Final score

Final score

examination result

attendance and respond in class

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sign in andrespond in class

select question sign in andexperiment record

(100%) ( 80%) (10%) (10%)

(7 sections )

1. General Principles of Pharmacology (Yu

an)

2. Peripheral Nervous Pharmacology (Cao)

3. Central Nervous Pharmacology (Liu)

4. Cardiovascular Pharmacology (Zang)

5. Splanchnic and Blood Pharmacology (M

a)

6. Endocrine Pharmacology (Zhao)

7. Chemotherapeutic Pharmacology (Lin)

PharmacologyPharmacology

PART 1 GENERAL PRINCIPLES OF

PHARMACOLOGY

Dr. Yuan Bing-Xiang Department of Pharmacolog

y, Medical School,

Xi’an Jiaotong University, Tel: 82657724,

Email: ybx@mail.xjtu.edu.cn

1. Pharmacology can be defined as the science or course studying the interaction between drugs and bodies (living systems) including human being, animals and pathogens including pathogenic microorganisms (bacteria, virus, fungus…) , parasites and tumor cells…

Ⅰ CONCEPTION

CHAPTER 1 Introduction of Pharmacology

PharmacologyGENERAL PRINCIPLES

Drugs are the chemicals beneficially altering biochemical and physiological states of body, applied to prevent, treat or diagnose diseases.

Pharmacology

DrugsAct onBodies

Peripheral Nervous Pharmacology Central Nervous Pharmacology Cardiovascular PharmacologySplanchnic Pharmacology Blood Pharmacology Endocrine Pharmacology

Systemsof bodies

Pathogens- Chemotherapeutic Pharmacology

Antibacterial drugs; Antifungal drugs; Antivirus drugs; AntiparasiticsAnticancer drugs

GENERAL PRINCIPLES

Pharmacodynamics, PD

Pharmacokinetics, PK

Impact factors

2. Three aspects of pharmacology

drug body

PharmacologyGENERAL PRINCIPLES

* therapeutic effects* adverse reaction

E

D

1) Pharmacodynamics (drug acts on body)

effects

action（mechanism of effect）

Drugs actions effects

* Specific actions: drug-receptors; drug-ion channels; drug-enzymes; * Unspecific actions: drugs influence physical and chemical condition around cells (pH, osmosis …)

Primary actingon the target

Secondary Inducing effects in the organ or system

PharmacologyGENERAL PRINCIPLES

* dose-effect curves └→PD parameters (KD, EMAX…)

drug blood Concentration-Time curves

└→PD parameters from C-T curves: t1/2, Ka, Ke, F, Vd…

2) Pharmacokinetics (body acts on drug)

Undergoing of drug in body

absorption distribution excretion biotransformation

C-T curves

C

T

PharmacologyGENERAL PRINCIPLES

transportation

GENERAL PRINCIPLES Pharmacology

3) Impact factors

drug

Drugphysico-chemical propertydosage formbatch number

Medicationdose and route

time and intervalcourse of treat

association

PK

PD

physiolo-patho-

psycho-geno-

living habit ……

body

DrugBody

CHAPTER 2

pharmacokinetics

（ body Acts on drug ） 

PHARMACOLOGIC PRINCIPLES

(sites of action) binding free

(accumulation) free binding

drugs po sc im

(plasma)

Free drugs

binding drugs metabolites

(renal) excretion

Metabolism (liver)

absorption

distribution

distribution

distribution

pharmacokineticsUndergoing of drugs

transporttransformation

out of body

The membranes with pore

are composed of lipids and

proteins in a ratio of 70:1.

The liquid-form double-deck

of membranes is formed

from lipid molecules; The

special proteins inserted into

the double-deck are

receptors, enzymes, ion

channels, carriers……

Ⅰ.Drug permeation across membranes1. Membrane

pharmacokinetics

O ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞O

O ＜ ＞OO ＜ ＞O

O ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞OO ＜ ＞O

ATP

a Lipid diffusion

b Filtration

c Facilitated transport

d Active transport

eIon

transport

lipids

pore

carrier

ion channels

carrier

permeation across membranes

passive

A drug molecule moves from a side of membrane relatively high concentration to another side of low concentration without requiring energy, until an equilibrium has been achieved on both sides of the membrane.

2. Passive transport across membranes(down hill)

high low

equilibrium

pharmacokinetics

Lipid diffusion; Filtration; Facilitated transport

permeation across membranes

…..…..…..…..…..

…..…..…..…..

…..…..…..

…..…..…

..

…..…..…

…..

…..…..

Nonionized form Ionized form

1) Lipid diffusion ( Simple

diffusion)

ion trapping

←less polar molecules polar molecules→

The most important mechanism of drug transport

pharmacokinetics

pH (pKa) ┐ pKa is pH when Ionized rate is 50%

permeation across membranes

more lipid soluble less lipid soluble easy permeation hard permeation

Drug movement across membranes is driven by a concentration gradient after solution in the lipids of membranes.

k1

k2

　 k1 [H+][A-] 　 　 k1 　 [H+][B]

Ka ＝──＝───── Ka ＝──＝ ──── 　 k2 [HA] k2 [BH+]

　 [A] [B] pKa ＝ pH － log ─── pKa ＝ pH － log ─── [HA] [BH+]

[A-] 　 [B] pH － pKa ＝ log ─── pH － pKa ＝ log ─── [HA] [BH+]

HA (weak acids) B (weak bases)　 k1 k1 HA H+ ＋ A- B ＋ H+ BH+

k2 k2

pharmacokineticsLipid diffusion

[A-] [B]─── ＝ 10pH － pKa ─── ＝ 10pH － pKa

[HA] [BH+]

weak acids weak bases ★ pH↑↓→[A-]↑↓→ ★ pH↑↓→[BH+]↓↑→

Degree of ionization↑↓ degree of ionization↓↑

→lipid solution↓↑ →lipid solution↑↓

→permeation↓↑ →permeation↑↓

pharmacokinetics

[A-] [B] ─── ＝ 10pH-pKa ─── ＝ 10pH-pKa [HA] [BH+]

Lipid diffusion

Neither weak acids or weak bases are dissolved in same acid-base solution, the lipid solution↑, permeation↑; They are dissolved in opposite solution, the lipid solution↓, permeation↓.

pharmacokineticsLipid diffusion

For example, Bicarbonate (NaHCO3)

is very effective for treatment of acute

toxication from weak acid drugs (like

barbiturates).

why ？

① Alkalization of gastric juice →ionization↑

→ permeation↓ →absorption ↓

② Alkalization of blood plasma → permeation↓→across blood-brain barrier↓

gastric juice blood

drugdrug

blood Cerebrospinal fluid

drug drug

pH ↑ > pH[A-]↑ > [A-]

pH↑> pH[A-]↑> [A-]

Gastrolavage of NaHCO3

Intravenous drop of NaHCO3

pharmacokineticsLipid diffusion

③ Alkalization of humor (extra-cellular fluid) →ionization↑ →permeation↓

④ Alkalization of urine→ionization↑ →permeation↓→ drug tubular reabsorption↓→ excretion↑

drug drug

drug [A-]↑urine pH ↑

pH < pH↑ [A-] < [A-] ↑

blood

cell

pharmacokineticsLipid diffusion

　 * Water-soluble drugs with low molecular weight (Inc. some polar molecules) can diffuse through the aqueous pores of membrane.

* A almost free drugs can be filtrated across large pores of capillaries from or to plasma. (like drug distribution, glomerular filtration and absorption following im or sc injection)

2) Filtration (Aqueous diffusion):

pharmacokinetics

Small molecules (<100-200 dalton) pass through aqueous pores without requiring energy driven by concentration gradient.

filtration

The movement of a drug across the membrane could be facilitated by its special carrier and concentration gradient. In the carrier-mediated transport, the drug is released to another side of the membrane, and the carrier then returns to original side and state.

3) Facilitated transport (Carrier-mediated transport)

pharmacokineticsfacilitated transport

a. saturable process;

b. special binding to the carrier

c. cannot move against a concentration

gradient without energy.

The properties of facilitated transport are as follows:

pharmacokineticsfacilitated transport

2. Active transport (up hill)

A drug molecule moves from a side of membrane relatively low to one of high concentration with requiring energy and special carrier.

pharmacokinetics

a. saturable process

b. special binding to the carrier

c. transport against concentration gradient with consuming energy.

Active transport

For example: penicillin and probenecid

After glomerular filtration, penicillin undergoes tubular secretion (an active transport), having a very short half-life (t1/2=

20~30 min); probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin. The t1/2 & effects of penicillin are prolonged.

Glomerular filtration (passive)

penicillin tubular Secretion (active)

Blood→tubule

Excretion of penicillin

probenecid

competitively inhibit

Blood→tubule

pharmacokineticsActive transport

H2O absorption

Tubule high osmosis

The transport of drugs from administration locale to bloodstream.

Ⅱ.Absorption

pharmacokineticsAbsorption

1. The routes of absorption

1) im or sc

Absorption of drugs in solution through filtration from subcutaneous or intramuscular injection sites to blood is limited mainly by blood perfusion rate.

pharmacokinetics

im > sc (adrenalin), why?

a. blood perfusion rate (im > sc)

b. adrenalin ┌α↑→vesseel↑(subcutaniea) → perfusion↓ └β↑→vesseel↓(skeleton muscle) →perfusion ↑

Absorption

2) po (per oral)

　 Drugs are absorbed in gastrointestinal tract through lipid diffusion. The absorption takes place mainly in the upper small intestine.

With oral administration of drugs, extensive gastrointestinal and hepatic metabolism may occur before the drugs are absorbed into systemic circulation and reach its site of action. This process is defined as the first-pass elimination.

pharmacokinetics

gastric mucosa small intestine mucosa

Absorption

What about weak acids?

Nitroglycerin given sublingually bypasses liver and enters the superior vena cava and, in turn, perfuses the coronary circulation, therefore is immediately effective to relive patients with angina pectoris.

3) Sublingual or rectal administration

Absorption properties of the administration a. incomplete and irregular absorption;

b. without or less First-pass elimination.

pharmacokineticsAbsorption

For example

F would be the extent and rate of drug absorption following extravascular administration (like orally). F could be the absolute rate of a drug, used for indicating the absorption amount (AUC) compared with that of intravenous administration, or relative rate of a pharmaceutical product, used for indicating the absorption amount (AUC) compared with that of standard preparation in the same administration (same route and dose).

2. Bioavailability (F)

pharmacokineticsAbsorption

A (drug amounts in body)＝───────────── ×100%　 D (administered dose)

AUC (area under extravascular curve)＝────────────────── ×100% AUC (area under intravenous curve)

AUC (test pharmaceutics)＝────────────── ×100% AUC (standard preparation)

test

TT

standardC

iv

po

pharmacokinetics

F (absolute)

F(absolute)

F (relative)

im

C

Absorption

The transport of drugs from

bloodstream to various organs

and tissues, or to different p

hysical compartments of bod

y.

Ⅲ.Distribution

pharmacokineticspharmacokinetics

Distribution

1. Compartments

　　 According to perfusion rate of drugs to various organs and tissues, body can abstractly be divided into one, two or more parts (one compartment model, two compartments model, three…).

pharmacokineticsDistribution

Drugs within the model are assumed to be

distributed just to the organs or tissues with high

blood flow and rapid uniform (brain, heart, liver,

kidneys, lungs, active muscle, …). The C-T curve

have one phase: elimination. The distribution is

too rapid to be found in the C-T curve..

。。

Distribution

T

1) One compartment model

Kadrug

Ke

drug

Ke

Distribution

Co

Tt1/2 t1/2

C

1/21/4

Ke。。

KCdt

dC

KteCC 0

t303.2

KlogClogC 0

logC

T

logC0

pharmacokineticsDistribution

2) Two compartments model

Drugs are not only distributed to the organs or

tissues with rich blood perfusion (central

compartment), but also to that with low blood flow

(peripheral compartment: fat, skin, bone, resting

muscle). The C-T curve have two phases:

a. The distribution rate is known as the alpha

half-life, t1/2α.

b. The elimination rate is known as the beta

half-life, t1/2β.

Ka

Ke

K1

K2

T

β

α

C

Ct ＝ CAe-kαt ＋ CBe-kβt

。。

pharmacokineticsDistribution

α

β

distribution

elimination

peripheral central

Vd is that drug in a plasma concentration should

be solved in apparent volume of body fluid includi

ng the general circulation and the tissues. Vd is u

sed for measuring distribution range, relating the

amount in the body (A) to the concentration of dru

g (C ) in blood.

　　 total amount of drug in body, A(mg) F.D Vd(L) ＝──────────────────── ＝──　　　 concentration of drug in plasma, C(mg/L) C

2. Apparent volume of distribution (Vd)

pharmacokineticsDistribution

1) Barrier: blood-brain barrier, placental barrier)

a. less ionized drug & small particle→permeable

b. inflammation→permeable

iodium thyroid

2) active transport→tissues concentration↑ active transport

3) regional blood flow

subcutaneous < intramuscular

3. Factors influencing distribution

pharmacokineticsDistribution

free drug ＋ plasma binding drug (active form) 　 (inactive storage form) small particle of drug 　 large particle of drug →rapid filtration → no filtration 　 → rapid distribution → → no distribution → ┌ action ┌no action└elimination └no elimination (metabolism & excretion)

moving balance

4) Binding rate to plasma ： binding ratio to plasma protein at the therapeutic dosage. 　

pharmacokineticsDistribution

Characters of binding to plasma a. saturability

Dose↑→binding rate ↓→free drug ↑

Malnutritionliver function↓

Renal function↓

free drug↑

Plasma-albumin↓

binding rate↓

b. Unspecific competition

combinationcompetive

bindingbinding

rate↓ free drug↑

B 92% (8%) →90% (10%) →effect (toxicity) ↑┅ ┅ ┅ ┅ ┅

A 98% (2%) ┅ ┅ ┅ ┅ ┅→96% (4%) →effect (toxicity)↑↑→bleeding2%↓

warfarin

phenylbutazone

Phase 1

oxidation reduction hydrolysis

drug activity↓

Phase 2conjugation

toxicity↓ binding rate↓ more polar excretion↑

Inactivation

Prodrugs activation

Ⅳ.Biotransformationmainly in the liver

hepatic microsomal mixed function oxidase system

pharmacokineticsBiotransformation

with glycuronic acid

1. two phases

2. Factors affecting drug metabolism

1) drugs

enzyme inducer

Chlorpromazine phenobarbital

activity of enzyme↑

→tolerance (dosage↑)

enzyme inhibiter

phenylbutazone chloromycetin

activity of enzyme↓

→hypersensitivity (dosage↓)

pharmacokineticsBiotransformation

For example:

* Deficiency in the activity of acetylase results peripheral neuritis from isoniazid;

* Absence of glucose 6-phosphate dehydrogenase (G6PD) results hemolytic anemia from:

2) Pharmacogeneticshereditary variation in handling of drugs

pharmacokineticsBiotransformation

sulfonamides vitamin K (antihemorrhagic)primaquine (antimalarial agent) phenacetin (antipyretic analgesic) broad beans.

Glucose

G-6-P

ATP

ADP

6-PG Acid

G6PD↓NADP

NADPH↓

GSSG

GSH↓

H2O2 ↑↑

H2O↓

Hemolytic anemia

Oxidizing agent

Absence of G6PD

sulfonamides vitamin K primaquine anminopyrine broad beans

+

Biotransformation pharmacokinetics

3) Physiological and pathological condition

Age

elder

newborn

deficiency of drug elimination

toxicity of drugs

newborn

gray syndrome chloromycetin

numerous drugselder

toxicity↑

Less dosage

pharmacokineticsBiotransformation

liver functionrenal function

For example:

完善 flaw

Circulatory failure

Illness

hepatic disease

enzymeproduction↓

hypersensitivity

Plasma production↓

drug metabolism↓

Plasma binding↓→free drug↑

Renal dysfunction

Plasma loss↑

Should dosage↓

pharmacokineticsBiotransformation

Drugs and their metabolites in circu

lation are excreted by kidneys, bile, mi

lk, sweat and lungs.

Ⅴ.Excretion of drugs

pharmacokinetics

glomerular filtration

tubular water reabsorption

Plasma (Drug & metabolites)

hyperosmotic in renal tubules

tubular reabsorption

lipid-solubility

tubular secretion

active diffusion

Drug excretion ↓ Drug excretion ↑

1. Renal excretion tubular secretion tubular reabsorption

Bicarbonate? Penicillin?

pharmacokineticsexcretion

Probenecid?

Plasma(drug)

2. Excretion in bile

liver active transport

Hepato-enteric circulation

intestine

Excretion

portal vein

bile

prolongation of half-life high concentration in bile

Exclusion

pharmacokineticsexcretion

PO

Beneficial for antiinflammatory of cholecystitis

3. Excretion in milk

weak alkaline drugs (morphine,

atropine)

nursing mother

lactiferous Ducts milk (low pH)

reabsorption concentrations in breast milk↑

effects↑

reactions in infant

fat-soluble drugs(sodium pentothal)

dissolved in the milk↑

pharmacokineticsexcretion

If the mather is the addict, whai would be resulted?

pharmacokinetics

Ⅴ.Kinetics and rate process

Differental equation

Kinetics model

KCdt

dC

CPP

PCCC

CKCKdt

dC

CKCKKCdt

dC

1221

2112

Kinetics

K

drug

1 compartmentK12

K 21

Kdrug

2 compartment

pharmacokinetics

1 compartment

Exponentequation

KteCC 0

tt BeAeC

Linear equation

t2.303

-logA)Be-log(C t 303.2

KlogClogC .-

0

t

t303.2

logBlogC

Semi-logarithmicequation

Kinetics

2 compartments

α

T

C

T

C

β

A

B

α

T

logC

T

logC

β

1. Elimination of drugs

pharmacokineticsElimination

0 1 2 3 4 5 …… 9 10 11 12

1st-order 100 50 25 12.5 6.25 3.125

0-order 1000 900 800 700 600 500 …… 100 50 25 12.5

Drugs and their metabolites are eliminated from the body by excretion and metabolism with decrease of drug blood concentration.

Blood concentration of drug is reduced in equal rate or in constant half-life (t1/2). The eliminated rate is direct ratio with blood concentration of a drug.

1KCdt

dC

1) First-order kinetic

t1/2

C

T

one compartment

pharmacokineticsElimination

All most drugs

KCdt

dC

2) Zero-order kinetic

Blood concentration of drug is reduced in equal amount or eliminated in continuant shorten half-life (t1/2).

C

T

0K 0

dCC

dt

0

dCK

dt

3) non-linear kinetics Low dose→ 1st order Overdose→ zero order

T

zero

T

Cfirst

aspirin

Low dose

1st order kinetics T1/2=2-3 h

Large dose Urine pH↓→reabsorption↑

zero order kinetics

T1/2=15-30 hC

salicylic acid, phenytoin, alcohol

The half-life (t1/2) is the time required to decrease the

drug plasma concentration by one-half (50%) during elimination. It is considered that drugs are almost (97%) eliminated after 5 t1/2.

T1/2 is relates to drug character (lipid-solubility, size of

particle, molecular structure, drug interaction) and body condition (function of kidneys and liver…), but generally not relates to drug blood concentration and the routes of administration (therapeutic dose). 　

4) Half-life of drug (t1/2)

pharmacokineticsElimination

pharmacokineticsElimination

C

TT1/2

C

TT1/2 T1/2

iv

po

t1/2

constant of a drug

Relation todrug character

lipid-solubility, size of particle, molecular structuredrug interaction

Individual variation

No relation to concentration of drug (therapeutic dose)way of administration

Relation tobody condition

KidneysLiver……

When given at a regular interval, a drug plasma conc

entration approximately could reach a plateau after 5 t1/

2.

1) Level of Css relates to:

* dose ↑→Css↑

* interval shorten → wave of Css ↓

intravenous drip → smooth concentration curves.

（ the most effective and safe administration)

2. Steady state concentration (Css)

pharmacokineticsSteady state

* When a drug is given at a regular interval, its Css c

ould reached after 5 t1/2;

* loading dose →reaching Css rapidly

When the regular interval is t1/2 and loading dose is d

ouble ， Css can be reached immediately in intravenous

injection.

2) Time to reach Css relates to:

pharmacokineticsSteady state

0-order1st-order

C

T

pharmacokineticsSteady state

2D-D D

50%75%

87.5%

93.8%97%

ivd

C

T

T1/2 0 1 2 3 4 5… n

first -order

A. dose 100 100 100 100 100 100

amount 50 75 87.5 93.5 96.9… 100

B. dose 200 200 200 200 200 200

amount 100 150 175 187.5 193.8… 200

C. dose 200 100 100 100 100 100

amount 100 100 100 100 100

zero -order

dose 100 100 100 100 100 100…

amount 50 100 150 200 250…

Steady state concentration

pharmacokineticsSteady state