General Principles of Pharmacology

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General Principles of Pharmacology

• Targets for drug action
• A drug is a chemical that affects physiological
  function in specific way
• Most drugs are effective because they bind to
  particular target protein including receptors

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• TEXT BOOK
• PHARMACOLOGY BY
• RANG DALE

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TYPES OF RECEPTORS
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• TYPES OF RECEPTORS
• 1- Channel-linked receptors
• - coupled directly to an ion channel such
  acetylcholine, GABA Glutamate receptors
• 2- G-protein-Coupled receptors
• - it produces second massenger as well as opening
  channel
• -stimulated by adrenergic drugs, muscarinic
  hormones

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Continue TYPES OF RECEPTORS 3- Kinase-linked
receptors - insulin growth hormone receptors -
this type also linked to guanylate cyclase
ALL PREVIOUS TYPES OF RECEPTORS ARE MEMBRANE
BOUND 4- Receptors that regulate gene
transcription They are soluble receptor usualy
inside the cell (cytosol or intranuclear
protein) Steroid , thyroid, retinoic acid vit
D
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Drug Specificity
Drug binds only to certain targets
Individual targets recognise only certain class
of drug There are no drugs completely specific
in action Increase the dose will affect other
targets in cell
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Binding of Drugs to Receptors Binding of drugs
to receptors obeys the law of mass action (the
rate of chemical reaction is proportional to the
product concentrations of reactants) At
equilibrium, receptor occupancy is related to
drug concentration The higher the affinity of
drug for receptor, the lower the concentration
needed for occupancy
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Agonist antagonist(blocker) drug acting on
receptor may be agonist or antagonist A- Agonist
initiates changes in cell function Full
agonist has high efficacy Partial agonist -
it produces submaximal effects - it has
intermediate efficacy Partial agonist What is
is the efficacy ? It is the ability of drug to
initiate biochemical changes leads to the effect
of drug

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Inverse Agonists
The actions of an inverse agonist may also be
blocked by an antagonist of that receptor.
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BLOCKER it binds with receptor without
initiating biochemical changes it has zero
efficacy it binds with any state of receptor
(active inactive)

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Types Drug Antagonist A- Chemical antagonist B-
Pharmacokinetic antagonist one drug affecting
other drug via - Absorption -
Metabolism - Excretion C- Competitive
antagonism(BLOCKER) Reversible
Irreversible

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Continue Types Drug Antagonist D-
Non-Competitive antagonism - interrupts
receptor-effector linkage - e.g. calcium
channel blocker prevents the effects epinephrine
on the heart and blood vessels E- Physiological
antagonism - Two drugs producing opposite
effects - Omeprazole blocks histamine in
gastric acid secretion
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Desensitization and Tachyphylaxis They are
synonymous which describe RAPID loss in the
effect of drug despite an increase in the dose of
drug Due to depletion of endogenous
neurotransmitters TOLERANCE It is a decrease
in effects of drug as a result of repeated use of
drug It take few days or weeks to develop
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Mechanism of Tolerance, Tachyphylaxis
desensitisation etc..

• 1- Change in Receptors
• - (agonist failure to induce biochemical
  changes)
• 2- Loss of Receptors
• 3- Exhaustion of mediators (depletion)
• 4- increased metabolic degradation
• 5- Physiological adaptation (kidney
  antihypertensive)
• 6- Active extrusion of drug from cells

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DOSE RESPONSE RELATIONSHIP

• It is a relationship between the drug amount
  (concentration) and pharmacological effects
• Types of responses
• a- Graded response
• - response increases by
  increase the dose
• b- All or none response such as
• anti-convulsant.

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Therapeutic index

• it is a measure of drug safety
• How to calculate ?
• - LD50/ED50
• Potency of drug
• It is the minimum dose required to cause
  maximum response
• Potency of drug is not important clinically

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HOW DRUGS MEDIATE THEIR ACTIONS ?

• Via interacting with its target(s) leading to
• 1- activation or blocking of receptors
• 2- block endogenous mediators (counterfeit)
• 3-open or close ionic channels (Benzodiazepine
  L.A. )
• 4- compete with uptake system (carrier)
• - imipramine, cocaine, proton pump inhibitor,
  digoxin, probenecid

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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?

• 5- Enzymes (dihydrofolate reductase targeted by
  methotrexate trimethoprim, cyclooxygenase,
  xanthine oxidase, MAO, Dopa decarboxylase, ACE
  etc..)
• 6- Other targets such as
• Immunophilins in lymphocyte targeted by
  immunosuppresants such as Cyclosporin
  Tacrolimus
• Tubulin of phagocytes and other cells including
  cancerous cells
• - Targeted by Colchicine, Vincristine Taxol

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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?

• 7- Physical means
• - Osmotic diuretics
• - inhalational anesthesia
• 8- Chelating agent
• reacts with DNA or ions

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Examples on the mechanisms of drugs action

• 1- activation of muscarinic receptor in the
  heart(M2)
• ACTIVATE Gi-protein which lead to decrease in
  Camp
• This leads to decrease in calcium influx
• This causeS bradycardia
• 2- Activation of muscarinic receptor in smooth
  muscle (M3)
• This leads to activate Gs-protein leads which
  leads to increase calcium influx which causes
  contraction

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Examples on the mechanisms of drugs action

• 3- activation of alpha-1 receptor in the blood
  vessels
• ACTIVATE Gi-protein which lead to increase in
  IP3(Inositol triphosphate VIA activation of
  G-protein
• This leads to an increase in calcium influx and
  vasoconstriction
• 4- Activation of beta-1 receptor in heart
• This leads to activate Gs-protein leads which
  leads to activate adenylate cyclase which causes
  phosphorylation of calcium channel
• calcium influx which causes contraction(Tachycar
  dia increase in the force of cardiac muscle
  contraction (ve inotropic

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Examples on the mechanisms of drugs action

• 5- Activation of beta-2 receptor in smooth muscle
• This causes to activate Gs-protein and to
  activate adenylate cyclase
• CAMPactives protein kinase which leads to series
  of phosphorylation of various protein
• phosphorylation either activates or inhibits
  target enzyme or channel
• in smoth muscle , CAMP dependent protein kinase
  phosphoryate myosin-light chain kinase which
  required for contraction (relaxation occurred)

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Classification of adverse effects

• 1- TYPE A
• - It is dose related
• - It depends on therapeutic index
• 2- Type B
• - Non-dose related
• - immunological reactions
• - Pharmacogenetic
• 3- Long-Term effects
• - Adaptive changes

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Classification of adverse effects

• - Rebound Phenomena
• - It depends on therapeutic index
• 4- Delayed effects
• - Non-dose related
• - Carcingenesis
• - impair fertility
• - Teratogenicity
• - drug in breast milk

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Pharmacokinetic of drugs

• 1- ABSORPTION OF DRUG
• - From the site of administration
• 2- Distribution
• - To reach the site of action
• 3- metabolism
• - to inactivate or activate
• 4- Excretion

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ROUTE OF DRUG ADMINISTRATION

• 1- Oral administration (P.O.)
• 2- Subcutaneous (S.C.)
• 3- Intradermal
• 4- Intramuscular (I.M.)
• 5- Intravenous (I.V.)
• 6- Sublingual
• 7- Rectal

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ROUTE OF DRUG ADMINISTRATION

• 8- Intrathecal epidural
• 9- Inhalation
• 10- Topical
• skin
• eye
• mucous membrane
• -nasal, vaginal, oropharynx

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ORAL ADMINISTRATION

• 1- PROS
• Convenient
• Safe ?
• Economical (does not need sterilization)
• 2- CONS
• Requires patient compliance
• Drugs irritant to stomach
• Drugs not stable in GIT
• Drugs extensively metabolize by the liver
• Drugs NOT absorb from GIT
• Leads to food drug interaction

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INTRAVENOUS ADMINISTRATION

• 1- PROS
• Rapid action
• Delivered the desired amount
• irritant drug can be given only I.V. but NOT
  S.C.
• 2- CONS
• Increase the risk of adverse effects
• Must inject slowly in order to minimize the
  effects of drug on the heart
• It needs constant monitoring the reponse of
  patient

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SUBCUTANEOUS ADMINISTRATION

• 1- PROS
• It provides sustain effects because of slow
  absorption
• Addition of vasoconstrictor decreases further
  the rate of absorption from the site of injection
• It is suitable for insoluble drugs such as
  pellets
• and suspension
• 2- CONS
• can not inject large volume
• can not inject irritant drug
• repeated injection leads to necrosis (atrophy of
  skin)

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INTRAMUSCULAR ADMINISTRATION

• 1- PROS
• Suitable for oily vehicle and irritant drug
• The rate of absorption is very high because of
  high blood flow in the muscle
• 2- CONS
• It is not recommended in patient taking
  Anti-coagulant
• Increase CPK

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PULMONARY ADMINISTRATION

• 1- PROS
• Rapid absorption
• Local administration into the lung is beneficial
  in bronchial asthma
• Avoid hepatic effects
• Can absorb fine droplets (aerosol), prticle size,
  gaseous and volatile drugs
• 2- CONS
• Difficult to regulate administered the dose
• some drugs cause lung irritation

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TOPICAL ADMINISTRATION

• 1- Mucous membrane
• Rapid absorption such as local anesthetic ADH
• 2- Skin
• Lipophilic drugs absorb rapidly from skin such
  as nitroglycerin skin batch, scopolamine batch
• Inflammed, burned, abraded skin absorb drug
  faster

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TOPICAL ADMINISTRATION

• 3- Ophthalmic absorption
• it is used for local effectss
• systemic absorption occurs through NASOLACRIMAL
  CANAL such as ß-adrenergic blockers eye drops
• Ointment and suspension minimized systemic
  absorption
• Ocular insert provides continous delivery of drug
  with minimum systemic absorption

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SUBLINGUAL ADMINISTRATION

• Excellent absorption for non-ionized drug
  Example Nitroglycerin, apomorphine (Uprima)
• It has high absorption rate close to intravenous
  injection
• Avoid hepatic first pass metabolism

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RECTAL ABSORPTION

• It is used when oral route is warranted such as
  vomiting or coma
• It has erratic, irregular and incomplete
  absorption (50)
• It goes in partial hepatic first pass metabolism
• Some drugs may cause rectal irritation

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DRUGS DISTRIBUTION

• Factors influence drug distribution
• 1- Permeability of drug to biological membranes
• Blood brain barrier
• Testicular barrier
• Placental barrier
• - LIPID SOLUBLE DRUGS
• They have large Vd (volume of distribution)
• 2- Extent of plasma protein
• - Highly protein bound stay in circulation also
  have large Vd

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DRUGS DISTRIBUTION

• Factors influence drug distribution
• Drugs with large Vd have the following
  properties
• High protein binding
• High lipid solubility
• High affinity to other tissues such as bone
  liver

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DRUGS DISTRIBUTION

• Factors influence drug distribution
• 3- Availability of transport mechanism
• - passive diffusion The drug must be in
  unionized form
• - Active transport require ATP
• - Facilitative diffusion it requires carrier
  but without energy such vit B12, glucose and
  amino acid
• - ion pair transport the ionic compound
  combines reversibly with endogenous compound such
  as MUCIN in GIT
• 4- Regional pH
• - breast milk more acidic than blood
  Weak base drugs accumulate in breast milk

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DRUGS DISTRIBUTION

• Factors influence drug distribution
• 4- Rate of blood flow to tissues
• - Skeletal muscles have high blood flow
• 5- Regional pH
• - breast milk more acidic than blood
  Weak base drugs accumulate in breast milk
• 6- Tissues mass

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DRUG METABOLISM

• OBJECTIVES OF METABOLISM
• 1- To make the drug more water soluble in order
  to facilitate its excretion
• 2- To activate or inactivate the drug
• Some drugs become highly toxic or carcinogenic

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Factors influence Metabolism

• 1- Drugs
• - inducer rifampicin, dilantin, barbiturate
• - inhibitors cimetidine, macrolide antifungal
  drugs
• 2- Liver diseases
• 3- Diet
• - grape fruit, vitamins deficeincy such vit B6 is
  cofactor for decarboxylation

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Types of reactions in metabolism

• Phase-I reaction
• - consist of oxidation (dealkylation
  deamination) , reduction or hydrolysis
• - the product is reactive such as hydroxyl
• -Some time highly toxic
• - the product ready to enter other phase of
  metabolism
• Phase-II
• - Normally results to inactive compound
• - involve conjugation of glucuronyl, sulfate Play
  a role in enterohepatic cycle

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EXCRETION OF DRUGS

• 1- TYPES OF EXCRETION
• Renal excretion
• Biliary excretion
• Pulmonary excretion
• Excretion via other body fluids
• - Saliva
• -Breast milk

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RENAL EXCRETION OF DRUGS

• Some drugs mainly excreted via kidney such as
  metformin sotalol etc
• Factors influence renal excretion
• GFR
• Interference with renal active transport of drug
  such as probenecid
• Altering passive diffusion by change PH, lipid
  solubility

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RENAL EXCRETION OF DRUGS

• Altering passive diffusion by change PH
• - When pH of urine acidic, weak base drug will
  not be reabsorb from renal tubule
• When pH of urine alkaline, weak acid drugs will
  not reabsorb from renal tubule
• Lipid water solubility
• - Highly lipid soluble drug stay in
  circulation for longer time

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BILIARY EXCRETION ENTEROHEPATIC CYCLE OF DRUGS

• Liver cells transfer various drug from plasma to
  bile by
• Transport system similar to renal tubule
• conjugates drugs and concentrate these drugs in
  bile and the delivered into the intestine
• Some conjugate drugs which is delivered into the
  intestine hydrolyzed to unconjugated drug (free
  drug)
• The free drug reabsorb back into circulation
• This called enterhepatic cycle.

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BILIARY EXCRETION ENTEROHEPATIC CYCLE OF DRUGS

• This creates a reservoir of recirculating drugs
  which represent around 20 of total drug in the
  body
• This cycle maintains drug blood levels leading
  to prolongs the drug action
• Examples of drugs go through enterohepatic
  cycle
• - Digoxin
• - morphine
• - steroids including sex hormones

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PULMONARY EXCRETION OF DRUGS

• Pulmonary excretion does not require metabolism
• Factors influence pulmonary excretion
• 1- Rate of respiration
• 2- Cardiac output
• 3- solubility of gas in blood
• - High blood solubility decreases gases loss
  from lung
• - In contrast less blood soluble, leads to
  faster loss of gas via lung such nitrous oxide

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Excretion of drugs via other body fluids

• 1- Sweat
• - Drugs or its metabolite may be responsible
  for induction of dermatitis or other skin
  reactions
• 2- Saliva
• - change in taste or induction metallic
  taste
• 3- Milk
• - The PH of milk is 6.5, therefore the weak base
  drugs will concentrate in milk

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