General Pharmacology )343(

7/28/2019 General Pharmacology )343(

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I. General Pharmacology

Objectives:

After listening to the lecture (s), and studying the textbook the student

should be able to:

I Introduction to pharmacology:

1. Define and describe the concepts of: Pharmacology, Pharmacokinetics,

Pharmacodynamics, Pharmacotherapeutics and Toxicology

2. Outline sources of drugs and drug nomenclature

3. Know sources of information and literature of pharmacology

4. List different dosage forms of drugs

5. Outline routes of drug administration with regard to advantages and

disadvantages as well as the effect on the therapeutic outcome6. Discuss the therapeutic vs. adverse effects of each drug class

A) Pharmacokinetics:

I. Principles and concept

1. Define pharmacokinetics

2. Write down major processes involved in pharmacokinetic (absorption,

distribution, metabolism and excretion).

3. Define pharmacokinetic parameters and list factors influencing those(genetics, disease states, age, hepatic and renal function).

4. Estimate the values of the following pharmacokinetic parameters from

the drug plasma concentration-time curve: peak concentration (Cmax)

peak time (Tmax, half-life (t1/2), elimination rate constant (Ke), clearance

(Cl), volume of distribution (Vd) and area under the plasma

concentration-time curve (AUC).

5. Explain the importance of pharmacokinetics in drug therapy (drug of

choice, dose & dosage regimen, therapeutic outcome, adverse drug

reactions and drug interactions.

II. The fate of drug in the body: absorption and distribution:

1. List and explain physicochemical factors in transfer of drugs across

membrane (influence of pH and pKa)

2. Describe and compare drug absorption, bioavailability and routes of

administration.

3. Anticipate the host and drug factors affecting absorption of drug

(physicochemical properties of the drug, physiological and pathological

conditions and exposure to xenobiotics)


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4. Describe the process, consequence and significance of drug

distribution, redistribution, plasma protein binding, tissue binding and

placental transfer of drug with regard to factors affecting distribution

and redistribution of drug (tissue perfusion, physicochemical properties

of the drug, accumulation of drugs in tissues and its consequences.

III. The fate of drug in the body: metabolism and excretion:

1. Define the terms: elimination, metabolism (biotransformation) and

excretion. List the major biotransformation reactions resulting in drug

metabolism (phase 1 and phase 2 reactions).

2. Identify the factors that can affect drug metabolism (nutritional,

physiological, genetic and environmental effects, chemical effects, enzyme

inhibition and induction)

4. Describe the different excretion routes and the mechanisms by whichdrug excreted from the body (hepatic excretion, and enterohepatic

circulation, other excretion processes: lungs, milk, placenta, eggs, nails,

hair, sweat, etc.)

5. Define the following terms: total clearance, renal clearance, hepatic

clearance, biliary clearance and extraction ratio.

B. Pharmacodynamics:

1. Define the following terms: agonist, partial agonist, inverse agonist and

antagonist (competitive and irreversible, physiological and

pharmacological antagonism)

2. Define terms being used in describing drug action: specificity,

selectivity, efficacy, and potency

3. Describe the concept of drug receptors and its theories

4. Describe the molecular drug targets (membrane receptors,

intracellular receptors enzymes, carriers, ion channels and etc.)

5. Explain the functional roles of the four receptor super families

(Voltage- and receptor operated ion channels, G protein-linked receptors,

Enzyme-linked receptors, and DNA-linked receptors

6. Describe factors that contribute to variation in drug responsiveness7. Classify adverse drug reactions and explain how to reduce the risk of

adverse drug reactions. Outline factors affecting adverse drug reactions

(disease, dose, co-medications and genetic).

OCULAR DRUGS AND PHARMACOLOGY


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OPTO-343

GENERAL PHARMACOLOGY

Frequently asked questions on general pharmacology

Bioavailability (Biological availability)

Q1: Definition, significance, calculation, and factorsaffecting bioavailability of drug:

1. Bioavailability is the percentage of drug released from aformulation that becomes available for biological effect

2. It measures the rate and extent of drug transfer from its siteof administration to the systemic circulation

3. It is calculated by comparison of the area under the serumconcentration curve (AUC) after IVI with that observed whenthe same dose is given by another route

4. Factors affecting bioavailability include: a) Factors

affecting GI absorption and b) first pass metabolism

A. Factors affecting GI absorption:

1) Drug: molecular weight, lipophilicity, pKa, and stability inthe gut contents.

2) Formulation: disintegration time and rate of dissolution

3) Patients: pH of the gut, gastric emptying rate, surface area

available for absorption, presence of GI diseases and otherdrugs that can modify absorption of drugs

4) Food: food reduces the absorption of some drugs likepenicillin-V, cephalexin, tetracyclines and aspirin whileincreases the absorption of another drugs as propranolol,diazepam and dicoumarol.

B. First- pass effect (first-pass metabolism, presystemicelimination) is the metabolism of some drugs in a single


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passage through the liver, gut wall or the lungs beforereaching the systemic circulation.

Q2: Mention some notes on first pass-effect?

1. Some drugs are extensively metabolized in their first-passas propranolol and morphine

2. First-pass also occurs due to intestinal mucosalmetabolism as isoprenaline and flurazepam

3. Pulmonary drug metabolism after aerosol inhalation canoccur after isoprenaline administration

4. First-pass effect can be avoided by sublingualadministration and to some extent by rectal administration

Q3: Define drug distribution?

After a drug is absorbed, it will distribute between blood andtissues. The drug passes through the various body fluid

compartments (plasma, interstitial fluid and intracellular fluid)

Q4: Define compartment Concept?

The body can be represented as series of compartments thatcommunicate reversibly with each other. A compartment isnot a real physiologic or anatomic region but is considered asa tissue or group of tissues which have similar blood flow and

drug affinity. Within each compartment the drug is consideredto be uniformly distributed

Q5: Define One-compartment model?


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The simplest pharmacokinetic model. It considers the body asa single homogenous compartment. I.e. any change in theplasma levels of the drug reflects proportional changes intissue drug levels.

Q6: Define two-compartment model?

It involves a central compartment and a more slowlyequilibrating deeper peripheral compartment. It explains thebiphasic fall in log plasma concentration seen after IVI.

Q7: Mathematical interpretation of drug distribution?

Drug distribution is interpreted mathematically as theapparent volume of distribution (Vd)

Q8: Definition, calculation and importance of Vd?

Vd is the apparent volume that would accommodate all drugin the body if its concentration throughout the body was thesame as that in the plasma. It is not a real volume

Vd = Amount of drug in the body / plasma concentration

Q9: What is the importance of Vd:

1. It is an estimate of the extent of extravascular tissue uptakeof drugs. When Vd is small (frusemide 0.1 L/Kg) tissue uptakeis limited. Large values (digoxin 7L/Kg) indicate extensivetissue distribution)

2. Vd is important to calculate the size of a loading andestimate the fluctuations in plasma levels during repetitivedosing


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3. Drugs with high Vd are not amenable to dialysis because ofextensive tissue distribution

4. Small Vd is favored by low lipid solubility, high degree of

plasma protein binding and low level of tissue binding. Thereverse is true

Q10. Mention factors affecting distribution of drugs?

1. Physicochemical properties of the drug as MW, polarity,lipophilicity

2. Size of the tissue and amount of its blood flow

3. Binding to plasma proteins like plasma albumin and Alpha-1-acid glycoprotein. The bound portion is inactive, nondiffusible, can't be metabolized or excreted. The free drug isactive, diffusible and can be metabolized and excreted. Thetwo fractions exist in equilibrium; when the free part ismetabolized and/or excreted, another part is released fromplasma proteins

4. Binding to cell and tissue constituents due to an affinity tosome cellular constituents as chloroquine (concentrated inthe liver because it is highly bound to nucleic acids) also canbind to retinal nucleoproteins. Arsenic is deposited in the skinand hair as it is bound to keratin. Iodides are concentrated inthyroid and salivary glands, calcium is deposited in bone dueto its affinity to collagen, tetracyclines deposit in bone andteeth as they chelate with calcium

Q11: Mention the results of binding drug to plasma proteins?

1. Drugs with higher affinities to plasma proteins can displacedrugs of lower ones.

2. It provides a reservoir as the bound part is in equilibriumwith the free part


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3. It prolongs the half life of the drug because the bound partis not metabolized or excreted

4. Binding of drug to plasma protein determines its Vd,

penetration into tissues and secretion

5. Binding of a drug may facilitate drug absorption byreducing its free concentration in the plasma

The results of binding to plasma proteins (continued):

6. The concentration of free part of highly protein bound

drugs may be too low to be effective against dangerousinfections

7. When a drug that is extremely protein bound is given by IVI,the concentration of the free (active) drug will depend on theinjection rate

Q12. Passage of drugs to CNS:

1. The glial cells are the blood brain barrier (BBB)

2. Lipid soluble drugs pass freely through the BBB as generalanesthetics and other CNS depressants

3. Secondary and tertiary amines can pass while quaternaryammonium compounds cannot

4. Dopamine cannot penetrate easily into CSF, so inparkinsonism we give L-dopa instead of dopamine

Q13. Passage of drugs to the fetus:

1. Many drugs pass across the placental barrier by simplediffusion depending on their lipid solubility and their degree

of ionization. Lipid soluble drugs pass readily to the fetus ashypnotics, narcotics, anesthetics, most antibiotics, cortisone


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Q14: Examples of drugs that cross the placenta and can harmthe fetus:

1. In early pregnancy (third to tenth weeks), drug-induced

congenital anomalies may occur

2. Morphine can cause respiratory depression (asphyxianeonatorum)

3. Oral anticoagulants may initiate fatal hemorrhage in thenewborn

4. Sulfonylurea may cause prolonged neonatal hypoglycemia

5. Aminoglycosides can cause eighth cranial nerve damage

Q15: Define prenatal therapy "Fetotherapy":

A) Glucocorticoids reduce the incidence of respiratorydistress syndrome

B) Enzyme inducers as phenobarbitone given to the motherbefore labor enhance the ability of the newborn to conjugatebilirubin to prevent Kernicterus . However, phototherapy isnow used instead

C) Rho(D) immunoglobulin injected into the RH-negativemother to prevent the development of erythroblastosis fetalis

D) Low dose aspirin (60-75 mg/day) for prophylaxis ofuteroplacental insufficiency and pre-eclampsia

Q16: Define Biotransformation or metabolism?

Changes that occur to drugs after absorption until excretion.Drug metabolism occurs mainly in the liver though also inother organs as intestinal lumen, lung, skin and kidney


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Q17: What are the consequences of drug metabolism?

1. Abolishes the activity as with most drugs

2. Increases the activity as chloral hydrate to trichlorethanol,cyclophosphamide to various alkylating metabolites

3. Changes active drug to another active substance ascodeine to morphine, propranolol to 4-hydroxypropranolol

Q18: What are types of biotransformation reactions?

1. Phase I (non-synthetic reactions) as oxidation, reduction,hydrolysis, usually converts the parent drug to a more polarmetabolite. Non-synthetic reactions occur first and may befollowed by synthetic reactions

2. Phase II (Synthetic reactions): the body add one of itsconstituents to the drug to form highly polar, rapidlyeliminated conjugates (conjugation)

Q19: What are types of metabolizing enzyme systems?

1. Microsomal drug metabolizing enzyme systems

2. non-microsomal enzyme systems

Q20: What are microsomal drug metabolizing enzymes?

Group of enzymes synthesized in the smooth part of theendoplasmic reticulum and concentrated mostly in the liverbut also in many other tissues


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Q21: What are the characters of MDMEs?

1. They contain the mixed function oxidase ormonooxygenases. This oxidation reduction process require

cytochrome P-450, cytochrome P-450 reductase, NADPH andmolecular oxygen

2. They metabolize lipid soluble drugs into water solubleeasily excreted metabolites

3. They metabolize drugs as well as some body constituents

4. They lack substrate specificity

5. They are not well developed in the newly born so drugs aschloramphenicol are highly toxic in early infancy

Q 22: What are characters of NMDEs?

Specific enzyme systems that act on natural products presentin the body and on water soluble foreign compounds as

oxidases, peroxidases and dehydrogenases

Q23: What are the factors affecting biotransformation?

1. Species variation

2. Age: extremes of age are more susceptible to drug effects

3. Sex: estrogens inhibit while testosterone stimulates MES

4. Pathological factors: in liver disease, drug metabolism isdepressed. In addition, the metabolism of some drugs isreduced in cases of heart failure, shock and with B-blockersthat reduce hepatic blood flow

5. Environmental factors as tobacco smoking and pesticides


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6. Drugs can stimulate (enzyme induction) or inhibit (enzymeinhibition) microsomal drug metabolizing enzymes. Enzymeinduces as phenobarbitone, rifampin and phenytoin andenzyme inhibitors as cimetidine, chloramphenicol

Q24: Drug clearance (definition, calculation, and factorsaffecting drug clearance)?

1. Drug clearance is the volume of a fluid from which all drugis removed per unit time. It is a measure of the body's abilityto eliminate drugs

2. Clearance (CL) = Rate of elimination / Drug concentration

Elimination of drugs from the body involves two majorprocesses: hepatic metabolism-biliary excretion and renalfiltration-secretion. Total body clearance (CL) consists ofrenal clearance (Clr) and non-renal clearance (Clnr)

3. Factors affecting drug clearance:

1. Blood flow to the clearing organ

2. Binding of the drug to plasma proteins

3. Activity of the processes responsible for drug removal ashepatic enzymes, glomerular filtration and secretoryprocesses

Q25: Define hepatic clearance and factors affecting it?

Hepatic clearance = hepatic blood flow X extraction ratio (E)

Hepatic clearance depends upon:

1. Intrinsic activity of metabolic enzymes and transportprocesses. 2. Free fraction of drug in the blood

3. Total effective hepatic blood flow


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Q26: Define extraction ratio (E)

Extraction ratio (E) is the proportion of drug removed by asingle transit of blood through an organ

E = arterial drug conc. venous drug conc. / arterial drug con

When E is more than 0.6, clearance is flow-dependent asverapamil and morphine, when E is less than 0.2, clearance isenzyme-dependent as warfarin and theophylline and when Eis between 0.2-0.6, clearance is both flow and enzymedependent as acetaminophen and chloramphenicol

Q27: Define elimination half life (t1/2)

The time required to reduce the plasma concentration of drugto half the initial concentration

It is the relationship between apparent volume of distribution(Vd) and clearance (CL)

Elimination half life = 0.693 Vd / CL

Q28: Define first order (linear or non-saturable) kinetics?

Clearance is directly proportional to the concentration of thedrug in the plasma. This means that a constant fraction orratio of drug is eliminated per unit time as with most drugs

Characteristics of first order kinetics:

1. Constant half life

2. AUC, Css and amount of drug excreted unchanged in urine,all are proportional to the dose

3. The composition of drug metabolites excreted isindependent of the dose

4. The time required to reach Css is about 5 times the half life


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Q29: define Zero order (non-linear) kinetics?

Drug elimination occurs at a constant rate and independent ofthe amount of drug to be eliminated. This means that a

constant amount of drug is eliminated per unit time as withethanol clearance

Characteristics of zero order kinetics?

1. Half-life increases with the dose

2. AUC, Css and renal clearance are not proportional to thedose

3. Composition of drug metabolites may vary with the dose

Q30: Adverse reactions of drugs (Definition and types)?

Harmful effects of a drug occurring at doses used fortherapeutic, prophylactic or diagnostic purposes and whichcall for reduction of dose, drug withdrawal and/or immediate

treatment


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Q31 what are types of adverse reactions?

1. Type A (side effects and over dosage toxicity)

2. Type B (hypersensitivity and idiosyncrasy)

Adverse reactions include:

A) Side effects: Unavoidable part of the pharmacologicactions of the drug used for a specific indication attherapeutic doses as sedation with antihistaminics

B) Over dosage toxicity: occur at high doses and theirincidence increases as the dose is increased as liver damage

from paracetamol overdosage, ototoxicity fromaminoglycosides

C) Allergic reactions: adverse reactions that are not dose-related, usually induced by prior contact with drugs that actas antigens

D) Drug abuse: the use for non-therapeutic purpose of drugsthat act on the CNS leading to dependence

Adverse reactions are due to many factors:

1. Some are related to the patient as age, sex, tendency toallergy, disease, personality and habits

2. Others are drug factors due to the drug itself or interactionsbetween drugs


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Q32: Define intolerance?

A low threshold to the normal pharmacological action of adrug. It is the reverse of tolerance

Q33; Define idiosyncrasy?

Inherent qualitatively abnormal reaction to a drug due togenetic abnormality as porphyria, favism.

Q34: Iatrogenic diseases (drug-induced diseases)

A drug prescribed for a disease causes another disease asdrug- induced asthma, peptic ulcer or parkinsonism

Q35: Define teratogenesis?

Foetal abnormalities caused by some drugs when given earlyin pregnancy as cytotoxic drugs (abortion or foetalanomalies), tetracyclines (dental enamel hypoplasia)

Q36: Define potency and efficacy?

Potency refers to the range of doses over which a drugproduces increasing response. It is determined along the

dose axis of the dose- response curve

Efficacy is the capacity of the drug to produce maximal effect.It can be determined along the response axis of the dose-response curve

Clinically, efficacy is more important than potency

Individuals vary in their response to a drug. They may be

hyporeactive or hyperreactive in comparison to mostindividuals


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Q37: What are factors modifying drug action?

The main factor that can modify drug action is the dose. Otherfactors include age, sex, weight, race, pathological states,

nutrition, pharmacogenetic defects, bioavailability,hypersensitivity, tolerance and tachyphylaxis, dependenceand drug interactions

The dose of the drug can be calculated according to the age,weight or surface area of the patient

Dose for infants (less than 2 years) = adult dose X infant'ssurface area / 1.73

Young's rule: Dose for children = adult dose X age (years) /age + 12

Clark's rule: Dose for a child = adult dose X weight in pounds /150

Percentage method: the dose is calculated as a percentage ofadult dose: 1 month (10%), 1 year (25%), 3 years (33%), 7years (50%), 12 years (75%)

Method considering pharmacokinetic parameters:

Loading dose = Vd/f X Css

Maintenance dose = Cl/f X Css X T

Weight: The dose is calculated according to the lean bodyweight. In the obese, lipid soluble drugs should be given inlarger doses

Sex:

Females are more susceptible to autonomic drugs asestrogens inhibit choline esterase. Certain drugs actspecifically in women as progesterone and women responddifferently to certain drugs as nitrous oxide leads to vividdreams


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Pathological states:

1. In sensitive patients, cholinomimetics, B-blockers canprecipitate an asthmatic attack

2. Myxedematous patients cannot tolerate morphine

3. Morphine is dangerous in liver disease

4. Aminoglycosides accumulate in renal impairment

5. Absorption of iron salts is increased in iron deficiency

anaemia

Nutrition:

1. Protein-deficient diet may decrease drug conjugation

2. Patients receiving MAO inhibitors should avoid dietcontaining tyramine as cheese, red wine, beans (Cheese

reaction)

Pharmacogenetic defects

(genetically determined variations that are revealed only bythe effect of drug. Examples include:

1. Drug acetylating enzymes: two classes of people exist, therapid and slow metabolizers. In the slow acetylators, the drugaccumulates and produce toxic effects more than in the rapidacetylators as with isoniazid

2. Plasma pseudocholinesterase: succinylcholine apnoeamay occur in patients deficient in ChE or having atypicalenzyme (has a lower rate of activity and decreased affinity forsuccinyl choline


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3. glucose-6-phosphate dehydrogenase: congenital deficiencyof the enzyme renders RBCs readily hemolyzaed in presenceof some oxidant drugs as antimalarials, antimicrobials

4. Porphyrias: increased levels of porphyrins and theirprecursors that can cause severe neurological disturbanceand may cause death. Drugs causing porphyria includebarbiturates (they increase the activity of ALA-synthetaseenzyme. Haemin is an ALA-synthetase inhibitor obtained fromRBCs, it can be used to ameliorate recurrent attacks of acuteintermittent porphyria

5. Malignant hyperthermia: marked muscle rigidity and rise oftemperature. It is a rare complication of anesthesia. The basicdefect is reduced uptake or binding of calcium to thesarcoplasmic reticulum. Occurs with suxamethonium orhalothane. Dantrolene can be used to treat this condition

6. Steroid-induced raised intraocular pressure in geneticallypredisposed persons

7. Acatalasia: deficiency of catalase enzyme which causesbreakdown of hydrogenperoxide into water and oxygen.

Affected persons develop severe ulcers in the mouth andsuffer loss of teeth


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Drug allergy:

A drug, metabolite or a non-drug element in the formulationactivates the immune system in an undesirable way that

appears as drug allergy. It is dose independent and occurs inminority of patients. Cross allergy occurs within a group ofdrugs. The chief target organs of drug allergy include skin,respiratory tract, GIT, blood and blood vessels

Types of allergic reactions:

1. Type I reaction: immediate type (Anaphylactic): It is an IgE-mediated reactions as anaphylaxis, asthma, urticaria andangioedema. Occurs with penicillin.

2. Type II reaction: It involves IgG or IgM antibodies., occursas autoimmune hemolytic anaemia (methyldopa),thrombocytopenia (quinidine), agranulocytosis(chloramphenicol)

3. Type III reactions: Involves IgG and includes serumsickness, glomerulonephritis and pulmonary disease. Occurswith sulphonamides, penicillin.

4. Type IV reactions: Delayed type (cell-mediated): involvesallergic contact dermatitis from topically applied drugs

Diagnosis of drug allergy:

1. History and type of reaction

2. Intradermal and conjunctival tests

Measures against allergy:

1. Drug treatment as epinephrine, corticosteroids,antihistaminics

2. Desensitization or hyposensitization


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Define tolerance and mention its mechanisms?

Tolerance is an acquired resistance to the ordinary doses ofdrugs. It develops upon repeated administration and moredrug is needed to produce the same effect. It disappearswhen the drug is stopped for sometime.

Mechanisms of tolerance:

1. Increased metabolism due to enzyme induction

2. Development of antihormones (against insulin for example)

3. Decreased sensitivity of receptors

4. Reduced efficacy at receptor sites (e.g. opiates)

5. Down regulation of receptors (decreased number ofreceptors), occurs with B-agonists

Cross tolerance:

When one develops tolerance to a drug, he may also showtolerance to other drugs of the same group as members ofopiods

Tachyphylaxis (acute tolerance):

It is a rapid form of tolerance in which we cannot get the sameresponse by increasing the dose. Ephedrine producestachyphylaxis due to depletion of CA stores and may be dueto down regulation


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Drug interactions:

Pharmacologic responses which cannot be explained by theaction of one drug but are due to multiple drugs acting

concurrently.

Clinically important drug interactions occur with drugs thathave a steep dose-response curve and a smalltherapeutic/toxic ratio. Examples are oral anticoagulants, oralhypoglycemics, antiarrhythmics.

Drug interactions may result in antagonism or synergism

Antagonism:

may be physiologic (as histamine/adrenaline), competitive(naloxone/morphine) or non-competitive (irreversible ChEIs)

Synergism:

may be in the form of summation 9additive effect) as alcohol

and ether or potentiation (the combined effect is morepowerful as trimethoprim-sulphonamide combination

Types (mechanisms) of drug interactions:

1. Pharmaceutical incompatibilities: occurring outside thebody

2. Pharmacokinetic interactions: at sites of absorption,distribution. Metabolism and excretion

3. Pharmacodynamic interactions: at sites of action or nearby

Mechanism of drug action:

1. Receptor-mediated mechanisms: involving interactionswith particular receptors at specialized sites within the body

2. Non-receptor-mediated mechanisms


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Receptors:

specific cellular structures, protein in nature, which may beextracellular or intracellular. They interact, by a variety ofchemical forces, with chemical transmitters or drugs(agonists) to trigger changes in activity which result in thefinal observed effect. They are blocked by other drugs(antagonists or blockers). They are characterized bysensitivity, selectivity and specificity

Drug receptor interaction can manifest itself in various ways:

1. Drug interacts with the receptor activating it resulting in apharmacologic effect, i.e. it has affinity and efficacy. It iscalled an agonist (acetylcholine, epinephrine, norepinephrine)

2. Drug interacts with the receptor without activating it. i.e., itonly occupies the receptor (affinity without efficacy). It iscalled a pure antagonist as naloxone

3. A drug may act as a partial agonist (agonist-antagonist),i.e., it interacts with the receptor activating it but not to theextent of that of a full agonist i.e., it produces a lowerresponse, at full receptor occupancy, than do full agonists. Itantagonizes the effect of a full agonist as nalorphine

4. A drug may bind receptors without effect. The receptors arecalled silent receptors. E.g., drug binding to plasma protein

5. A drug may attach to many receptors and have manyactions as morphine, dopamine


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Antagonists

1. Chemical antagonists: they chemically interact with theagonist away from the receptor site

2. Competitive antagonists: compete with agonists for thesame recognition site of the receptors. Antagonism may bereversible or pseudoirreversble

3. Non-competitive antagonists: bind to an allosteric site onthe receptor distinct from the agonist recognition site.Antagonism may be reversible or irreversible

4. physiological or functional antagonists: interfere with some

process or processes subsequent to agonist activation of thereceptor

The antagonism is reversible when the antagonist bindsreversibly to the receptor site.

Irreversible antagonism occurs when the antagonist bindscovalently to the receptor site and hence dissociates veryslowly.

Competitive antagonism is usually reversible. However, somecompetitive antagonists are also able to produce irreversibleantagonism if they are tightly bound to the receptor anddissociate slowly. This better called pseudoirreversibleantagonism

Noncompetitive, irreversible and pseudoirreversibleantagonism are defined as nonsurmountable antagonism asthey don't regain the original response by addition of high

agonist concentration


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Characters of competitive antagonism:

1. Reversible

2. Compete with the agonist for the receptors

3. The duration of action is dependent on the relative plasmaconcentration of both agonist and antagonist

4. Causes parallel shift to the right in the dose-response curvewith no change in maximal efficacy

5. Examples: B-blockers, atropine, naloxone

Characteristics of non-competitive antagonism:

1. Irreversible

2. Have high affinity for the receptors rendering themunavailable for agonist binding

3. The duration depends on the rate of turnover of thereceptor molecules

4. Causes non-parallel shift in the dose-response curve anddiminution of maximal response

5. Examples: phenoxybenzamine


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Theories of Drug-Receptor Interaction:

1. Receptor occupation theory:

Drug effect is proportional to the fraction of receptorsoccupied, and the maximum effect results when all receptorsare occupied

2. Paton's rate theory:

The stimulus provided by an agonist molecule is proportional

to their rate of association and dissociation to and fromreceptors rather than to the proportion of the receptorsoccupied. Drugs that associate and dissociate rapidly areagonists. Those which dissociate slowly are antagonists.

3. Two-state model:

The receptors exist in two interchangeable states, R1 whichpreferentially binds the agonist, and R2, to which theantagonist binds more readily.

When an agonist combines with R1, more R2receptorschange to the R1 configuration. The reverse occurs when anantagonist binds to R2.

Partial agonists can combine with either receptor. Givenalone, they interact with R1 state and produce an agonist

response. However, in the presence of a full agonist, theyinterfere with its action both by competing for R1 sites and bybinding to the R2 site causing more receptors to changeconfiguration from R1 to R2.


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Cellular receptors and their signaling mechanisms

The receptors has two functions: ligand binding and messagepropagation. Hence, two functional domains should existwithin the receptor; a ligand-binding domain and an effectordomain. The effector domain of the receptor is linked to aneffector system in order to generate its effects (Receptor-effector system).

Cellular signaling systems "Receptor Effector Systems":

An individual receptor molecule may interact with closelyassociated cellular protein in order to generate its effect; thisconstitutes a receptor-effector system or cellular signalingsystem:

1. Agonist-gated ion channels:

Receptors for fast neurotransmitters form ion-selectivechannels in the plasma membrane and convey their signalsby altering cell membrane potential or ionic composition.Ligand binding and channel opening occur in millisecondsthus they are involved mainly in fast synaptic transmission. Itincludes nicotinic ACh receptors, GABA-A receptor and

receptors for glutamate, aspartate and glycine


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2. Agonist-regulated enzymes:

1. Receptors for peptide hormones such as insulin. Theextracellular hormone-binding domain is connected to anintracellular protein kinase catalytic domain.

2. Receptors for ANP and EDRF: the intracellular domain isguanylyl cyclase that forms the second messenger cGMP

3. G-protein-coupled receptors: receptors for slow

neurotransmitters as biogenic amines. These receptorsinteract with G proteins at their cytoplasmic face. The Gprotein is a trimer (, , and ). Agonist binding leads todissociation of the subunit which regulates the activity ofspecific effectors. These effectors include:

1. Adenylyl cyclase (increases cAMP), phospholipase C(liberates diacylglycerol 'DAG" and inositol triphosphate"IP3", guanylate cyclase (increases cGMP)

2. Channels that are specific for calcium, potassium orsodium

3. Certain transport proteins

4. Trancriptional regulators:

Steroid hormones enter the target cell and combines withintracellular receptor proteins associated with nuclear

chromatin to activate or inhibit transcription of the nearbygene. This will modify protein production and thereby causechanges in the structure or function of the target tissue

5. Translational regulators: These bind to intracellularreceptors and affect RNA secondary structure, its stability ortranslational efficiency.

END OF THE LECTURE


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General Pharmacology )343(