complete General Pharmacology

7/29/2019 complete General Pharmacology

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WHO defines drug as:

A substance, material or product used or intended tobe used to modify or explore the physiological

processes or pathological states for the benefit of therecipient.

e.g., Aspirin, cimetidine,

Loperamide, Morphine, etc.

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Divisons/branches of pharmacology

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Pharmacokinetics (ADME) Pharmacodynamics (Mechanism of action of drugs)

DRUG

Pharmacokinetic

concentration in plasma

concentration at the site of action

Pharmacodynamic

effect

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Pharmacognosy

"the study of the physical, chemical,biochemical and

biological properties of drugs, drug substances or

potential drugs or drug substances of natural origin aswell as thesearch for new drugs from natural sources."

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Pharmacy

It is a science of identification, source, selection,preparation, standardization, compounding and

dispensing of medicinal substances or drugs suitablesuitable for administration to the patient for thetreatment of different diseases. Now pharmacy dealswith rational use of medicines in patients.

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Redstribution of Drugs

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Clinical Pharmacology

It is the science which deals with the clinical

application of drugs especially on human beings.

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Toxicology

Toxicology is the branch of pharmacology which

includes the study of adverse effects of drugs on the

body. It deals with the symptoms, mechanisms,treatment and detection of poisoning caused by

different chemical substances.

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pharmacopoeias, formularies

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Is an official book authorized by the respectivegovernments consisting of official standards for purity,strength, quality and analysis of drugs.

e.g., BP, USP/NF, European Pharmacopeia

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At hospital level e.g, hospital formulary

At national level e., Orange book

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Where to get the drug/ medicine information

Primary

Secondary

Tertiary

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Active priciples of drugs

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Doses of drugs

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It is the amount of drug which will produce certainmeasurable biological response either at once or aftersometime when administered.

Or

Dose is the minimum amount of drug which producesdesired pharmacological effects.

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Therapeutic Dose

Toxic Dose

Maximal Dose

Minial Dose Lethal Dose

Graded Dose

Fatal Dose

Booster Dose

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Test dose

Ceiling Dose

Initial Loading Dose

Maintenance Dose Median Effective Dose

Median Lethal Dose

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Dose calculation in adults and in children(Paediatrics)

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Paediatric dose calculation formulas

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Is the passage of drug through cell membrane

to reach its site of action

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1. Simple diffusion = passive diffusion.

2. Active transport or carrier mediated transport e.g.,

vitamins, sugars, amino acids.

3. Facilitated diffusion .

4. Pinocytosis (Endocytosis) e.g., BaSO4

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Drug related

Lipid water solubility

Particle size

Degree of ionization

Physical forms

Chemical nature

Dosage forms Formulation

Concentration

Area of absorptivesurface

Vascularity pH

Presence of othersubstances

GI Motility Functional integrity

Diseases

Body related


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Definition:

bioavailability is a measurement of the rate and extent

to which a drug reaches the systemic circulation. It is

denoted by the letter f(or, if expressed in percent,by F).


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Physical properties of the drug ( Hydrophobicity,hydrophilicity,

Drug formulation

Fasted or fed condition of the patient Gastric emptying rate

Interaction with other food or drugs

Health of the GIT

Individual variation in metabolic differences

Disease state

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Definition

The period of time required for the concentration or

amount of drug in the body to be reduced to

exactly one-half of a given concentration oramount. Denoted by t 1/2

For example, after intravenous administration, if

maximum concentration is 16 mg and the half life is 2

hours, after 2 hours 8 mg will be left, and so on.

e.g., Salbutamol is 1.6 hours,Morphine is 2 to 3 hours

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The concentration of a drug or chemical in a bodyfluidusually plasmaat the time a steady state

has been achieved, and rates of drug administration

and drug elimination are equal.

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Definition :the metabolism of orally administered drugs by

gastrointestinal and hepatic enzymes, resulting ina significant reduction of the amount of

unmetabolized drug reaching the systemiccirculation.

After a drug is swallowed, it is absorbed by the digestive system and enters the hepaticportal system. It is carried through the portal vein into the liver before it reaches therest of the body. The liver metabolizes many drugs, sometimes to such an extent thatonly a small amount of active drug emerges from the liver to the rest ofthe circulatory system. Thisfirst pass through the liver thus greatly reducesthe bioavailability of the drug. Alternative routes ofadministration like suppository, intravenous, intramuscular, inhalational aerosoland sublingual avoid the first-pass effect because they allow drugs to be absorbeddirectly into the systemic circulation.

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the passage of drugs from blood to tissues.

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BODY WATER COMPARTMENTS:50Kg 100Kg

(110 lb) (220 lb)

Total body water (60% body weight) = 0.6 L/Kg, 30 L 60 L

1. Extracellular (20% body weight) = 0.2L/Kg, 10 L 20 L

a). Plasma (4% body weight) = 0.04L/Kg, 2 L 4 L

b). Interstitial (16% body weight) = 0.16L/Kg, 8 L 16 L

2. Intracellular (40% body weight) = 0.4 L/Kg, 20 L 40 L

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Body compartments where a drug can accumulate are

reservoirs. They have dynamic effects on drug

availability.

plasma proteins as reservoirs (bind drug)

cellular reservoirs

Adipose (lipophilic drugs)

Bone (crystal lattice)

Transcellular (ion trapping)

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Passive movement of drugs across biological

membranes is influenced by protein binding. Binding

may occur with plasma proteins or with non-specific

tissue proteins in addition to the drugs receptors.

Only drug that is not bound to proteins (i.e., free

or unbound drug) can diffuse across membranes.

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albuminbinds many acidic drugs

Globulin

bind hormones, vitamins etc., 1-acid glycoprotein

for basic drugs

The fraction of total drug in plasma that is bound isdetermined by its concentration, its binding affinity,and the number of binding sites.

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Tetracycline antibiotics (and other divalent metal ion-chelating agents) and heavy metals may accumulate inbone. They are adsorbed onto the bone-crystal surfaceand eventually become incorporated into the crystal

lattice.

Bone then can become a reservoir for slow release oftoxic agents (e.g., lead, radium) into the blood.

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Many lipid-soluble drugs are stored in fat. In obesity, fat

content may be as high as 50%, and in starvation it

may still be only as low as 10% of body weight.

70% of a thiopental dose may be found in fat 3 hr after

administration.

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A highly lipid-soluble i.v. anesthetic. Blood flow to the

brain is high, so maximal brain concentrations brainare achieved in minutes and quickly decline. Plasma

levels drop as diffusion into other tissues (muscle)

occurs.

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Substances that undergo enterohepatic circulation aremetabolized in the liver (usually by conjugation),excreted in the bile, and passed into the intestinallumen (where the intestinal bacteria break some of the

conjugated drug, releasing the unmetabolized drugagain) where they are reabsorbed across the intestinalmucosa (thus returns to systemic circulation again)and returned to the liver via the portal circulation

E.g. vit B12, Folic Acid,steroid hormone.

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is the movement of drug from tissues and bloodto the external environment.

Renal excretion

Non renal excretion

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Occure by 3 machanismsGlomerular filteration

Active secretion

ReabsorptionFor drugs with mol wt. < 300

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Glomerular filteration rate

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Is the volume of the fluid filtered from the renalglomerular capillaries in the Bowmanns capsule perunit time.

GFR is calculated by either creatinine excretion orInuline excretion

So GFR is the measurement of the working efficiency

of the kidneys.

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Rate of bile secretion= 0.5-1ml/min For drugs with mol wt. > 500

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The main organs responsible for drug excretion are thekidneys (renal excretion) and the liver (biliary excretion). Breath Urine Saliva Perspiration Feces Milk Bile (

Hair cannot be excreted before metabolism into more polar

compounds.

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Is defined as the rate of drug elimination divided by theplasma concentration of the drug.

Drug clearance is concerned with the rate at which activeactive drug is removed from the body ; and for themost drugs at steady state, clearance remains constantso that drug input remains equal to drug output.

Increased clearance shorter the plasma half life of thedrug.

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What the drug does to the body Def:

Mechanism of action or the physiological andbiochemical processes through which a drug producescertain effects or changes at the organ as well as at thecellular level.

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Local action Systemic action

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Do not impart any new function to any system, organor cell.

Only alter the pace of ongoing activity

Stimulation

Depression

Irritation

Cytotoxic action

Replacement

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Primary effects ( required therapeutic effects)

Secondary effects (undesirable effects/side effects)

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Action on specific receptors Action on specific enzymes

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Receptors

Definitions

Classification

Ligands (Drugs)

Definitions

Classification

Ligand-Receptor interaction

Interaction and consequence

Receptor-mediated mechanism of action


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Drugs usually do not bind to these biomoleculesdirectly but act through specific macromolecules-

Receptors

Definition:

It is defined as a macromolecule or binding site locatedon cell surface or inside the effector cell that interactwith a drug and initiate the chain of events leading to

the drugs observed effects.

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Reversible

ionic attraction, hydrogen

bonds

Van der waals forces.

Slowly reversible

/irreversible

high affinity covalent

binding, covalent binding


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Drugs or endogenous compounds binding to receptors are described asLigands.

Ligands are classified into 2 groups

Agonist: molecule that binds to receptor and produces similar response to that of

the endogenous ligand

Partial agonist agonist that produce partial effect

Full agonist

Antagonist: molecule that binds to a receptor, but does not cause a response

Competitive reversible or weak binding

Non-competitive non-reversible or strong binding


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Ligands(Agonist and Antagonist)


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Affinity: the attraction of the drug for the

receptor.

high affinity: low concentrations bind

low affinity: high concentrations bind

no affinity: does not bind

Efficacy: the intrinsic activity

Max. effect efficacy = 1

Min. effect efficacy = 0


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Intrinsic activity or efficacyIs defined as the capacity to stimulate for a given

receptor occupancy. It is determined by the molecularproperties of the drug.

The configurational pecularities that determine theintrinsic activity are different from those whichdetermine the effinity to the receptor.

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Affinity Efficacy

Agonist yes high

Partial agonist yes low

Antagonist

Competitive low-medium no

Non-competitive high no


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Mechanism of of action:

anti-cholinesterase

Inhibits activity of acetyl-cholinesterase

ACh

AChE

acetate choline

Effects: increase Acetylcholine (ACh) levels in the

synapse.

Clinical use: treatment ofmyasthenia gravis


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Graded dose-response curveQuantal dose-response curve

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It is defined as the quantitative curve in whichincreases doses of a drug produce varying changes ineffects.

Threshold dose

Ceiling effect

Graphical presentation of drug concentration onarithmatic scale (hyperbola shape) and when on log

scale (S shape).

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log dose

response

BA


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For effects like prevention of cardiac arrythmias, convulsions death. ALL OR NONE

A test animal pool is given a fixed dose and then the dose is noticed atwhich the effect and death s produced in 50% of animals

Percentage

individualResponse

ED 50 LD 50

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age Body weight

Sex

Routes of administration

Time of administration

Effect of climate

Racial difference Dosage form of drugs

Age of drug

Absorption distribution and excretion of drugs

Pathologcal condtions

Hypersusceptibility Allergy

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Drug-drug interactions Drug-food interactions

Drug lab interactions

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When two or more drugs are given at the same time they mayexert their effect independently or they may interact i.e., onedrug may iinf luence the action of another drug. So

Is a situation in which one drug effects the action or efficacy ofanother drug when both drugs are administered together

As a result the final effect will be Synergism

a) Summation e.g., administration of two general anestheticsat a same time

b) Potentiation e.g., aspirin potentiate theanticoagulant effect of heparin and warfarin

Antagonistice.g., acetyle choline antaginise by atropine

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In-vitro (outside the body before applicationto the patient)

In-vivo (within the body after intake by the

patient)

In vitro drug-drug interactions are alsocalled drug incompatiblities e.g., in thiopentone andsuxamethonium should not be filled in the same

syringe, in blood, amino acid, fat emulsions no drugshould be mixed. Heparin should not be mixed withdexrose solution etc.,

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At Pharmacokinetic level At Pharmacodynamic level

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What is pharmacokinetic?

ADME

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Interactions effecting drug absorption : Due a reduction in total amount of drug absorbed is likely

to cause ineffective therapy

Drug effect the absorption of another drug by changing the

Gut motility, pH of gut motility, altering gut f lora byantimicrobials, and physicochemical interactions.

examples:

Antacids containing Ca or Al and tetracyclines,

Metoclopramide reduces absorption of cimetidine, liquidparaffin interferes with the absorption of vit D etc.,

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Interactions due to changes in protein binding ofdrugs:

Drugs with high protein binding affinity displace thedrugs of low protein binding affinity drug and thus

increasing its concentration in the blood andincreasing efficacy . Drugs which have protein bindingaffinity of about 90% can do this e.g., indomethacine,sulphonamides displace anticoagulant warfarin

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Interactions effecting drug metabolism: Enzyme induction many drugs induce the enzyme and

thus increase in the metabolism of the drug and reducingits plasma concentration and so its efficacy. For examplephenobarbitone accelerate the metabolism of oral anti-

coagulant (warfarin). Enzyme inhibition Some drugs inhibit the metabolism of another drug thus

increasing its plasma concentration and efficacy or toxicitydepending upon the concentration. For example isoniazid

potentiate action of phenytoin by inhibiting itsmetabolism.

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Interaction effecting the renal excretion of thedrugs:

Drugs are eliminated through kidney by

glomerular filteration

Active tubular secretion

Compitition between drugs which share active transportmechanism in the proximal tubule

Example:Probenecid delays the excretion of many drugs e.g.,

penicillin, indomethacin etc,.

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Due to similar or antagonistic pharmacological effectsor side effects.

Which may be due to competition at receptor site or occurebetween drugs acting on the physiological system

Potentiation: alcohol potentiate the effect of hypnotics andsedatives, aspirin potentiate effect of heparin

Summation: administration of two general anesthetics at asame time.

Antagonism: metoclopramide antagonises the effect ofatropine .

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complete General Pharmacology