given for the first time to make the blood concentration reach the effective therapeutic concentration, and then the effective therapeutic concentration will be maintained with the maintenance dose.

2. Nonlinear pharmacokinetics and statistical moment method

First, nonlinear pharmacokinetics

Linear differential equations are used to describe the regularity of these processes in vivo. When the dosage of the drug with the characteristics of single-chamber or double-chamber model changes, the corresponding blood concentration changes in direct proportion to the dosage change, the biological half-life of the drug has nothing to do with the dosage, and the total area under the blood concentration-time curve is in direct proportion to the dosage. [Collected by Medical Education Network]

Nonlinear dynamics is produced when the drug concentration exceeds a certain limit and the enzymes involved in drug metabolism are saturated. It can be studied by Michaelis-Menten, which describes the kinetic equation of enzyme.

The equation is based on the formation of another chemical substance with the participation of enzymes or carriers. Because this process needs to be carried out with the participation of specific enzymes or vectors, these processes have strong specificity. Enzymes are involved in biotransformation of drugs, secretion of renal tubules and bile secretion of some drugs, so they have nonlinear kinetic characteristics.

3. Identification method of bioavailability and pharmacokinetic model

I. Bioavailability

Bioavailability refers to the relative quantity and speed of drugs entering the systemic circulation in the preparation, that is, bioavailability includes two aspects: absorption speed and absorption degree of drugs. www.med66.com

The bioavailability of pharmaceutical preparations is one of the important indexes to evaluate the quality of pharmaceutical preparations, and it is also an important content of new drug research. Generally, the bioavailability of the following drugs should be studied: drugs used to prevent and treat serious diseases, especially drugs with a therapeutic dose close to poisoning; Drugs with steep dose-response curve or adverse reactions; Drugs with slow dissolution rate; Some drugs are relatively insoluble or become insoluble in the gastrointestinal tract; Drug preparation, its dissolution rate is affected by particle size and polymorphism; The auxiliary materials in the preparation can change the characteristics of the main drug.

(1) absorption rate

① The absorption rate can be expressed by the time to peak (tmax) on the plasma concentration-time curve.

② Ka can be obtained by residue method.

(3) ③Wagner-Nelson method (absorption percentage plotted against time), which is suitable for single-chamber model, and its formula is:

(4) Loo-Reigeiman method is suitable for two-compartment model.

(2) degree of absorption

The absorption degree can be determined by the total area (AUC) under the plasma concentration-time curve of the test preparation and the reference preparation.

1. Absolute bioavailability

AUCiv is the area under the plasma concentration-time curve of intravenous administration.

2. Relative bioavailability.

AUC test is the area under the blood concentration-time curve of the test sample, and the AUC reference ratio is the area under the blood concentration-time curve of the standard preparation.

AUC's solution:

(three) the design and principle of bioavailability and bioequivalence test

1. Basic requirements of biological sample analysis methods

① strong specificity; ② High sensitivity; ③ Good accuracy; ④ High accuracy; ⑤ The standard curve shall cover the whole concentration range to be measured and shall not be extrapolated.

2. Common preparations

1) The bioavailability and bioequivalence of the subjects are generally conducted in human body, and normal and healthy volunteers should be selected. The selection conditions are: the age is generally 16~40 years old, male, and the weight is 10% of the standard weight. The subjects should have liver, renal function and electrocardiogram examinations, and stop all drugs two weeks before the trial. Subjects must have enough cases, requiring at least 18~24 cases.

2) reference preparation research must have reference preparation as control. Its safety and effectiveness should be qualified. In the study of ethics, we should consider choosing the same dosage form and market-leading preparations that have been listed at home and abroad as standard reference preparations. Only when there is no corresponding preparation at home and abroad will other similar preparations be considered as reference preparations.

3) The safety of the preparation to be tested should meet the requirements, and data such as dissolution, stability, content or titer should be provided. The sample to be tested should be a pilot scale-up sample.

4) Experimental design For the double-agent test of a test preparation and a standard control preparation, a double-cycle crossover randomized trial design is usually adopted, and the interval between two test cycles is at least 7~ 10 half-life of the active substance, usually 1 week.

The complete plasma concentration-time curve should include absorption period, equilibrium period and elimination period. There are enough sampling points correspondingly, and the total sampling points shall be no less than 1 1. Generally, there are 2-3 points in the absorption stage, 2-3 points in the equilibrium stage and 6-8 points in the elimination stage. For sustained and controlled release preparations, the sampling points should be increased accordingly. The whole sampling period should be at least 3~5 half-lives, or the sampling should continue until the blood concentration reaches110 ~1/20 of Cmax.

5) Determination of drug dosage In the study of bioavailability, the drug dosage should generally be consistent with clinical medication. If the sensitivity of the blood concentration determination method is limited, the dosage can be increased appropriately, but the dosage should not exceed the clinical dosage under the premise of safety. The standard participating preparation of the test preparation is equal dose. [Collected by Medical Education Network]

6) During the study, the subjects fasted for the test preparation or the standard reference preparation overnight, took it with 200~250ml warm boiled water, and unified diet after 2~4 hours.

7) The main pharmacokinetic parameters in pharmacokinetic analysis are biological half-life (t 1/2), peak concentration (Cmax), time to peak (tmax) and AUC under plasma concentration-time curve. Cmax and tmax should be measured, not extrapolated

8) calculation of bioavailability the bioavailability f was calculated from AUC0~∞ of each subject, with an average of SD.

9) Evaluation of bioavailability and bioequivalence The 95% confidence limit of the parameter AUC of the test preparation falls within the range of 80%~ 125% of the standard reference preparation, the acceptable range of Cmax is 70%~ 145%, and the relative bioavailability of the test preparation should be 80%~ 120%.

3. Sustained-release and controlled-release preparations

1) single dose, double cycle crossover test

2) Multi-dose dual-cycle steady-state study

Chapter XVII Compatibility Changes and Interaction of Pharmaceutical Preparations

Key content

Compatibility changes of pharmaceutical preparations

Subkey content

Compatibility changes of injections

Test site summary

This chapter is a new chapter in this book.

I. Changes in physical compatibility

1. Precipitation or stratification

2. deliquescence, liquefaction and caking

3. Dispersion state or particle size change

Second, the chemical compatibility changes

1. Discoloration

2. Turbidity and precipitation

3. Gas production

4. Decompose and destroy, and the curative effect decreases.

5. There was an explosion

III. Changes of pharmacological compatibility:

It refers to the change of pharmacological action caused by the interaction of drugs in vivo after compatibility.

Fourth, the main reasons for the compatibility changes of injection are familiar to everyone.

1. Changes in solvent composition

2.pH change

3. Buffer

4. Ionization

Step 5: Direct reaction

6. salting out

7. Mixing amount

8. Mixing sequence

9. Reaction time

10. Effects of oxygen and carbon dioxide

1 1. photosensitivity

12. Composition purity

Biopharmaceutics and pharmacokinetics

Examination questions over the years

Type a problem

1. The absorption mechanism of most drugs is

A. Energy consumption process of reverse concentration removal

It consumes energy and does not need the process of moving the carrier from high concentration to low concentration.

C. the process of moving from high concentration to low concentration without consuming energy, which requires carriers.

D, no energy is consumed, and the process of moving carriers from the high concentration side to the low concentration side is not needed.

E. passive diffusion process of competitive transshipment

(answer d)

2. The factors that do not affect the gastrointestinal absorption of drugs are

A. dissociation constants and fat solubility of drugs

B. dissolution rate of drug from preparation

C. Drug particle size

D. optical rotation of drugs

E. crystalline forms of drugs

(answer d)

3. The gastrointestinal absorption mechanism of drugs is not

A. Active transshipment

B. Facilitated diffusion

C. infiltration

D. drinking

E. passive diffusion

(answer c)

4. Which of the following accords with the pharmacokinetic law of dose intravenous injection?

A. the average steady-state plasma concentration is the arithmetic mean of (Css)max and (css)min.

B. When the steady state is reached, the AUC in each dose interval is equal to the AUC of a single dose.

C. When the steady state is reached, the AUC of each dose interval is greater than that of single dose administration.

D. the steady-state accumulation factor is dose-dependent.

E. the average steady-state plasma concentration is the geometric mean of (css)max and (Css)min.

(answer b)

5. When the elimination rate constant of lidocaine is 0.3465 h ~, its biological half-life.

Answer: 4h

B. 1.5h

C.2.0h

D.O.693h

E. 1h

(answer c)

6. Among the following statements about the apparent distribution and dissolution of drugs, the correct statement is.

A. The apparent distribution volume is large, indicating that the drug concentration in plasma is small.

B Apparent distribution volume indicates the actual volume of drug distribution in vivo.

C. the apparent distribution volume cannot exceed the body fluid volume.

The unit of apparent distribution volume is "liter/hour"

E. the expression distribution volume has physiological significance (answer a)

Tip: There are many concepts and formulas in this chapter, which are difficult to understand. The concept and calculation of apparent distribution solution product are the easiest to understand and test.

7. Intravenous injection of a drug, X0=60rag. If the initial plasma concentration is 15ug/ml, its apparent distribution volume v is

A.20L

4 ml

C.30L

D.4LE. 15L

(answer d)

8. The following description of bioavailability is correct.

A taking vitamin B2 after meals will reduce the bioavailability.

B The bioavailability of amorphous drugs is greater than that of stable drugs.

C. the bioavailability can be improved after the drug is micronized.

D. the greater the fat solubility of drugs, the worse the bioavailability.

E. the greater the water solubility of the drug, the better the bioavailability.

(answer b)

9. The half-life of digoxin is 40.8h, and what percentage of it is eliminated in the body every day?

A: 35.88%

40.76%

66.52%

D.29.4 1%

E.87.67%

(answer a)

The half-life, elimination rate constant, storage period and steady-state plasma concentration were determined by first-order pharmacokinetics.

Calculation is one of the few test sites in the exam where you can work out calculation questions.

10. Assuming that the drug elimination conforms to the first-order kinetic process, how many TL/2 drugs can eliminate 99.9%?

A.4h/2

B.6tl/2

C.8tl/2

D. 10h/2

E. 12h/2

(answer d)

Type b problem [1-5]

A. drug diffusion from high concentration area to low concentration area

B. Need energy

C, diffusing the non-fat soluble drugs from the high concentration area to the low concentration area through the carrier.

D, drug molecules smaller than the membrane pores enter the cell membrane through the membrane pores.

E. Some drugs adhered to the cell membrane enter the cell with the inward depression of the cell membrane.

1. Facilitating diffusion

Step 2 drink.

3. Passive diffusion

4. Positive transshipment

5. Membrane hole transmission

(answer CEABD)

Tip: To master the characteristics of various transmembrane transport in biopharmaceutics.

Biopharmaceutics and pharmacokinetics

X-type questions in exams over the years

X type problem

1. The following preparations are quick-acting preparations.

A. isoproterenol aerosol

B. nifedipine controlled-release pellets

C. epinephrine injection

D. nitroglycerin sublingual tablets

E. sulfadiazine suspension

(answer ACD)

2. The factors affecting the gastric emptying rate are

A. Fasting and satiety

B. Drug factors

C. Composition and nature of food

D. Polymorphism of drugs

E. Oil-water partition coefficient of drugs

(Answer ABC)

3. The first-pass effect of drugs on the liver is great, and the following suitable dosage forms can be selected.

A. enteric-coated tablets

B. sublingual tablets

C. oral emulsion

D. transdermal drug delivery system

E. aerosol

(answer BDE)

4. The following preparations are immediate release preparations.

A. Aerosol

B. sublingual tablets

C. transdermal absorption preparation

D. nasal mucosa administration

E. intravenous drip administration

(answer ABDE)

5. Physiological factors related to drug absorption are

A. PH value of gastrointestinal tract

B. pKa of drugs

C. the content of fat in food

D. Drug distribution coefficient

E. gastrointestinal drug metabolism (answer ACE)