Topics for Prelim: 1. Basic Principles I. Introduction II. Drug Receptors & Pharmacodynamics III.

Pharmacokinetics & Pharmacodynamics: Rational Dosing & Time Course IV. Drug biotransformation V. Development & Regulation of Drugs

Midterm 2. Autonomic Pharmacology I. Introduction to autonomic Pharmacology II. Cholinoreceptor-Activating & CholinesteraseInhibiting Drugs III. Cholinoreceptor Blocking Drugs IV. Adrenoreceptor Agonists & sympathomimetic Drugs V. Adrenoreceptor Antagonist Drugs

Finals: I. Antihypertensive Drugs II. Vasodilators & the Treatment of Agina Pectoris III. Drugs used in Heart Failure IV. Agents used in Cardiac Arrhymias V. Diuretic Drugs
References: Lippincot Basic Pharmacology Katzungs Basic Pharmacology Good and Gilman Pharmacology and therapeutics Latest editions

I. General Principles of Pharmacology: A.Introduction a. Definition of terms b. History of Pharmacology c. Pharmacology and The Pharmaceutical Industry d. General Principles Of Pharmacology The nature of drugs 1. The Physical Nature of Drugs 2. Drug size 3. Drug reactivity 4. Drug Shape 5. Rational Drug Design 6. Receptor Nomenclature

e. Drug-Body Interactions d. Pharmacodynamic Principles

1. Types of Drug Receptor Interactions 2. Agonist That Inhibit Their Binding Molecules 3. Agonist, Partial Agonists and Inverse Agonist 4. Duration of Drug Action 5. Receptors and Inert Binding Sites f. Pharmacokinetic Principles A. Permeation 1. Aqueous diffusion 2. Lipid diffusion 3. Special Carriers 4. Endocytosis and exocytosis

B. Ficks Law of Diffusion C. Ionization of Weak Acids and Weak Bases, The Henderson- Hasselbach Equation

Drug groups Sources of information

II. Drug Receptors and Pharmacodynamics:

A. Overview
B. Macromolecular Nature Of Drug Receptors C. Relationship Between Drug Concentration & Response I. Concentration-effect Curves and Receptor Binding Agonists II. Receptor-Effector Coupling and Spare Receptors III. Competitive and Irreversible Antagonists D. Partial Agonists E. Other mechanism of drug antagonism F. Signaling mechanism and drug action

III. Pharmacokinetics and Pharmacodynamics 1. Volume of Distribution 2. Clearance a. Capacity-Limited Elimination b. Flow Dependent Elimination 3. Half-life 4. Drug Accumulation 5. Bioavailability a. Extent of Absorption b. First Pass Elimination c. Rate of absorption 6. Extraction Ratio & the First-Pass Effect 7. Alternative Routes of Administration

a. Definition of Terms

Defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.

Medical Pharmacology science of substances used to prevent , diagnose, and treat disease. Toxicology branched of pharmacology which deals with the undesirable effects of chemicals on living systems, from individual cells to complex.

b. Historical facts of Pharmacology Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plants and animals. Earliest written records from China to Egypt list remedies of many types including a few still recognized today as useful drugs.

 In the late 18th and 19th centuries Francois Magendie and later his student Claude Bernard began to develop the methods of experimental animal physiology and pharmacology Materia Medica the science of drug preparation and medical use of drugs, began to develop as the precursor of pharmacology 18th, 19th, and early 20th centuries laid down foundation needed for understanding how drugs work at the organ and tissue levels.

 About 50 to 60 years ago years ago there also began a major expansion of research efforts in all areas of biology. As new concepts and techniques were introduced, information accumulated about drug action and biologic substrate of that action , the drug receptor.

 Last 3 decades have seen an even more rapid growth of information and understanding of the molecular basis for drug actions. The molecular basis of many drugs have now been identified and numerous receptors have isolated, structurally characterized and cloned. The extension of scientific principle into everyday therapeutics is still going on, though the medication consuming public is still exposed to vast amounts of inaccurate, incomplete, or unscientific information regarding the pharmacologic effects of chemicals

Pharmacogenomics- the relation of the individuals genetic makeup to his or her response to specific drugs.

Two general principles that the student should remember are: 1. That all substances can under certain circumstances be toxic, and the chemicals in botanicals are no different from chemicals manufactured drugs except for the proportion of impurities. 2. That all dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies.

Pharmacology and Genetics:

c. Pharmacology and The Pharmaceutical Industry Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to big pharma, multibillion-dollar corporations that specialize in drug discovery and development.

d. General Principles Of Pharmacology:

Nature of drugs: In most general sense- a drug may be defined as any substance that brings about a change in biologic function through its chemical action. In the great majority cases, the drug molecule interacts with specific molecule in the biologic system that plays an important role. This molecule is called a receptor.

 Drugs may synthesized within the body ( eg. Hormones ) nor maybe chemicals not synthesized in the body ( xenobiotics ) Poisons are drugs that have almost exclusively harmful effects Toxins are defined as poisons of biologic origin synthesized by plants and animals in contrast to inorganic poisons such lead and arsenic.

A. Physical nature of drugs: Drug may be: solid at room temperature liquid gaseous Drugs are absorb by different routes of administration Many drugs are considered to be weak acid and weak base. B. Drug size The MW size of drugs varies from very small (eg. Lithium ion MW 7) to a very large ( eg.alteplase a protein MW of 59,050) The vast majority of drugs have MWs between 100 to 1000.

C. Drug reactivity and drug receptor bonds. Drugs interact with receptors by means of chemical forces or bonds. Three major types : 1. Covalent 2. Electrostatic 3. hydrophobic

1. Covalent bond are very strong and in many cases not reversible under biologic conditions.
receptor Phenoxybenzamine Blockage of receptor

The blocking effect of phenoxybenzamine last long after the free drug has disappeared from the blood stream and is reversed only by the synthesis of new alpha receptor a process that takes about 48 hours .
Another example of covalent bond forming drugs are the DNA alkylating agents used in cancer therapy to disrupt cell division in the neoplastic tissue

2. Electrostatic bonding much more common than covalent bonding in drug-receptor interaction. most involve the van der Waals forces.

1) Drug molecules are attracted by the particle through electrostatic forces. 2) After particle surface saturation low molecular weight drugs start to diffuse into the sphere matrix. 3) Drug molecules are bonded by attractive hydrophobic and electrostatic interactions. 4) After complete loading and incubation in release media drug molecules are transported to the particle surface due to concentration gradient driven transport processes. 5) Upon time drug molecules are slowly released from the surface allowing constant release rates.

3. Hydrophobic bonding are usually quite weak and are

probably important in the interactions of highly lipid soluble drugs with the lipids of cell membrane and perhaps in the interaction of drugs with the internal walls of receptors

D. Drug shape
The shape of a drug molecule must be such as to permit binding to its receptor. Phenomenon of chirality ( stereoisomerism ) is so common in biology that more than half of all useful drugs are chiral molecules they exist in enantiomeric pairs.

E. Rational drug design Implies the ability to predict the appropriate molecular structure of a drug n the basis of information about its biologic receptor. F. Receptor Nomenclature- involves systems in the identification and characterization of receptors.

e. Drug-Body Interactions: The study of chemical and physiological effects of drugs and their mechanisms of action.

f. Pharmacodynamic Principles: Most of the drug must bind to a receptor to bring an effect .
Drug (D) + receptor-effector (R) D+R drug-receptor complex D-R-E complex effector molecule effect effect

D+R D-R complex Increased activator

activation of coupling molecule effect

Inhibition of metabolism of endogenous activator increased activator increased effect

Mechanism of action of drugs: The effects of most drugs result from their interaction with macromolecular components of the organism. The interactions alter the function of the pertinent component and thereby initiate the biochemical and physiological changes that are characteristic of the response to the drug.

A. Types of Drug- receptor Interactions.

B. Agonists that inhibit their Binding Molecules Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist.
Acetylecholinesterase Inhibitors Bethanecol , pilocarpine

Action

Slowing the destruction of endogeneous acetylcholine

Cause

Cholinoreceptor agonist

Closely resemble as

Cholinomimetic effect

C. Agonist, Partial agonists, and Inverse agonist.

Receptor
Exist

Ri

Ra

Thermodynamic consideration
Indicate that even the absence of agonist Receptor pool must exist

Ra form
Constitutive activity

Agonist-induced activity

Receptors that have constitutive activity and are sensitive to inverse agonist include benzodiazepine, histamine, opioid, cannabinoid, dopamine, B adrenergic, calcitonin, bradykinin, and adenosine.

Ri

Ra

Effect

Ri -- D

Ra-- D

Effect No effect

 1. Agonist drugs- are those drugs that have a much higher affinity for the Ra configuration and stabilize it, so that a large percentage of the total pool in the Ra-D affinity and large effect is produced.
Example is the binding of of nicotine drug with nicotinic acetylcholine receptor

 Inverse agonist

One of the best documented examples of inverse agonist aminobutyric acid ( GABA) receptor-effector system ( a chloride channel ) in the NS.

Activation

X X X Block

 2. Many agonist drugs, when administered at concentration sufficient to saturate the receptor pool, can activate their receptor- effector systems to the maximum extent to which the system is capable , that is , they cause a shift of almost all of the receptor pool to the Ra-D pool, such drugs are term as full agonist drugs 3. Partial agonist drugs- Bind to the receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration .

Example the pindolol a Beta-adrenoreceptor partial agonist, may act as an agonist ( if no full agonist is present) Or as an antagonist ( if a full agonist such as epinephrine is present).

Ra + Da

Ra + Dpa Ra + Ri

Ra+Dant+Ri+Dant

Ri + Di

 4. Antagonist drugs - bind to the receptor, compete with and prevent binding of other molecules .

The presence of the antagonist at the receptor site will block access of agonist to the receptor and prevent the usual agonist effect. Such blocking action can be termed as neutral antagonism.

Dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors.

5. allosteric drug- Drugs that binds to the same receptor molecule but do not prevent binding of the agonist and may enhance or inhibit the action of agonist molecule. Take note: allosteric inhibition is not overcome by increasing the dose of agonist.

D. Duration of action : Termination of drug action is a result of one of several processes. In some cases the effect lasts only as long as the drug occupies the receptor and dissociation of drug from the receptor automatically terminates the effect. In many cases however the action may persist after the drug has dissociated for example coupling molecule is still present in activated form.

E. Receptors and inert Binding sites: To function as a receptor, an endogenous molecule must first be selective in choosing ligands ( drug molecules ) to bind. It must change its function upon binding in such a way that the function of the biologic system ( cell or tissues) is altered. Binding of drugs to a non regulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site.

Review of Pharmacokinetics principle:

A. Permeation:
1. Aqueous diffusion: 2. Lipid diffusion 3. Special Carriers 4. Endocytosis and exocytosis

Endocytosis

Vesicle Exocytosis

B. Ficks Law of diffusion: ( C1 - C2 ) x

Drug molecules will move from where they are at a high concentration to where they are at a lower concentration. i.e. they diffuse down a concentration gradient.
Drug molecules

C. Ionization of weak acids and weak bases , the Henderson Hasselbach equation:

Weak acid is best defined as a neutral molecule that can reversely dissociate into an anion

C8H7O2COOH Neutral aspirin

C8H7O2COO- + H+ Aspirin anion Proton

Weak base can be defined as neutral molecule that can form a cation ( positively charge molecule ) by combining with the proton
+ C12H11ClN3NH3

C12H12ClN3NH2 + H

Pyrithamine Cation
log

( ) = ( )

Neutral Proton pyrimenthamine

pKa-pH

For acids and bases

For acids:

For bases

acidifies

NH4Cl

+
Methampethamine

Concentration 25x than in the blood

Drug receptors:

The term receptor denotes the component of the organism with which the drug is presumed to interact. Macromolecular component may act as a receptor

 Drug receptor theories: 1. Hypothesis of Clark- The pharmacological effect depends on the percentage of receptors occupied. 2. Hypothesis of Ariens and Stephenson- There are many homologous substances which have various degrees of affinity for the receptor. 3. Hypothesis of Pathon- effectiveness does not depend upon actual occupation of the receptor by the drug, but upon obtaining the proper stimulus only. 4. Lock and key theory- the drug molecule must fit into a receptor like a key the fits into a lock.

STRUCTURES FOR DRUG RECEPTOR INTERACTION:

 Receptors are found within the cell surface, cytoplasm or inside the nucleus are also responsible for selectivity of drug action. Nucleic acid- are important drug receptors particularly for cancer chemotherapeutic agents.

 The receptors has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. 1. Receptors largely determine the quantitative relations or concentration of drug and pharmacologic effect. 2. Receptors are responsible for selectivity of drug action. 3. Receptors mediate the action of pharmacologic agonist and antagonist.

 Orphan receptor Their ligands are presently unknown, which may prove to be useful targets for the development of new drugs.
Best characterization of the receptors are regulatory proteins the action of endogenous chemical signals such as neurotransmitters , autacoids , and hormones.

Other Class of Proteins ( Receptors )

Includes

Enzymes

Transport proteins

Structural proteins

Inhibited, less commonly activated by binding a drug

Eg. Dihydrofolate reductase the receptor for the antineoplastic drug eg. methotrexate

Eg. Na,K, ATPase the membrane receptor for cardioactive digitalis glycosides

Eg. Tubulin, the receptor for colchicine, an antinflammatory agent

Three aspects of drug receptor function

1. Receptor as determinants of the quantitative relation between the concentration of drug and the pharmacologic response

2. Receptors as regulatory proteins and component of signaling mechanisms that provide targets for important drugs

3. Receptors as key determinants of the therapeutic and toxic effects of drugs in patients

Concentration effect Curves & Receptor Binding agonist

E - effect observed at concentration ( C ) Emax- is the max. response that can be produced by the drug EC50 conc. of drug that produces 50% of maximal effect E=
+

The hyperbolic relation resembles the mass action law, which describes the association between two molecules of given affinity This resemblance suggest that drug agonist act by binding to a distinct class of biologic molecules with a characteristics affinity for the drug receptor. Radioactive ligands have been used to confirm this occupancy assumption in many drug receptor systems. B- drug bound to receptors C- relates to the conc. Free ( unbound ) drug Bmax total conc. of receptor sites Kd represents the conc. of free drug at which halfmaximal binding is observed. B=
+

 If the Kd is low, binding affinity is high and vice versa

Receptor-effector Coupling & Spare receptors

The transduction process to process that links drug occupancy of receptors and pharmacologic response is often termed coupling.

 Spare Receptors- any of the receptors in excess of those required to evoke a given response to a drug, hormone, or other agonist. The size of the population of spare receptors (receptor reserve) can vary with the tissue and with the magnitude of the response being measured. For different drugs, the receptor reserve varies with drug efficacy.

Kd is the concentration of drug required to bind HALF of the receptors. In the hypothetical situation depicted below, of 100 receptors, only 10 need to be bound to achieve Emax; i.e. 90% of these are spare receptors.

100 %

50%

If EC50 is less than the Kd for a drug, then Spare receptors do not exist Because 50% of the maximal response has been achieved at the same concentration of drug required to occupy 50% of the available receptors

 Coupling efficiency is determined by the

biochemical events that transduce receptor into cellular response. Sometimes the biologic effect of the drug is linearly related to the number of receptor bound. This is often true for drug-regulated ion channels eg. in which ion current produced by the drug directly proportional to the number of receptors ( ion channels ) bound.

 The concept of spare receptors regardless of the precise biochemical mechanism involved, can help us to think about these effects. Receptors are said to be spare for a given pharmacologic response if it is possible to elicit a maximal response at a conc of agonist that does not result in occupancy of the full complement of available receptors.

Drug Molecules

-adrenoceptor activation promote Cell membrane

GTP

Binding

Intermediate signaling protein

Activation

Outlast the agonist-receptor interaction

If the concentration or amount of cellular components other than the receptors limits the coupling of receptor occupancy to response , then a maximal response can occur without occupancy of receptor. The sensitivity of a cell or tissue to a particular conc of agonist depends not only on the affinity of the receptor for binding the agonist but also on the degree of sparenesstotal number of receptors present compared with the number actually needed to elicit a maximal response

Competitive & Irreversible antagonist

Receptor antagonist bind to receptor but do not activate them. The primary function of antagonist is to prevent agonist from activating the receptors. Some antagonist also reduce receptor activity below basal body levels observed in the absence of bound ligand.

 In the presence of a fixed conc. of agonist, increasing concs. of a reversible competitive antagonist progressively inhibit the agonist response. High antagonist concs. prevent response completely.

A A

A needs higher conc. If CA is present

X Outside

A
CA CA

A X
CA

X R

Cell membrane
Inside

 The mathematical relation has two important therapeutic implications: Depends 1. Produced by Degree of
inhibition CA

Conc. Of antagonist

Competitive B-adrenoceptor antagonist propranolol provides useful example. Patients receiving fixed dose of this drug exhibit wide range plasma conc, owing to differences among individuals in clearance of propranolol. as a result inhibitory effects on physiologic responses to norepinephrine and epinephrine ( endogenous adrenergic receptor agonists) may vary widely, and the dose of propranolol must be adjusted accordingly.

2. Clinical response to a competitive antagonist depends on the conc of agonist is competing for binding to receptors.
E Heart rate

R
However , increase in the release of norepinephrine that occurs with exercise postural Changes or emotional stress may suffice to overcome this competitive antagonism. If the same dose of Propranolol is given it will decrease the therapeutic response.

 Some receptor antagonist bind to the receptor in an irreversible or

nearly or nearly irreversible fashion, either by forming a covalent with receptor or by binding tightly that, for practical purposes the receptor is unavailable for binding of agonist.

Full agonist

Full agonist + irreversible antagonist

Phenoxybenzamine
pheochromocytoma Irreversible -adrenoceptor antagonists Control Caused by Hypertension Released from

catecholamines

If administration of phenoxybezamine lowers blood pressure , blockade will be

maintained even the tumor episodically release very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If overdose of occurs , however real problem arise If the alpha adrenoceptor blockade cannot overcome, excess effects of the drug must be antagonized physiologically, by using a pressor agent that does not act via alpha receptor

 How does the presence of spare receptors affect the impact that a low dosage of irreversible antagonists will have on the dose response for an agonist? The potency of the agonist will decrease, but the efficacy will not change because the low dose of irreversible antagonist will only occupy the receptors that are not saturated by the agonist.

 Partial Agonists
Agonists

R
Full occupancy Partial agonist

Full agonists

Produce conc-effect curves that resemble those observed with full agonist in the presence of antagonist that irreversibly blocks some receptor site.

Failure of partial agonist to produce maximal response is not due to decreased affinity for binding of receptors but partial agonist competitively inhibit the responses produced by full agonist.

 Many drugs used clinically as antagonist are actually partial agonist . For example buprenorphine a partial agonist of -opioid receptors, is generally safer analgesic drug than morphine because it produces less respiratory depression in overdose Buprenorphine is effectively anti analgesic when administered with morphinedependent individuals, however and may precipitate a drug withdrawal syndrome.

Other mechanisms of Drug Antagonism: Not all the mechanisms of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor, and some types of antagonism do not involve a receptor at all. When two substances combine in solution such that the effect of the active drug is lost. Term as Chemical antagonism. eg. Protamine that is positively charge at physiological pH can be used clinically to counter act the effects of heparin, an anticoagulant that is negatively charged.

Physiologic antagonism- a drug that produces the opposite effect to a specified agonist by an action that is unrelated to that of the agonist. e.g. several catabolic actions of the glucocorticoid hormones leads to increased blood sugar, an effect that is physiologically opposed by insulin although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose hyperglycemic effects of glucocorticoid hormone, whether the latter is elevated by endogenous synthesis or as a result of glucocorticoid therapy.

Partial agonist

% of MB Total Response

Full agonist

Full agonist

Log ( partial agonist )

Partial agonist

Full agonist
Log ( partial agonist ) R Partial agonist

Log of partial agonist or partial agonist

Signaling Mechanisms and Drug action Until now we have considered receptor interactions in terms of equations and concentration-effect curves. We must also understand the molecular mechanisms by which drug acts. Most transmembrane signaling is accomplished by a small number of different molecular mechanisms

Five basic mechanisms of transmembrane 1. A lipid-soluble ligand that crosses the membrane and acts on the intracellular receptor 2. A transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds and stimulates a protein kinase 3. A transmembrane receptor that binds and stimulates protein tyrosine kinase 4. Ligand-gated transmembrane ion channel that can be induced to open or close the binding of a ligand 5. A Transmembrane receptor protein that stimulates a GTP binding signal transducer Protein ( G protein ) which in turn modulates production of an intracellular second messenger

1. Intracellular Receptors for Lipid-soluble agents several biologic ligands to cross the plasma membrane and act on intracellular receptors. Ligands: corticosteroids, mineralocorticoids, sex steroids, Vitamin D. ) and thyroid hormone whose receptors stimulate the transcription of genes by binding to specific DNA sequences near the gene whose expression is to be regulated Binding of glucocorticoid hormone to its normal receptor protein relieves an inhibitory constraint on the transcription-stimulating activity of proteins.

Ligand - binding domain hsp 90 Steroid

hsp 90

Transcription Activating domain DNA binding domain Altered Transcription

Response

2. Ligand- Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinase. This class of receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor-B ( TGF-B ) and many other trophic hormones. The receptor tyrosine kinase signaling pathways begins with binding of ligand, typically a polypeptide hormone or growth factor, to the receptors extracellular domain.

 The resulting change in receptor conformation causes receptor molecules to bind to one another , which in turn bring together the tyrosine kinase domains, which become enzymatically active and phosphorylate one another as well as additional downstream signaling proteins. Activated receptors catalyze phosphorylation of tyrosine residues on different target signal proteins, thereby allowing a single type of activated receptor to modulate a number biochemical receptor.

Extracellular hormone binding

EGF Molecules

Outside

Inside

P Y Y

S P

ATP

ADP

protein tyrosine kinase Serine kinase Guanylyl cyclase

3. Cytokine receptors Cytokine receptors respond to heterogeneous group of peptide ligand, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. The receptors use a mechanism closely resembling that of receptor tyrosine kinase except in this case the protein tyrosine kinase activity is not intrinsic to the receptor molecule.

extracellular

Cytokine molecules

R
JAK

R
JAK

P Y

R JAK JAK

Y P Y P

P Y

STAT

STAT

Intracellular

STAT

Y P P Y

STAT

Nucleus Response

4. Ligand and Voltage Gated Channels Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. Natural ligands are Ach, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.

ACh

Na ACh

Outside

Inside

Na

Depolarization

5. G Proteins and Second Messenger Many extracellular ligands act by increasing the intracellular concentrations of second messenger such as cyclic adenosine-3,5-monophosphate (cAMP), calcium ion, or the Phosphoinositides. In most cases they use a transmembrane signaling system with three separate channels.

Extracellular

Extracellular ligand

Detected by

Cell-surface detector
Cell membrane triggers Intracellular
G Protein activation

Change

Activity of an effector element

Eg. Element or ion

Changes

Conc. of intracellular 2nd messenger

Examples of receptors : B adrenoceptors, glucagon receptors, thyrotropin receptors & certain types of dopamine and serotonin receptors

cAMP

Effector enzyme

Adenylyl cyclase ATP

Agonist GTP

release

E GDP

entry
regulate

G-GDP

G-GTP Nucleotide binding site

terminate E hydrolysis Pi

 Receptors coupled to G proteins ( GPCRs) make up family of seven transmembrane (7-TM) or serpentine receptors so called because the receptors polypeptide chain snakes across the plasma membrane seven times. Receptors for adrenergic amines , serotonin, acetylcholine ( muscarinic but not nicotinic ) many peptide hormones , odorants, and even visual receptors all belong to serpentine family.

Agonist Outside N
II I VII VI III Eg. Acetylcholine or Catecholamines

Ag

IV V

Activating

Inside

OH

C
OH

Serine & threonine

OH OH
phosphorylated

G Protein

.Receptor Regulation: G protein-mediated responses to drugs and hormonal agonists often attenuate with time. After reaching an initial high level the response ( eg. cAMP accumulation, Na influx, cintractility) diminishes over seconds and minutes. This desensitization is often rapidly reversible a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response

Desensitization- decline in the response to repeated or sustained application of an agonist

Agonist R E S P O N S E c A M P 1 2 3 4 Time 5 1 2

Agonist in extracellular

Down regulation- reduction of cells response to hormone Other ligand by internalizing its cognate receptor and degrading It within an coated pit

1 -OH -OH -OH

GRK 2 ATP -OH -OH -OH P P B arr 4 P ase P -OH -OH P endosomes prolonged 6 lysosomes

Gs
5

P Coated pit 3 Down regulation

B. Well- Established Second Messenger:

1. Cyclic Adenosine Monophosphate (cAMP) Acting as an intracellular second messenger, cAMP mediated such hormonal responses as the mobilization of stored energy, conservation of water, Ca homoestasis and increased rate and contractile force of heart muscle. It also regulates the production of adrenal and sex steroids, relaxation of smooth muscle and many other endocrine and neural processes

2. Calcium and Phosphoinositides: Another well- studied system involves hormonal stimulation of
phosphoinositide hydrolysis. Some of the hormones, neurotransmitters , and growth factors that trigger this pathway bind to receptors liked to G proteins, whereas others bind to receptor tyrosine kinases.

Agonist

Stimulates

R
Linked

PLC

Splits

PIP2

DAG Activate

IP3 Release elevated ++ S ATP

PK-C *
ADP S P

CaM
Pi E caM-E *

Response

3. Cyclic Guanosine Monophosphate (cGMP) Unlike cAMP, the ubiquitous and versatile carrier of diverse messages, cGMP has established signaling roles in only a few cell types. In the intestinal mucosa and vascular smooth muscle, the cGMP-based signal transduction mechanism closely parallels the cAMP-mediated signaling mechanism.

Ligands

R
Stimulate

GC produce cGMP

PK
Acts by stimulating

Membrane

terminates
ANP Cyclic Nucleotide and dephosphorylation kinase S

Activating GC

Membrane

Interplay among signaling Mechanisms the Ca-phosphoinositide and cAMP signaling pathways oppose one another in some cells and are complementary in others. Example vasopressin agents that contrast smooth muscle by IP3- mediated mobilization of Ca whereas agent that relax smooth muscle often act by elevation of cAMP. cAMP + IP3- phosphoinositide= stimulate glucose from the liver

Phosphorylation : A common theme

Is the addition of a phosphate group to a protein or other organic molecule. The metabolic process of introducing a phosphate group into an organic molecule.

Dose & Response in Patients To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to be desired therapeutic effect.

Equal maximal efficacy and greater than

EC 50

Log drug dose

Shape of Dose- Response Curves

Log Drug dose

Quantal Dose Effect Curves

Review of Pharmacokinetics principle:

Drug Metabolism

Drug molecules

Non-polar Active metabolites

PHASE I

(OXIDATION, REDUCTION, & OXIDATION)

PHASE II Metabolite

( glucuronidation ) Inactive metabolite polar Excreted

LADMER process of drugs: Route of administration Liberation and Absorption process Distribution Metabolism and Excretion process (Elimination) 2. Clinical pharmacokinetics Clearance Vd One compartment model equation Individualized dosing regimen Steady state concentration

Pharmacokinetics & Pharmacodynamics: Rational Dosing & The Time Course of Drugs Action

Physiological receptors: Structural and Functional Families:

DRUG G Protein- Coupled Receptor Signaling GPCR Agonist EFFECTOR y Receptors for biogenic amines, peptides, acetylcholine Outside Ligand Binding membrane Cytosol Catalytic Activities Tyrosine kinase, tyrosine phospohatses, serine/threonine kinases, guanylyl cyclases Receptors as Enzymes

membrane