Pharmacology: General Pharmacologic Principles

Pharmacology PART 1 GENERAL PHARMACOLOGIC PRINCIPLES YUAN Bing-xiang （袁秉祥） 7275165, [email protected]

Pharmacology (7 parts) 1. General Principles 2. Peripheral Nervous Pharmacology 3. Central Nervous Pharmacology 4. Cardiovascular Pharmacology 5. Splanchnic Pharmacology 6. Endocrine Pharmacology 7. Chemotherapeutic Pharmacology

PART 1 GENERAL PHARMACOLOGIC PRINCIPLES CHAPTER 1 INTRODUCTION OF PHARMACOLOGY

【 CONCEPTION 】 1. Pharmacology is the discipline studding interaction or relationship between drugs and bodies including animals, human being and pathogen including microorganisms (bacteria, virus) , parasites and tumor cells…. Drugs is the chemicals beneficially altering biochemical and physiologic state of body, applied to prevent, diagnose and treat diseases.

2. Two areas of pharmacology 　　　 pharmacodynamics drugs body pharmacokinetics pharmacodynamics (drugs on body) ┌effects┌beneficial or ┤ │ therapeutic action │ └untoward reaction └mechanism of action 　 　　　

pharmacokinetics (body on drugs) ┌* undergoing of drugs in body:

┤ absorption, distribution, biotrans│ formation and excretion └* drug blood concentration--time curves (C-T) and the pharmacokinetic parameters.

【 RESEARCH METHOD OF PHARMACOLOGY 】

Other medical research methods (physiology, biochemistry, pathology, clinical medicine….) plus special methods of pharmacology.

　

1. Method of preclinic pharmacology: The experimental object is animals ( healthy animals or ill animals) ┌①clear-headed animals ┤②anesthetic animals │③normal or abnormal organs, tissues, │ cells, cell substructures and molecules └④pharmacokinetics

2. Method of clinic pharmacology: The experimental object is human being ( healthy volunteer and patients ） .

PART 1 GENERAL PHARMACOLOGIC PRINCIPLES

 。

CHAPTER 2 Pharmacodynamics （ drugs Acting on body ）

【 Basic action of drug 】 1. Excitation and Inhibition The intrinsic functions of body are altered by drugs: 1) Excitation or stimulation ： the functions are increased by drugs. (heart rate↑, BP↑, contraction, unstable …) • 2) Inhibition ： the functions are decreased by drugs. (heart rate↓ 、 Bp↓ 、 relaction, stable …)

2. Local action and general action ： 1) Local action ： action on the locale before absorption of administered drugs. 2) General action (absorptive action, systemic action) ： action of drugs on general system after absorption.

3. Selectivity ： Selective action of drugs on some organs or tissues in general action. 1) Selective action ┌high sensitivity of the organ or tissue on │ the drug └high concentration of the drug in the organ or tissue 2) Extensive action ┌low selectivity of the drug itself └overdose

4. Clinical effect┌therapeutic action └untoward reaction 1) Therapeutic action ┌etiological treatment ： eliminate cause. └symptomatic treatment ： remission of symptoms.

2) Untoward reaction* ① Side reaction ： Reactions without relationship to therapeutic purpose of a drug administrated in normal dose are occurred in almost patients, because of the extensive action of the drug. 　　　　　 therapeutic purpose therapeutic action side reaction

② Toxic effect ： Pharmacological responses are too strong and induce injury in the body when administration in overdose or improper long time. ③ Allergy: It can occur in minority of idiosyncrasy patients without relationship to pharmacology and dose. ④ After effect ： Effects remain when drug blood concentration is reduced below threshold concentration.

Dependence is new balance induced following repeated administration of some drugs. Physical dependence is addiction induced following repeat administration. The vital activity of body depends on drugs, abstinence syndrome is induced after discontiune. psychic dependence ： Psychic desire and pleasand feeling are induced following repeat. Mental state depends on drugs, without abstinence after discontiune.

【 Dose-response relationship 】 1. Dose-responses curves or concentration-effect curves ： Coordinate ┌ordinate┌graded response ： gaugeable data ┥ (effects)└quntal response ： frequency │ (all-or-none response) └ abscissa┌ arithmetic ： "long tail S" (dose) │ curves 　　 　 └ logarithm ： symmetry "S" curves

2. Graded response （ mean±standard deviation,  ±S ） effect t test Emax E Kd

logD (C) D (C)

threshold maximal minimal dose dose toxic dose ↓  ↓ ↙ ├─┴┴─────┴─┥─┴───┴── D (C) └ common ┘ ↑ dose minimal lethal dose

① Threshold dose ： Minimum effective dose ② Efficacy (Emax) ： Maxiumum effect of a drug or the limit of the drug response. ③ Potency ： Doses necessary for inducing given effect, or a dose (Kd) inducing 50% Emax. Dose or Kd↑→ Potency↓ Efficacy is usually more important than potency in selecting drugs for clinical use.

④ Slope ： Slope at 50% Emax (slope↑→range of common dose↓→less safety ） ⑤ Maximal dose: The limit of dose permitted in pharmacopeia for some drugs. ⑥ Common dose ： The effective dose in most of patients. maximal dose ＞ common dose ＞ threshold dose

Ｂ E Ａ

potency ：Ａ＞Ｂ＞Ｃ Ｃ efficacy ：Ｂ＞

C ＞Ａ threshold dose ：Ｃ＞Ｂ＞ Ａ 　　　　　　　　 slope ：Ａ＝Ｂ＞Ｃ logD (C)

3. Qualitative Response or Enumeration Data （ response rate, %, χ2 test ） An all-or-none response to a drug and relates to the frequency with which a specific dose of a drug produces a specific response in a population. (e.g., death among the the mice in a preclinical study or effective among the patients in a clinical trial.

1) Frequency distribution curves ： Ordinate is response frequency or ratio (%) of a dose. E 100% ( frequency or ratio) 50% normal distribution skew distribution log dose

dose

dose (mg) 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.4 2.6 T frequency 0 1 3 5 7 12 8 7 4 2 1 50 ratio (%) 0 2 6 10 14 24 16 14 8 4 2 100

Individual variation: There is variation of sensitivity to a drug among patients or animals. Supersensitivity or tolerance to a drug can occur in a few patients or animals, most of them are middle sensitivity. E %

D

2)Cumulative frequency curves ： Vertical is accumulative response frequency or ratio (%). E

Frequency distribution curves

logD

dose

Cumulative frequency curves

logD

dose (mg) frequency ratio (%) CF CR (%)

1 0 0 0 0

1.2 1 2 1 2

1.4 1.6 3 5 6 10 4 9 8 18

1.8 7 14 16 32

2 12 24 28 56

dose

2.2 8 16 36 72

2.4 2.6 2.4 2.6 7 4 2 1 14 8 4 2 43 47 49 50 86 94 98 100

E 100%

effective

toxicity or death

95%

50%

5%

ED50

ED95 LD5 LD50

dose

Therapeutic index (TI): The index used for judging drug's safety. TI ＝ LD50 ／ ED50 ED50 (Median effective dose) ： The dose at which 50% of individuals (experimental animals) exhibits specified effect. LD50 （ Median lethal dose ）： The dose requied to produce death in 50% of animals.

The TI may be misleading if the doseresponses curves for effectiveness and toxicity have different slopes (i.e., not parallel). Therefore, the Safety index may be more useful. Safety index (SI), SI ＝ LD5/ED95

【 Mechanism of action of drugs 】

1. Alteration of chemical or physical character of locale administered to: Osmotic diuretics; antacid. 2. Participate or interference in metabolism of cells ： Vitamin, ferrous sulfate 、 sulfa-drugs.

3. Influence on activity of enzymes ： Insulin→hexokinase↑→oxygenase of glucose↑→blood sugar↓; neostigmine→cholinesterase↓→ACh↑ 4. Influence on ion-channel of ： antiarrhythmic 5. Influence on release of transmiters or hormones ： Ephedrine→release of noradrenaline↑ 　　 Iodide→release of thyroxine↓

【 Drug receptor and pharmacodynamics 】 1. Drug-receptor concept Receptor ： The receptive substances of a cell or an organnism that specificly interacts with a ligand (a corresponding drug, transmiter or hormone) and initiates the chain of biochemical and physiological changes. ligand ： A corresponding drug, transmiter or hormone binding to a receptor.

2. Drug-receptor binding Character 1) Saturation for finitude of number of receptor→Emax 2) Specific binding 3) Reversible binding: ionic bond, hydrogen bond, molecular attraction covalend bond. Therefore, there is competitive binding between 2 drugs binding to same receptor

3. Drug-receptor binding Theory 1) Occupation theory ： The relation between drug given and effect is described as: the magnitude of effect observed depends on the ammount of occupied receptors.

In general, the effect (E) is a function of the the quantity of the drug -receptor complex (DR), and can be expressed as: E = α[DR] Once all receptors are saturated, the maximum effect (Emax) is achieved. If the 50% of receptors were Occupied, 50% Emax is produced.

2) Rate theory ： The effect associate not only with binding rate, but also with dissociation rate. Dissociation rate↑→the ffect↑→Emax↑

3. Parameter of receptor-specific interaction Affinity (or potency) ： The ability of a drug's binding to receptor. A drug's affinity for binding its receptors detemines the concentration of drug required to occupy 50% of drug-receptors or elicits 50% Emax. The greater concentration required, the weaker affinity of a drug; The smaller concentration required, the greater affinity of a drug.

pD2: The parameter of agonist's affinity. The negative logarithm of gram -molecular concentration (mol) of a drug required to binding 50% receptor or inducing 50% Emax. Emax

Emax

50%

50% Kd

pD2

c

-log c

Intrinsic activity (or afficacy) The ability of a drug's inducing effect after binding to receptor. The faster dissociation rate, the greater intrinsic activity, the greater Emax.

4. Classification of drugs binding to receptor Classification of drugs Classification agonist

Affinity ＋＋

intrinsic activity ＋＋

antagonist (blocker) ＋＋

－

＋＋

＋

partial agonist

5. Competitive antagonism 1) In the presence of a fixed concentration of antagonist, dose-effect curves of the agonist would

be

shifted

following

increasing

concentration of agonist: a. Threshold concentrations are increased; b. Curves is shifted to the right in equal slope; c. Emax is unchanged.

pA2: The parameter of blocker’s affinity. The negative logarithm of gram -molecular concentration (mol) of a blocker required to inducing same effect ( or 50% Emax) in double

concentrations of agonist . E

A

A+B’ A+B’’ pA2=-log B’

50%

1

2

3

log c

2) In the presence of a fixed concentration of partial agonist, dose-effect curves of the agonist would be altered following increasing concentration of agonist. a. Threshold concentrations are decreased; b. Emax is unchanged; c. Curves is shifted to the left at low concentration of agonist (partial agonist would like agonist); Curves is shifted to the right at high concentration of agonist (like antagonist). E



A

A+P' A+P''

logC

6. Noncompetitive antagonism After administration of a noncompetitive antagonist, high concentrations of agonist cannot completely overcome the antagonism and Emax cannot be obtained. Dose-effect curves of agonost are altered: a. Threshold concentrations are unchanged; b. Shifted to the right ; c. Emax is decreased. E A A+B’ A+B’’ log c

The End of

pharmacodynamics