DRUG RECEPTOR AND PHARMCODYNAMICS
To explain the biochemical or biophysical actions of drugs on the body, the
mechanisms of their actions, the dose-relationship of drugs and the basis for
reasonable clinical uses of drugs.
SECTION 1
Pharmacological Actions and Effects of Drug
Action
Referred to the initial or primary interaction between drug molecule with
receptors on the cells. Adrenaline stimulate a, β receptors on the myocardiac
cell to stimulate the heart.
Effect
Physical effects secondary to initial drug action. A drug produce its effect by
changing the body function rather than provide new function. Adrenaline act on
a, β receptors called action, stimulating heart called effects .
Excitation(stimulation)
The body function increase or potentiated by the drug. Adrenaline accelerate
the heart rate and output. With the dose increase of the drug it may induce
augmentation. For example, overdose of adrenaline may cause heart failure.
The selectivity of drug action
It is also called electivity or specificity idealy, specificity means that a drug
only binds to one single type of receptor and cause one single effect. Selectivity
means that a drug binds to one or a few types of receptors with higher affinity
than to other receptors.
Selectivity due to the drug chemical structure
Chemical structure, shape and electrical charge of a drug determine the
selectivity to the receptor,(a)stereospecificity: only levorotatory form of
chloramphenicol possesses pharmacological effects; (b)lipid and water
solubility: propantheline (M receptor blocker) has low lipid solubility and has
little effect on CNS because it does not readily pass through blood brain
barrier as atropine does.
Selectivity related to receptors
The receptor structure provide the base for the selectivity of the drugs. For
example, pilocarpine selectively acts on muscarine receptors, and noradrenaline
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selectively acts on  adrenoceptors.
Selectivity related to tissue difference
Selective tissue vulnerability, e.g., the concentration of digitalis requires to
inhibit Na+/K+ ATPase is lower in heart muscle than in other tissues.
Selectivity to different species
For example, sulfonamides inhibit the formation of dihydrofolate synthase of
susceptible microorganisms. However, manmalian cells is not affected because
of the ability to directly utilize folic acid.
Selectivity related to drug concentration
For example, atropine selectively block muscarinic receptors in therapeutic
doses, however, atropine also antagonize nicotinic receptors if the dosage is
high enough. As the dose increases, some barbiturates exert sedation, hypnosis
and anesthesia progressively.
Inhibition
The body function decrease or suppressed by the drug. if dose increase large
enough it may produce paralysis or failure. Diazepam induce sedation and
hypnosis. Aspirin lowers the elevated body temperature.
2. Therapeutic Effects of Drugs
Therapeutic Effects
Any drugs effects which are beneficial in preventing or treating diseases are
belong to therapeutic effects.
Therapeutic Effects can be divided into Etiological treatment and symptomatic
treatment.
(1)Etiological treatment
Elimination of the etiological factors which can cause diseases by using drug to
cure diseases
a. Therapy by killing pathogens
b. Drug for gene therapy
c. Immuno-therapy
d. Supplementary(replacement) therapy
(2)Symptomatic treatment
The disease symptoms improvement without eliminating the cause of the
disease. For instance, pain relieved by aspirin; hypertension lowered by
antihypertensive drugs.
3. Adverse Drug Reactions(ADR)
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The World Health Organization(WHO) defined the drug adverse reaction: any
response to drug that is noxious and unintended and that occurs at dose used in
man for prophylaxis, diagnosis or therapy of a disease, or for the modification
of physiological function”.
(1)Side effects
In the range of therapeutic doses, the drug effects, which are not related to the
current therapeutic purposes, are called side effects.
The pharmacological basis of the presence of side effects is low selectivity of
the drug. For instance, if a muscarinic receptor antagonist, atropine is used to
prevent airway secretion caused by anesthetics, all other effects of atropine,
such as mydriasis, dry mouth, belong to the side effects of atropine; however, if
it is used in ophthalmology(eye), all other effects such as, dry mouth accelerate
cardiac rate etc., belong to the side effects of atropine.
(2)Toxic reaction
All drugs are capable of producing toxic reactions if the dose is high enough or
drugs long term used.
Toxic reaction may be divided into:
a. According to on-speed of drug toxicity
if toxicity caused by short term use of a drug, it is called acute toxicity, and if
caused by long term use, called chronic toxicity.
b. According to the distribution of drug toxicity
Drug toxicity may be classified local or systemic toxicity.
c. According to the extent of drug toxicity
Pharmacological toxicity(most cases are reversible) and pathological
toxicity(part of cases irreversible)
d. Special toxications:
Carcinogenesis: some drug may cause cancer.
Teratogenesis: in few cases, some drug may induce teratogenesis, such as
thalidomide.
Mutagenesis: some special drug can induce DNA change, resulting in
carcinogenesis or teratogenesis.
(3)After effect (residual effect)
After withdrawal of the drug, the drug concentration is below the threshold, the
effect still exists, such as after taking barbiturates, the second morning, the
patient feels hangover, drowsiness, fatigue.
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The remaining effects after stop of drug administration and the plasma
concentration of drug is low than the threshold. For instance, stop
administration of hydrocortisone after its long-term use will cause
hypoadrenocorticism which need several months to recover.
(4)Allergic reaction
It is also called hypersensitive reaction: drug allergy is an altered response to a
drug resulting from a previous sensitizing exposure and an immunological
mechanism. It is also a pathological allergic reaction of a drug. It differs from
drug toxicity in a number of respects:
a. the altered response occurs only in a fraction of the population;
b. It is rarely predictable and its dose-response is unusual in that minute amount
of an otherwise safe drug elicits a severe reaction;
c. The manifestations of the reaction are different from the usual
pharmacological and toxicological effects of drug.
Drug induced allergy have been reported for almost every drug in extensively
clinical use. Some agents, such as streptokinase, penicillin, iodides, phenytoin,
and sulfonamides are truly allergic in nature.
The drug allergies are manifested as skin eruption, edema, anaphylactoid
reactions, eosinophilia, immune complex disorders and contact dermatitis, and
may be most severe allergic shock in some cases.
(5)Idiosyncrasy
Drug idiosyncrasy refers to an abnormal response to a drug by an individual
and the response is not immunologically mediated. It is quite likely that
idiosyncrasy are genetically abnormallities of enzymes and receptors.
Therefore, these abnormal response are often referred to as phamacogenetic
disorders.
For example, hemolytic anemia elicited by primaquine in patients whose red
blood cells are deficient in glucose-6-phosphate dehydrogenase; apnea caused
by succinylcholine in patients with abnormal serum acetylcholinesterase which
is incapable of destroying succinylcholine.
(6)Withdrawal reaction (rebound)
Rapid withdrawal when long-term use some drug may lead to accelerate the
symptoms of ordinary disease, such as when stop use propranolol for its
long-term use in angina patients, which can provoke anginal attacks,
arrhythmias, or myocardial infarction, even more severe than before.
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(7)Drug tolerance
Drug tolerance is said to develop when the response to the same dose of a drug
decreases with repeated uses. Tolerance can be subdivided into
pharmacokinetic tolerance and pharmacodynamic tolerance.
Pharmacokinetic tolerance
Pharmacokinetic tolerance is also described as metabolic or drug disposition
tolerance. pharmacokinetic tolerance is caused by the induction of metabolic
degrading enzymes, mainly in the liver, and the enzyme induction deactivates
the inducer, e.g., phenobarbital, and other concurrently administration drugs.
Pharmacodynamic tolerance
Pharmacodynamic tolerance is also described as Cellular tolerance.
Pharmacodynamic tolerance is referred to the nervous tissue or other target
tissue that adapt to the drug at the cellular level. Consequently, the effect of the
same concentration of a drug decreased.
Cross tolerance
Cross tolerance is referred to such a condition, i.e., if the patient tolerate to one
drug, he/she will tolerate to other drugs in the same class. For instance,
barbiturates, penicillins.
(8)Dependence
Physical dependence An adaptive physiological state produced by repeated use
of a drug, which is characterized by occurring abstinence
syndromes(withdrawal syndromes) if drug administration is stopped, is called
physical dependence.
Psychological dependence
The feeling of satisfaction and psychic drive that require periodic or continuous
administration of the drug to produce a desired effect or to avoid discomfort is
called psychological dependence.
SECTION 2
Drug Dose and Dose-Effect Relationship
Drug dose (dosage)
Drug quantity used in the prevention or treatment diseases.
Concentration-effect relationship (CER)
In a certain range of doses, the pharmacological response is increased with the
increase in doses without evident toxic effects (usually log concentration is
used), the relationship between dose(or concentration) called CER. The curve
of this relationship called dose-effect curve.
1. Graded Dose Response
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Graded dose response means that a slight increase of drug should bring about a
small increase in the response, for example, increase doses of histamine cause
gradual contraction of the guinea-pig ileum. Very low doses of histamine have
virtually no effect and responses can be observed, only beyond a threshold does
of about 20ng. Again, very high doses of more than 50g have no additional
effects, and the response remains constant at this maximal level.
Graded dose response means the pharmacological effects of the drugs
expressed in quality or number, such as the heart rate by beat, blood pressure
by mmHg, also the contract of ileum in height effected by the drugs.
(1)Minimum effective dose(minimum effective concentration, threshold
concentration, Cmin)
Means in that minimum dose can cause the pharmacological effect, indicate the
least amount of drug needed to exert therapeutic effects.
(2)Maximum efficacy (efficacy, Emax)
This term describes the maximal biological response produced by a drug.
Efficacy of a drug depends on the receptor density or the number of active
receptors.
(3)Dose(or concentration) for 50% of maximum effect(ED50, EC50)
The dose of a drug that gives rise to one-half of the maximum response
(continuous effect)is called median effective dose.
(4)Potency
The term describes the comparative expression of a drug activity measured in
term of dose required to produce a particular effect of given intensity related to
a given standard reference. Potency is determined by the affinity of a drug to
the receptor(the higher affinity, the less amount of drug needed), but also by the
efficacy of the drug, namely the ability to produce the therapeutic effects. If the
effects of a drug produced can not reach the therapeutic level, it can not be
compared with other drugs. ED50 is often used to compare potency of drugs. A
drug with low ED50, is more potent than that with large ED50.
2. Quantal Response(all-or-non-response)
Quantal response(all-or-non-response) indicates that a given dose of a drug has
or has not evoked a certain effect in the various subject under investigation, that
is the pharmacological effects are expressed in passive or negative. For
example, to test either presence or absence of hypnosis for a sedative.
(1) Median effective dose(ED50)
For all-or-none response, the dose of a drug that gives rise to a response in
50% of the subject. The more potent the drug, the lower its ED50
(2) Lethal dose
The dose of a drug can cause the experimental animal death.
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(3) Median lethal dose(LD50)
A dose of a drug that gives rise to the death of 50% of experimental animals is
called LD50.
(4)Median toxic dose(TD50)
A dose of a drug that cause a toxic effect in 50% of experimental animal is
called TD50.
3. The Safety of Drug
(1)Maximum dose
The largest dose of drug is permeated in clinical use by pharmacopoeias, if a
doctor uses a dose beyond the maximum dose, it is over the law. If some thing
happened inducing some harm or injure on the patient, the doctor prescribed
drug may be responsible for this.
(2) Therapeutic index (TI)
TI ＝ LD50/ED50 or TD50/ED50
TI describes the safety of a drug. The larger value of the TI is, the wider margin
between effective dose and toxic dose is safe.
(3) Certain safety factor or margin of safety
If the log-dose-response curve of therapeutic and toxic effects of two drugs are
not parallel, Certain safety factor(CSF) is used for comparison. CSF is also
described as margin of safety of the drug.
ED99 ～ LD1
Section 3
DRUG AND RECEPTORS
Drugs can do two things to receptors:
(1) bind to them (affinity) and
(2) possibly change their behavior toward the host cell system (efficacy).
1. Mechanisms of Drug Action
The types of mechanism of drug action includes as follows.
(1) Physical and chemical reaction
Some drugs are used to treat diseases by physical and chemical reaction in the
body. Such as antacids neutralizing gastric acid are used to treat ulcer and
osmotic diuretic dextran increasing osmolarity of plasma, is used to treat edema;
and metal chelating agents combine to toxic metals.
(2)Joining or interfering with cell metabolism
Vitamins, iron preparations and some anticancer drugs whose chemical
structure resemble purine or pyrimidine are called counterfeit incorporation or
antimetabolite. The effects of these substances are through joining or
interfering with cell metabolism.
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(3) Affecting transportation of physical substances
The actions of ephedrine and aramine induce partly the release of
norepinephrine from noradrenergic nerves. And reserpine affect the uptake of
norepinephrine.
(4) Affecting enzyme activity
Many drugs produce their effects by selectively interacting with corresponding
enzymes, for example, neostigmine exerts its cholinergic effect by inhibiting
activity of AChE; digitalis enhance the cardiac contraction by inhibiting
Na/K-ATPase activity on myocardial membrane; sulfonamides produce
bacteriostatic effects by inhibiting the activity of dihydrofolate synthase of
bacteria.
(5) Affecting ion channels on the cell membrane
Calcium, sodium and potassium ion channels may be affected by drugs and
then to exert its pharmacological effects. Calcium and sodium channel blockers,
and potassium channel openers used in the treatment of cardiovascular diseases
because of the affection to these ion channels.
(6) Affecting immunology function
The immunosuppressive and immuno-mudolating agents result in efficiency by
influencing body immunity function.
Regulation of immunity system includes:
(a)active immunity obtained by using vaccine; (b)passive immunity acquired
by applying immuoglobulin; (c)inhibition of immunosystem by
immunosuppressants, e.g., glucocorticoids or cyclosporin;
(d)potentiation of immunosystem by immuno-modulators, interferons,
levamizole.
(7)Affecting nucleotide metabolism
The DNA and RNA are vital substances which control DNA reproduce protein
synthesis and cell split, many anticancer drugs exert effective action on cancer
cells by interrupting DNA and RNA metabolism of cancer cells.
(8) Drugs and receptors
A (specific) receptor can be defined as many biologic target macromolecule in
cells that interacts specifically with extracellular signal, e.g., a drug and
converts it into intracellular effects. Receptor determine the maximum effect of
a drug, i.e., the response extent is proportional to the number of drug-receptor
interaction.
2. Drug and Receptors
(1) Development of receptor theory
a. Langley(1878): Intercounter of atropine with pilocarpine in salivary
excretion.
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b. Langley(1906):Intercounter tubocurarine with nicotine in skeletal muscle –
“receptive substance”
c. Ehrlich(1908): “lock and key (receptor)”
d. Clark(1926-33): Acetylcholine on heart contraction.
e. Dale, Ahlquist, Gaddum, Schild, Sutherland, et al.
3. The concept and properties of receptors
(1)Concept
A specific receptor can be defined as any biological component of cells that
specifically with a endogenous ligand or with a exogenous drug, and induce
pharmacological effects.
Ligand or drug: first messenger
Autacoid: prostaglans, Second messenger: cAMP, cGMP, IP3 and DAG.
(2) Properties
a. Senitivity
b. Specificity
c. Saturability
d. Reversibility
〔R〕+ 〔L〕≒ 〔RL〕→ Effect
〔E〕+ 〔S〕≒ 〔ES〕≒〔ES〕’ → E + Metabolites
e. Multiple-variation
4. Interaction between receptor and drug (receptor theory)
Binding force for receptor and ligand with Van der Walls force, ion, hydrogen,
convalent band.
(1) Occupation theory
Interaction between receptor and drug corresponding with Occupation theory
by Clark(1926) ---receptor theory
[D] + [R] = [DR] →→ E
If the receptors are occupied by drug increasing, the effects of drug are
increasing, when total receptors are occupied by drugs, the effect of this drug
reach to maximum effect(efficacy, Emax).
(2) Kinetics of Receptor and Drug
[D] + [R] = [DR] →→ E
KD = [D][R]/[ DR]
KD is dissociation constant, because [RT] = [R]+ [ DR]
(RT: total receptors)
[DR]/[RT] = [D]/ KD + [D]
Because only DR is effective,
E/Emax = [DR]/[RT] = [D]/ KD + [D]
When [D] = 0, E = 0
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When [D] >> KD,
[DR]/[RT] = 100%, Emax
[DR]max = [RT]
When [DR]/[RT] = 50%, EC50, KD = [D]
KD is dissociation constant, express affinity (mole) of drug to receptors.
Affinity means the measure of the propensity of a drug to bind with a given
receptor. The more the KD, the little the affinity.
If pD2 = -log KD, pD2 is the affinity index, the larger the pD2 , the higher the
affinity of the drug.
Intrinsic activity proposed by Ariens (1954): Intrinsic activity (α) is the
biological response induced by drug-receptor interaction. The efficacy of a drug
is decided by its intrinsic activity.
0 <α≤100%
E/Emax = α[DR]/[RT]
5. Drugs on the Receptors
(1)Agonist
Agonist which can be a drug or a endogenous ligand, has two properties:
one is the Affinity to bind with receptor, other is to exert maximal biological
effect(intrinsic activity).
a. Full agonist: α= 1
b. Partial agonist (mixed agonist): α< 1
Partial agonist has affinity to bind with receptors, but can only produce low
intrinsic activity. When the corresponding receptor is 100% occupied by full
agonist, the efficacy of is “one”, by pure Antagonist, the efficacy is “zero”,
and by partial agonist, the efficacy is between zero and one.
(2) Antagonist
Antagonist which can bind with receptor, without intrinsic activity, antagonize
the biological effects of corresponding agonist.
α= 0
a. Competitive antagonist
The characteristic of competitive antagonist are as follows: (1)it reversible
binds to receptors;(2)the maximum effects of an agonist are not depressed by
corresponding competitive antagonist, because the antagonism can be
overcome by increasing the concentration of the agonist with increase of the
dose of an agonist.
Ligand (L, agonist); Inhibitor(I, antagonist)
[RT] = [R] + [LR] + [IR],
[LR]/[RT] = [L]/KD + [L],
[LR]/[RT] = [L]/[L] + KD(1 + [I]/KI)
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The effect of agonist depends on [I]/KI，The higher the concentration of [I]or
the little of KI, the lower the effect of agonist, and the antagonism of antagonist
is stronger.
If [LR]/[RT]→100%, the dose-effect curve of agonist is shift to right parallel by
antagonist. The antagonism of antagonist can be overcomed by increasing the
concentration of agonist, the Emax still can be reached.
E/Emax = [L]/(KD + [L] ) = [L’]/[L’] + KD(1+[I]/KI)
[L’]/[L] – 1 = [L]/KI
[L’]/[L] is dose ratio, If [L] increases to [L’]/[L] times, it overcomes the
antagonism of [I] .
pA2 is the antagonism parameter, pA2 = -log[I] = -logKI
pA2 express the extent of antagonism of a given antagonist, when the agonist
and antagonist are used in same preparation, two times concentration (X2) of
agonist(A2) only produce ordinary concentration of that agonist effect, in that
time the negative log concentration of antagonist is called as pA2
6. The Types of Receptors
According to protein structure, transmembrane signaling mechanisms, effect
properties and sites of receptors, the classifications of receptors as follows:
(1) G-protein-coupled receptors
Many receptors in the plasma membrane regulate distinct effect or proteins
through the mediation of a group of GTP-binding proteins known as G protein.
Receptor for biogenic amine, eicosanoids, and many peptide hormones utilize
G protein coupled receptor. Receptor in this group act by facilitating the
binding of GTP to specific G protein.
GTP binding activates the G protein, such that it in turn regulate the activity of
specific effector, the effectors include enzymes such as adenylyl cyclase, and
phospholipase A, C and D, channel that specific for Ca2+, K+, or Na+ and
certain transport proteins.
The G-protein are bound to interface of cytoplasma membrane, they are
heterotrimeric molecules(subunit are designate(,  and ) and their
classification is based on the identity of their distinct  subunit. An individual
cell may express multiple G proteins, each of these may respond to several
different receptors and regulate several different effectors with a characteristic
pattern of selectivities.
G-protein-coupled receptors are an important family of receptors with over a
hundreds members cloned to date. Characteristics of G-protein-coupled
receptors include:
(a)the receptors are located on cell surface.
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(b)the binding of extracellular ligand to the GPCR induce the activation of
G-protein by interacting with the receptor in the cytoplasma face.
(c)mediated by stimulating GPCR(Gs)
β adrenergic amine, glucogens, and histamine activate adenylyl cyclase to
covert intracellular ATP to cAMP, and mediated by inhibiting GPCR(Gi), α,
Ach, and opioids inhibit adenylyl cyclase activity; (d)the increase or decrease
of cAMP influence the subsequent protein kinase activity.
(e)other subfamilies of G-protein, e.g., Gq mediated the increase of IP3 by
activating phospholipase C.
(2) Ligand-gated ion channel receptors
Also called receptors containing ion channel receptors for several
neurotransmitters form agonist-regulated, ion-selective channel in the plasma
membrane termed ligand-gated ion channels, which convey their signals by
altering the cell’s membrane potential or ionic composition, their group
includes the N, GABA receptors, they all melt-subunit protein with each
subunit predicted to span the plasma membrane.
Ach + N2 receptor → Na+ channel open → depolarization → skeletal
muscle contraction.
(3) Receptors with tyrosine kinase activity
A transmembrane kinase receptor possesses two domains, i.e., an extracellular
domain which is responsible for binding to ligands, i.e., insulin, growth factor,
and an inner cytoplasmic protein kinase domain which is capable of
phosphorylating diverse effector protein. The phosphorylation of the effector
protein induce a change of activities of series protein vas interaction. Most
transmembrane kinase are tyrosin kinase. Insulin, epidermal growth
factor(EGF), platelet-derived growth factor (PDGF), Transforming growth
factor-β (TGF-β) and insulin-like growth factor
(4) Intracellular receptors
Intracellular receptors exist in cytoplasma or nucleus. They are the receptors for
lipid soluble agonists such as glucocorticosteroids, mineralocorticoids, sex
steroids, vitamin A, D, thyroid hormone, retinoic acid. The complex of agonist
bound intracellular receptor can bind to specific DNA sequences, acting as
transcriptional factors.
(5) Cytokin receptors
Interleukins, erythropoietin, granulocyte macrophage colony stimulating
factors (GM-CSF), granulocyte colony stimulating factors, (G-CSF) prolactin,
lymphokines receptors belong to cytokine receptors.
6. Intracellular Signal Transduction and the Second Messengers
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Many extracellular ligands act by increasing the intracellular concentration of
second messengers such as cAMP. In most case, they use a transmembrane
signaling system with three separate components. First the extracellular ligand
is specifically detected by a cell surface of the receptor. The receptor in turn
triggers the activation of a G protein
Located on the cytoplasma side of the plasma membrane. The activated G
protein then changes the activity of an effector element, usually an enzyme or
ion channel.
(1) Cyclic adenosine-3’, 5’- monophosphate(cAMP)
Acting as an intracellular second messenger, cAMP mediates such hormonal
responses as the mobilization of stored energy, vaspressin-mediated
conservation of water by kidney, Ca2+ homeostasis and increased rate and
contraction force of the heart muscle. It also regulates the production of adrenal
and sex steriods, the relaxation of smooth muscle and many endocrine and
neural processes.
β, D1, H2 → Gs → cAMP↑
α, D2, M, opioid → Gi → cAMP↓
(2)Cyclic guanosine-3’,5’- monophosphate (cGMP)
cGMP has established signaling roles in only a few cell types. Ligands detected
by cell surface receptors stimulate membrane bound guanylic cyclase to
produce cGMP, and cGMP acts by stimulating a cGMP-depended protein
kinase.
(3)Phosphatidyl inositol
Some of the hormones, neurotransmitters, and growth factors that trigger their
pathway bind to receptors linked to G protein. While others binds to tyrosine
kinase receptors. In all cases, however, the crucial step is stimulation of a
membrane enzyme, phospholipase C(PLC), which specifically hydrolyzes a
minor phospholipid component of the plasma membrane called
phosphatidyl-inositol-4,5-bisphosphate(PIP2). PIP2 is split into two second
messengers, diacylglycerol(DAG) and inositol-1,4,5-trisphosphate(IP3). DAG
activates a phospholipid and calcium-sensitive protein kinase called kinase C.
IP3 triggers the release of Ca2+ from internal storage vesicles.
α1, H1, 5-HT1, M1, M3 receptors mediated through DAG and IP3
(4)Calcium ion
Ca2+ participates many functions regulation, such as contraction of muscle,
release of neurotransmitters, and excretion of gland etc. The concentration of
cytoplasmic Ca2+ can be elevated by calcium influx from the extracell, And by
release of Ca2+ from internal storage vesicles. Ca2+ intracellular less than 1μ
mole/L.
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8. The Regulation of Receptors
The number, affinity and sensitivity of receptors may be changed in some
condition, such as the agonist or antagonist were used for long time.
(1) Receptor desensitization
Receptors were exposed by agonist for long time, the number or sensitivity of
receptor to agonist is decreased, this phenomena was called down-regulation
of receptors.
Isoprenaline used in the treatment of bronchial asthma for some time, the
tolerance occur because of the down-regulation.
(2)Receptor hypersensitivity
Receptors were exposed by antagonist for long time, the number or sensitivity
of receptor to agonist is increased, this phenomena was called up-regulation
of receptors. When propranolol was used in the anginal patients for long time,
if stop the use suddenly it may provoke anginal attacks, even more severe than
before, this phenomena is called rebound.
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