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We Fri lcom en ds e Let’s learnPHARMACOLOGY
PHARMACOLOGY Greek Word Pharmacon Logos Drug ScienceScience of drugs- dealing with the study of Desirable and Undesirable effects.
Pharmacology is the study of drugs and their actions on the body
What is PHARMACOLOGY ? Pharmacokinetics Pharmacodynamics What the body does to drug What the drug does to body PharmacologyPharmacotherapeutics PharmacyThe study of the use of drugs Preparing suitable dosage forms Toxicology
PHARMACO THERAPEUTICS It is a branch of medicine concerned with the cure of disease or relief of symptoms and induces drug treatment.
PHARMACYIt is the science of: •Identification •Selection •Preservation •Standardization •Compounding, and •Dispensing of medicinal substances
PHARMACOPOEIA• It is an official code containing a selected list of the established drugs and medicinal preparations with descriptions of their physical properties and tests for their identity, purity and potency. e.g. IP, BP, USP, etc. IP: Indian Pharmacopoeia BP: British Pharmacopoeia USP: United states Pharmacopoeia
DRUG“ Drug is any substance or product that is usedor is intended to be used to modifyphysiological systems or pathological states forthe benefit of the recipient .”
“Poisons in small doses are thebest medicines; and usefulmedicines in too large doses arepoisonous” William Withering 1789
DRUG NAMES• Chemical…states its chemical composition and molecular structure.• Generic…usually suggested by the manufacturer.• Official…as listed in the Pharmacopoeia. (I.P., B.P., U.S.P.)• Brand…the trade or proprietary name.
DRUG NAMES 1,4 benzodiazepine analogChemical NameGeneric Name AlprazolamOfficial Name Alprazolam, USPBrand Name Alprax®
THE NATURE AND SOURCES OF DRUGS• Mineral • Liquid paraffin, magnesium sulfate, etc• Animal • Insulin, Thyroid, etc.• Plant • Morphine, Quinine etc• Synthetic • Aspirin, Sulfonamides, etc.• Micro-organisms • Penicillin & other antibiotics.• Drugs produced • Human insulin, human growth, by genetic hormone etc. engineering
DRUG DEVELOPMENT PROCESS Chemistry Synthesis & Purification Formulation Animal Pharmacology Animal Toxicity (Short / Long term) Studies in Humans Drug Authorities Market
DOSE Vs DOSAGE• Dose: The quantity of drug administered at one time • 500mg of Paracetamol• Dosage: The amount of the drug that should be given over time • 500 mg Paracetamol TID for 3 days
DRUG DOSAGE FORMS Tablets Aerosol CapsuleSuspension Injection Cream Infusion Solution
ROUTES OF DRUG ADMINISTRATION How the drug is given Enteral Parenteral Topical (injectable)1. Oral 1. Intravenous 1. Intranasal2. Sublingual 2. Intramuscular 2. Inhalation3. Rectal 3. Subcutaneous 3. Intravaginal
ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION SAFETY High Oral > SC > IM > IV Low CONVENIENCE High Oral > SC > IM > IV Low COST High IV > IM > SC > ORAL Low
ADVANTAGES AND DISADVANTAGES OF ORAL, IV, IM AND SC ADMINISTRATION BIOAVAILABILITYHigh and Reliable IV > IM = SC > ORAL Low &/or Variable ONSET OF ACTION Immediate IV > IM > SC > Oral Delayed PATIENT COMPLIANCE High Oral > SC > IM > IV Low
PHARMACOKINETICS• The study of what the body does to the drug• It is the study of absorption, distribution, metabolism and excretion (ADME) of drugs• “Fate of drug”
PHARMACOKINETICS•Absorption How the drug is moved into blood stream from the site of administration ?• Distribution How much drug is moved to various body tissues / organs ? Depends on blood flow through tissue• Metabolism How the drug is altered – broken down ?• Excretion How much of the drug is removed from the body ?
ABSORPTION BIOLOGICAL BARRIERSite of Administration Vascular System DRUG
Drug Absorption of Various Dosage Forms Oral Preparations Liquids, elixirs, syrups Fastest Suspension solutions Powders Capsules Tablets Coated tablets Enteric-coated tablets Slowest
IV Route What would the graph of blood level against time look like?Bloodlevel Time
ORAL RouteWhat would the graph of blood level against time look like? Blood level Time
What is happening in these two phases? ? ?Bloodlevel Time
Absorption Metabolism and and Distribution ExcretionBloodlevel Time
BIOAVAILABILITY• Bioavailability is a fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form.• Bioavailability of IV route : 100 %
BIOAVAILABILITY Destroyed Not Destroyed Destroyed in gut absorbed by gut wall by liver toDose systemic circulation
BIOAVAILABILITYFactors influencing bioavailability • Dosage forms • Chemical form • Dissolution & Absorption of drug • Route of administration • Presence of food/drugs in GI tract • First pass effect • Extent of drug metabolism before reaching systemic circulation
Concept of Critical Threshold• MEC (Minimum Effective Concentration): The minimum level of drug concentration needed for the desired therapeutic effect to be present.• MSC (Maximum Safe Concentration): The maximum level of drug concentration above which toxic effects occurs. OR• MTC (Minimum Toxic Concentration): The minimum level of drug concentration that produces toxic effects.
•Maximal Effect: Greatest response that canbe produced by a drug, above which nofurther response can be created (sometimescalled “peak effect”)•Onset: How long before a drug is able toexert a therapeutic effect•Duration: How long a drug effect lasts
DRUG HALF-LIFE (t1/2 )• Half life is the time required to reduce the plasma concentration to 50% of its original value• Will determine dosing requirements / how long a drug will remain in the body• Used in determining dosing interval• Goal - Plateau
DRUG HALF-LIFE (t1/2 ) 110 100 90 Concentration (m g/L) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 Tim e (hours)Half-life is the time taken for the concentration of drug in blood to fall by a half Half-life is 2 hrs
DRUG HALF-LIFE (t1/2 )• 1t 1/2 - 50 % drug is eliminated• 2 t1/2 - 50+25 (75 %) drug is eliminated• 3 t1/2 - 50+25 +12.5 (87.5 %) drug is eliminated• 4 t1/2 - 50+25 +12.5+6.25 (93.7 %) drug iseliminatedThus, nearly complete drug elimination occurs in 4-5half lives.
Cmax & Tmax Cmax not art nec no C Tmax Time•Cmax - Maximum conc. achieved in the blood i•Tmax - Time taken to attain maximum conc.
AUC (Area Under Curve) AUC• AUC is the area under the plot of plasma concentration of drug against time after drug administration.
DISTRIBUTIONDistribution is a branch of pharmacokineticswhich describes the reversible transfer of drugfrom one location to another within the body.
DISTRIBUTION Locus of Tissue action reservoirs “receptors” Bound Free Bound Free Systemic circulationAbsorption Free drug Excretion Excretion Bound drug Metabolites Biotransformation
Plasma- Protein Binding• Many drugs bound to circulating plasma proteins such as albumin, lipoproteins, glycoprotein, globulins etc.• Free form • Pharmacologically active• Bound form • Pharmacologically inactive Receptor Site Protein-bound drug Free Drug
Protein Binding• Drugs can bind with proteins• Acts as temporary store of drug• Prolongs it’s action• Cause prolonged low level of drugs• Slowly released from bound reservoir• Delays metabolism• Delays excretion• Decreases its entry into CNS
Dosing• Dosing Interval - How often the drug should be given• Loading dose – Which puts the plasma concentration in the therapeutic range• Maintenance dose - Routine smaller doses to maintain the steady state (Plateau)
METABOLISM Metabolism = change / biotransformation The conversion from one chemical form to anotherSite of drug biotransformation • Liver - cytochrome P450 pathways OR microsomal P450 pathways are used to metabolize most agents • Enzymatic alteration of drug structure Effect of metabolism 80% of drugs become inactive Inactive drug becomes active: Prodrug Some drugs do not get metabolised at all
METABOLISM Majority of drugs are metabolized in liver by enzymes – Cytochrome P 450 Drugs may induce (activate) or inhibit these enzymes Drug – Drug interactions
First Pass MetabolismThe first-pass metabolism (also known as first-passeffect or presystemic metabolism) is a phenomenon ofdrug metabolism whereby the concentration of a drugis greatly reduced before it reaches the systemiccirculation.
First Pass Metabolism HepaticSwallowed Digestive Rest of portal Liver Drug system the body system
First Pass MetabolismSystems that affect the first pass effect of the drug, • Enzymes of the gastro intestinal lumen • Gut wall enzyme • Bacterial enzymes • Hepatic enzymes
First Pass MetabolismEffect of first pass metabolism Part of administered dose made inactive ↓ bioavailability Drug converted into its active form• Nitroglycerin when given orally • Totally inactivated in the liver • 100% first pass effect • Always given sublingually
Prodrug Administered in an inactive form After administration converted into their active form usually in liver Designed to improve bioavailability Examples Enalapril – Enalaprilate Ramipril - Ramiprilate
METABOLISMFactors affecting metabolism :1. Age – Children / Elderly2. Disease condition – e.g. Liver disease3. Induction of drug metabolizing enzymes4. First-pass effect – Nitroglycerin5. Competition between drugs6. Genetics7. Environment e.g. Smoking
ExcretionDrugs &/or its metabolites are irreversiblyeliminated from the body • Elimination of the drug • Unchanged (Parent form) • Metabolites • Routes of excretion • Kidneys – Urine • GIT – Stools • Skin - Perspiration • Eyes - Tears
PHARMACODYNAMICS• The study of what the drug does to the body• It is the quantitative study of the biological and therapeutic effects of drugs.
PHARMACODYNAMICSDrug actions:• The cellular processes involved in the drug and cell interactionDrug effect:• The physiologic reaction of the body to the drug
PHARMACODYNAMICSOnset• The time it takes for the drug to elicit a therapeutic responsePeak• The time it takes for a drug to reach its maximum therapeutic responseDuration• The time a drug concentration is sufficient to elicit therapeutic response
Four targets of drug action on cells • Receptors • Ach receptors / Epinephrine receptors • Ion Channels •Voltage gated Na+ / K+ / Ca++ • Enzymes •Cyclooxygenase / Acetylcholine esterase • Carriers •Na+/ K+ pump / Proton Pump
Receptors• Specific macromolecular components of the cell which when binds with ligand produces positive or negative biological response• Situated - on the surface / inside the cell
• Affinity: Inherent ability of the drug to bind with the receptor• Efficacy (Intrinsic activity): Inherent ability of the drug to induce a physiological response• Potency: An expression of the activity of the drug, in terms of the concentration or amount needed to produce a defined effect
What drug can do?All that drugs can do is,• Mimic the physiological activity of the body’s own molecules• Block the physiological activity of the body’s own molecules
Drug at Receptor• Agonist : It activates a receptor to produce an effect similar to that of the physiological signal molecule• Antagonist : It prevents the action of an agonist on a receptor but does not have any effect of its own• Partial agonist : It activates a receptor to produce sub maximal effect but antagonizes the action of full agonist.
Agonist v/s Antagonist• Drug + Receptor EFFECT• Drug + Receptor Maximum Effect • Drug = complete or full agonist• Drug + Receptor Less than maximal effect • Drug = partial agonist• Drug + Receptor Block effect • Drug = Antagonist
Effects of combination of drug• Addition 1+1=2 • Response elicited by combined drugs is equal to the combined response of the individual drugs• Synergism 1+1=3 • Two drugs with the same effect are given together and produce a response greater than the sum of their individual responses
Effects of combination of drug• Potentiation 0+1=2 • A drug which has no effect enhances the effect of a second drug• Antagonism 1+1=0 • Drug inhibits the effect of another drug. Usually, the antagonist has no inherent activity
Factors affecting drug response• Pharmacological •Dose & Route of administration •Duration of treatment •Co-administration of other drugs• Individual •Age & Weight •Gender •Pathology •Diet
Indication & Contraindication• Indication: A clinical circumstance indicating that the use of a particular intervention would be appropriate• Contraindication: Any condition which renders a particular line of treatment improper or undesirable.
Adverse drug reactionWhat does the term adverse reaction refer to?A. A life-threatening response to a drugB. A drug-induced allergyC. A harmful, noxious, unintended & undesirable response to a drugD. An unpredictable response to a drug
Adverse drug reactions Side effect Toxicity – overdose Allergic reaction Physical dependence Carcinogenic effect
Adverse drug reactions: Definitions• Side Effect • Unavoidable unintended pharmacodynamic effects that occur at a therapeutic dose • Dryness of mouth with Atropine• Toxic effects • Result of excessive pharmacological action of the drug due to overdosage or prolonged use • Hepatic necrosis from paracetamol overdosage• Drug intolerance • Toxic effects of a drug in an individual at therapeutic doses • Vomiting with a single dose of salicylate• Drug tolerance • Decreased response to the same amount of drug after repeated administration
Adverse drug reactions: Definitions• Cross Tolerance • Tolerance for a drug that develops after administration of a different drug• Tachyphylaxis • Rapidly occurring tolerance to a drug.• Cumulative effect • Increased effectiveness when a drug is given in several doses.• Drug dependence • The patient becomes accustomed to the drug’s presence in his body.
Adverse drug reactions: Definitions• Idiosyncrasy • Drug effect unique to an individual, A. a toxic reaction B. an allergic reaction C. a reaction peculiar to the patient D. an anaphylactic reaction• Drug allergy • Immunologically mediated reaction • Symptoms unrelated to pharmacodynamic profile of drug • Independent of dosage E.g. Penicillin• Drug withdrawal symptoms • Functional disturbances induced by a drug Persists even after offending drug has been withdrawn
Adverse drug reactions: Definitions• Teratogenecity – induce birth defect • Capacity of a drug to cause foetal abnormalities • Thalidomide• Mutagenic Effect • Mutagenesis involves alteration of the genotype by modification of the DNA • Mutation is carried to the next generations• Photosensitivity • Cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation • Quinolones
Drug Safety–Therapeutic Window• Therapeutic Index (or Window) measures “how safe a drug is” or “Margin of safety”• High therapeutic index = safe• Low therapeutic index = not so safe The larger the ratio, the safer the drug
Therapeutic Index/Ratio• Therapeutic Index/Ratio: Is the ratio between lethal dose (LD) and effective dose (ED) this is useful measure of safety and efficacy of any drug.• Lethal dose: The amount of the drug which kills subjects when it is administered is called lethal dose• Effective dose: The amount of the drug which removes sign & symptoms of subjects when it is administered
PLACEBO:Drug devoid of intrinsic pharmacological activity andit works by psychological means.USES : ??????
Pregnancy Considerations• Increased maternal HR, CO and blood volume • May affect absorption, distribution, effectiveness• Drugs may cross placenta• Drugs may cross into breast milk• Tertatogens
Pregnancy Categories• A: controlled studies in pregnancy (<1 %).• B: animal studies show no risk; Inadequate human data.• C: animal studies show risk, inadequate human data.• D: human data show risk, benefit may outweigh risk.• X: animal or human data positive for risk. Use unwarranted.
Pediatric Considerations∀ ⇓ Oral absorption• Thinner skin (⇑ topical absorption)∀ ⇓ Plasma protein concentration ∀⇑ Free protein-bound drug availability∀ ⇑ Extracellular fluid in neonate• Altered metabolic rates∀ ⇓ Elimination/metabolism• BSA/weight based dosing important!
FUNDAMENTALS OF PHARMACOLOGY• The rational pharmacological treatment of any patient requires adequate knowledge about : The disease process, Pharmacodynamic properties of the drug(s) selected, and The individual’s handling of the drug(s) [pharmacokinetics].
OPTIMUM DRUG CONCENTRATION• The concentration must not be too low, nor too high.• In the former case, therapeutic failure may occur, while in the later, adverse effects may prove troublesome to the patient.
FUNDAMENTALS OF PHARMACOLOGY• Drugs act by affecting biochemical or physiological process in the body. Most drugs act at specific receptors.• The action of a drug is characterized by two variables: The magnitude of the response and The concentration required to produce the response.
FUNDAMENTALS OF PHARMACOLOGY• A specific drug acts only at one receptor but may produce multiple effects due to the location of the receptor in various organs.• A selective drug acts on one receptor in a particular tissue at concentrations that produce little effect on the receptor in other organs.• Most drugs have multiple actions and it is usually preferable to use more specific or more selective agents