1. 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

2. 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

3. TYPES OF RECEPTORS

4. 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

5. 3- Kinase-linked receptors
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

7. Drug Specificity * Drug binds only to certain targets
* Individual targets recognise only certain class of drug
* There rae no drugs completely specific in action
* Increase the dose will affect other targets in cell

8. 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

9. Agonist & antagonist A- Agonist initiates changes in cell function
* 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
What is is the efficacy ?
It is the ability of drug to initiate biochemical changes leads to the effect of drug

11. Antagonist * it has zero efficacy
* it binds with receptor without initiating biochemical changes
* it has zero efficacy
* it binds with any state of receptor (active & inactive)

12. Types Drug Antagonist A- Chemical antagonist
B- Pharmacokinetic antagonist
* one drug affecting other drug via:
- Absorption
- Metabolism
- Excretion
C- Competitive antagonism
* Reversible & * Irreversible

13. D- Non-Competitive antagonism
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

14. 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

16. 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

17. 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.

19. Therapeutic index Potency of drug
* 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

20. 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

21. 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

22. Continue HOW DRUGS MEDIATE THEIR ACTIONS ?
7- Physical means
- Osmotic diuretics
- inhalational anesthesia
8- Chelating agent
* reacts with DNA or ions

27. 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

28. 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(Tachycardia & increase in the force of cardiac muscle contraction (+ve inotropic

30. 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)

32. 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

33. 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

34. 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

35. 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

36. ROUTE OF DRUG ADMINISTRATION
8- Intrathecal & epidural
9- Inhalation
10- Topical
* skin
* eye
* mucous membrane
-nasal, vaginal, oropharynx

37. ORAL ADMINISTRATION 1- PROS 2- CONS Drugs NOT absorb from GIT
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

38. 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

39. 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)

40. 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

41. 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

42. 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

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

44. 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

45. 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

46. Factors influence drug distribution
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

47. Factors influence drug distribution
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

48. Factors influence drug distribution
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

49. Factors influence drug distribution
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

50. OBJECTIVES OF METABOLISM
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

51. 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

52. 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

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

54. 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

55. 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

56. 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.

57. 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

58. 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

59. 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

60. Thank you

61. TYPES OF RECEPTORS

62. 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

63. 3- Kinase-linked receptors
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

64. Drug Specificity * Drug binds only to certain targets
* Individual targets recognise only certain class of drug
* There rae no drugs completely specific in action
* Increase the dose will affect other targets in cell

65. 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

66. Agonist & antagonist A- Agonist initiates changes in cell function
* 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
What is is the efficacy ?
It is the ability of drug to initiate biochemical changes leads to the effect of drug

67. Antagonist * it has zero efficacy
* it binds with receptor without initiating biochemical changes
* it has zero efficacy
* it binds with any state of receptor (active & inactive)

68. Types Drug Antagonist A- Chemical antagonist
B- Pharmacokinetic antagonist
* one drug affecting other drug via:
- Absorption
- Metabolism
- Excretion
C- Competitive antagonism
* Reversible & * Irreversible

69. D- Non-Competitive antagonism
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

70. 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

71. 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

72. Therapeutic index Potency of drug
* 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

73. 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

74. 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

75. 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-proteinleads which leads to increase calcium influx which causes contraction

76. 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 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(Tachycardia & increase in the force of cardiac muscle contraction (+ve inotropic

77. 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
* Camp actives 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)

78. 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

79. DRUGS DISTRIBUTION * Permeability of drug to biological membranes
Factors influence drug distribution
* Permeability of drug to biological membranes
- LIPID SOLUBLE DRUGS
- They have large Vd (volume of distribution)
* Extent of plasma protein
- Highly protein bound stay in circulation & also have large Vd
* Availability of transport mechanism
* Regional pH

80. OBJECTIVES OF METABOLISM
DRUG METABOLISM
OBJECTIVES OF METABOLISM
1- To make the drug more water soluble inorder to facilitate its excretion
2- To activate or inactivate the drug
* Some drugs become highly toxic or carcinogenic

81. Factors influence Metabolism
* Drugs
- inducer: rifampicin, dilantin, barbiturate
- inhibitors: cimetidine, macrolide & antifungal drugs
* Liver diseases
* Food
- grape fruit

82. Types of reactions in metabolism
* Phase-I reaction
- consist of oxidation, 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

83. 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

84. 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

85. LOCAL ANESTHETICS

86. Local Anesthetics
Historically the first local anesthetic discovered was the tropane alkaloid cocaine:
Cocaine is still used in ocular surgery (anesthetic) and nasal/sinus surgery to decrease post-operative bleeding due to its vasoconstrictive properties-----cocaine addicts
Readily absorbed from the mucous membranes with good local activity - Rapidly hydrolyzed and inactivated due to the presence of two ester groups
Addiction includes both physical and psychological addiction

87. Desirable Properties of Local Anesthetics
1) Reversible
2) Non-irritating to the tissues
3) Rapid onset of acting
4) Long duration of acting
5) High therapeutic index
6) Effective topically and by injection
7) Proper physical properties (water solubility and stability in solution)

88. LOCAL ANESTHETICS CHEMISTRY It composed of hydrophilic domain
Which either tertiary or secondary amine
and hydrophobic domain
it aromatic residue
separated by alkyl chain
The hydrophobic & hydrophilic domains linked with either ester or amide
This bonds determine the pharmacology of L.A.

90. ANESTHETICS

91. Pharmacological Classes of Local anesthetic
a- Amide
1- Lidocaine (lignocaine) Risk B & C
2- Prilocaine Risk B & C
3- Bupivacaine (Marcain) Risk C
4- Ropivacaine (Naropin) Risk C
5- Dibucaine Risk C
6- Mepivacaine ( Scandonest or Carbocaine) Risk C
7- Etidocaine (Dranest) Risk B

93. Pharmacological Classes of Local anesthetic
B- Ester
1- Tetracaine (Amethocaine) Risk C
2- Benzocaine Risk C
3- Cocaine Risk C & X
4- Proparacaine (Fluoracaine) Risk C
5- Procaine Risk C
6- Chloroprocaine Risk C

95. Pharmacological Classes of Local anesthetic
C- Miscellaneous
1- Dyclonine (ketone) Risk C
2- Pramoxine (ether)

96. MECHANISM OF ACTION
* Block initiation & propagation of action potential
* By preventing the voltage-Dependent increase in sodium conduction
* Via physical plugging the transmembrane pore
* The binding site is in the inner end of sodium channel

97. SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE
1. Diffusion of the base form across the across the nerve sheath and nerve membrane
2. Re-equilibration between the base and cationic forms in the axoplasm
3. Penetration of the cation into and attachment to a receptor site within the sodium channel.
4. Blockade of the sodium channel

98. SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE
5. Inhibition of sodium conduction
6. Decrease in the rate and degree of the depolarization phase of the action potential
7. Failure to achieve the threshold potential
8. Lack of development of a propagated action potential
9. Blockade of impulse conduction

99. CONDUCTION OF A NERVE IMPULSE

100. Ionized

101. Common features of Local Anesthetics
Weak bases (pKa > 7.4) [poorly water soluble]
Packaged as an acidic hydrochloride [pH 4-7 now soluble]
In solution- non-ionized lipid soluble (free base) AND ionized water soluble (cation)
Body buffers raise the pH, increase free base
lipid soluble form crosses axonal membrane
water soluble form blocks sodium channel

102. Important Clinical Properties of Local Anesthetics
ONSET
POTENCY
DURATION OF ACTION

103. Important Clinical Properties of Local Anesthetics
ONSET = pKa
pKa = pH at which 50% of drug is ionized
LA’s <50% exists in the lipid soluble nonionized form
Only the nonionized form crosses into the nerve cell

104. ROLE of pH and pKa in LOCAL ANESTHETICS

105. Important Clinical Properties of Local Anesthetics
Speed of Onset
low pKa = fast onset
Bupivacaine 8.1 Lidocaine 7.7
? LA action in septic tissue
acid tissue -> é ionized % of LA -> slow entry into membrane -> low concentration of LA for block

106. Important Clinical Properties of Local Anesthetics
Anesthetic Potency
Potency <=> lipid solubility
Higher solubility <=> can use a lower concentration and reduce potential for toxicity [LA]

107. Duration <=> protein binding Bupivacaine 95% Lidocaine 65%
Important Clinical Properties of Local Anesthetics
DURATION OF ACTION
Duration <=> protein binding
Bupivacaine 95%
Lidocaine 65%
Procaine 6%

108. Important Clinical Properties of Local Anesthetics
CLEARANCE
ESTERS hydrolysis via pseudocholinesterase
AMIDES metabolism via hepatic enzymes

109. Absorption of local at site LA’s cause some vasodilitation
Important Clinical Properties of Local Anesthetics
Absorption of local at site
LA’s cause some vasodilitation
LA washout related to blood flow
LA toxicity related to rate of absorption via blood flow

110. Important Clinical Properties of LA’s
ADDITION of VASOCONSTRICTORS
1- Why it is combined with L.A. ?
Vasoconstriction <=> slows systemic absorption & increases duration
2- Epinephrine is commonly used in 1 in to (5ug-12.5ug/ml)
Least effective with high lipid soluble LA’s (bupivacaine/etidocaine)
Epi may produce distal and systemic effects

111. ADDITION of VASOCONSTRICTORS
3- The total dose should not exceed ug
4- Epi-Drugs interaction
Tricyclic anti-depressant
Sympatholytic drugs
5- Contraindications ?
not recommend for digits injection
6- Do you prefere Norepinephrine OR EPINEPHRINE?

112. Effect of pH on the efficacy
of local anesthetics
1- The activity of local anesthetic is strongly pH dependent
2- L.A. need to penetrate the nerve sheath and axon to reach the binding site of sodium channel
3- In acidic media penetration is very poor
7- Inflammed & infected tissues are acidic

113. ADDITION of Sodium Bicarbonate
NaHCO3 - é pH & nonionized base
Speeds onset of block
1 mEq NaHCO3 per 10 ml Lido/Mepiv
.1 mEq NaHCO3 per 10 ml Bupiv

114. Methods of administration of L.A.
1- Infilteration Lidocaine or Bupivacaine
2- Surface Lidocaine, tetracaine, benzocaine
3- Intravenous regional anesthesia mainly lidocaine , prilocaine
4- Nerve block lidocaine or bupivacaine
5- Spinal anesthesia mainly lidocaine , tetracaine
6- Epidural anesthesia mainly lidocaine , marcain

115. A. Surface or Topical Anesthesia
1. The oral cavity, pharynx, larynx and tracheobronchial tree provide examples of mucosal surfaces where local anesthetics are applied topically.
2. A great danger exists in these areas for overdosage since rapid absorption into the circulatory system may occur and exceed the rate of detoxification of the drug.
3. To avoid this danger use a fine spray with a low concentration of the drug and limit the volume of solution used.
4. Most often used agents cocaine (4-10%), tetracaine (1-2%) and lidocaine (2-4%)
B. Local Infiltration
1. Used for superficial surgery such as removal of moles, warts, sebaceous cysts, etc. Also for iv insertion.
2. Use the lowest concentration of drug which will block sensory perception. Large volumes are generally used.
3. Epinephrine approximately doubles duration of action.
4. Most frequently used agents include lidocaine 0.5-1% and Bupivacaine 0.5%

116. C. Regional Nerve Block and Field Block
1. Field block: Similar to local infiltration, but the goal is to specifically interrupt nerve transmission proximal to the site to be anesthetized.
2. Nerve Block - The goal is to inject local anesthetic into or about individual nerves or nerve plexuses. Produces even greater areas distal of anesthesia with a smaller amount of drug
8. Agents include Procaine ( %); Lidocaine (1-2%); Mepivacaine (up to 7 mg/kg of 1-3%); Bupivacaine ( % up to 3 mg/kg ); Tetracatine (up to 1.5 mg/kg of %).

117. D. Intravenous Regional Anesthesia
1. Consists of iv injection of local anesthetic into vein of exsanquinated extremity with proximal tourniquet.
2. Binding of drug occurs in tissues of extremity
- with tourniquet down (after min minimum up time) only 15-30% released into systemic circulation.
3. More effective in upper extremity
4. Lidocaine (1.5 mg/kg of 0.5%) frequently used.

118. E. Epidural Anesthesia (caudal anesthesia)
1. Epidural space terminates cephically at the foramen magnum.
2. Epidural anesthesia consists of epidural injection into the lumbar, or less frequently, the thoracic area.
3. Two sites of action
(a) diffusion into subarachnoid space
(b) diffusion into paravertebral area through intervertebral
foramina to produce multiple paravertebral blocks

119. Continue--. Epidural Anesthesia (caudal anesthesia)
4. Danger of inadvertent subdural and subarachnoid puncture.
* Lidocaine & Bupivacaine for longer action are used.
5. Unlike spinal, no differential zone of sympathetic blockade.
There is a zone of differential motor blockade 4-5 segments less than sensory block.
6. Other dangers include anterior spinal artery syndrome, hematoma, infection, and adhesions.
10. Advantages include
(a) blood pressure remains stable
(b) in obstetrical cases, the mother retains motor control of the abdominal muscles and can assist in the delivery of the fetus

120. F. Spinal Anesthesia (subarachnoid block)
1. Injection of local anesthetic into the lumbar subarachnoid space
; usually at T2-T3 or T3-T4 interspace.
2. Distribution of the drug in the subarachnoid space determines the level of anesthesia. This is controlled by:
a) Positioning of the patient
b) Speed of injection
c) Specific gravity of solution
d) Volume injected
3. Nerve fibers affected in the following sequence:
autonomic  sensory  motor
4. Zones of differential anesthesia: sympathetic block segments higher than sensory - motor segments lower

121. Continue-- Spinal Anesthesia (subarachnoid block)
5. It causes sympathetic blockade. Most important changes are on venous side of circulation.
6. Cardiovascular effects: hypotension, bradycardia, ↓preload ↓afterload
7. Respiratory complications: due to ischemic paralysis of medulla
and not usually phrenic paralysis
8. Other dangers:
* chemical transection of cord
* traumatic destruction of a spinal end artery
* traumatic damage of a nerve root & chronic arachnoiditis
* postural headache and infection.
9. Agents frequently employed include: Tetracaine & Lidocaine

123. Pharmacology of L.A.
They interfere with function of all organs in conduction occurs
A- CNS
Stimulate CNS leads to restlessness and may proceed by clonic convulsion
Then CNS depression
Respiratory failure is main cause of death
Drowsiness is the most complain

124. Pharmacology of L.A. B- Cardiovascular Decrease mycardium excitability
Conduction
Decrease force of contraction
Hypotension
These effects occurred in high dose which cause CNS toxicities
Arteriodilation
Rarely occurs in infilteration

125. Pharmacology of L.A. C- Hypersensitivity
Mostly occurred with ester type
Allergic dermatitis
asthmatic attack
Amide almost free of hypersensitivity

126. Lidocaine 2%
1- DOSE
*OVER 10 YRS: Not exceed 6.6 mg/kg or 300 mg per dental appointment
2- under 10 years mg per dental appointment
3- Drug interaction
-beta blockers
-antiarrhythmia agents
4- Metabolism

127. Prilocaine 4% 1- DOSE: Less than 10 yrs 40 mg per setting or less
greater than 10 yrs and adult mg
Not exceed mg in adult
1- Toxicities
* Methemoglobinemia
2- under 10 years mg per dental appointment

128. BUPIVACAINE 0.5% 1- DOSE: Less than 10 yrs NOT ESTABLISHED
greater than 10 yrs and adult 9 mg
Not exceed 90 mg in adult per dental appointment
2- duration
Nerve block 5-7 hrs
3- Toxicities
- much greater than lidocaine

129. MEPIVACAINE
Amide Products: Longer duration of action
1- Indications: Peripheral, transvaginal, paracervical, caudal, epidural and infiltration nerve block, dental procedures
2- protein bound 78%
3- Warnings:
* NOT recommended for obstetrical epidural anesthesia due to cardiac arrest and death
* Reserve the 0.75% solution for surgical procedures where prolonged activity is needed—danger of inadvertent IV injection and cardiac arrest

130. 2- Onset of action 3-5 minutes
ETIDOCAINE
Amide Products: - Longer duration of action
1- Indications: peripheral, central or lumbar peridural nerve block; intra-abdominal/pelvic/lower limb/ceasarean section surgery; caudal or maxillary block
2- Onset of action 3-5 minutes
3- with a duration of action of 5-10 hours
4- surprisingly epinephrine addition does NOT increase the duration—why?----Partition coefficient is 7050X of procaine---94% protein bound

131. 3- ideal for continuous infusion for epidurals during birth
ROPIVACAINE
Amide Products: - Longer duration of action
1- Indications: local or regional anesthesia for surgery, post-operative pain management and obstetrical procedures
2- Avoid rapid administration of large doses---use fractional or incremental administration
3- ideal for continuous infusion for epidurals during birth
4- Onset of action is minutes
5- with a duration of action of 2-8 hours---safe to use this as an epidural product for up to 24 hours

132. TETRACAINE
Ester Products:
1- Indications: Spinal anesthesia including high, median, low and saddle blocks including prolonged action of 2-3 hours
2- Slower onset of action than procaine but duration is 2-3 hours can increase to 3-5 hours by including epinephrine
3- This drug should not be used in children due to a lack of safety data

133. COCAINE (1)- Mechanism of action A- Blocks sodium channel
B- inhibit NE UPTAKE-1
(2) Direct vasoconstrictor action and potentiation sympathetic system
(3) Extensive cardiovascular actions
(4) Powerful CNS stimulant
(5) Considered a narcotic with potentially for psychic dependence
(6) Used for surface anesthesia in % solutions,
occasionally with epinephrine
(7) Metabolized by esterases and hepatic enzymatic degradation;
t1/2 after oral or nasal administration, approximately 1 hour

134. LOCAL HAEMOSTATIC AGENTS
LOCALLY ACTING AGENTS
LOCAL HAEMOSTATIC AGENTS

135. LOCAL HAEMOSTATIC AGENTS
LOCALLY ACTING AGENTS
LOCAL HAEMOSTATIC AGENTS
1- Sympathomimetic
Epinephrine with LA
Epinephrine-imprignated cord to retract and control gingival haemorrhage
2- Astringents & STYPTICS
They react with proteins of oral cavity and make protective layer:
Aluminum chloride (Sansilla)
Example of Styptics : Silver nitrate rod

136. 3- Mechanical haemostatics
LOCAL HAEMOSTATICS
Aluminum chloride retraction cord (HEMODENT 25%)
Tannins: Pyralvex
it is an oral paint contains tannic acid and salicylic acid
- It is used for mild peri-oral lesion & less effective in oral lesion
3- Mechanical haemostatics
They forms matrices in which blood cells and fibrin can trapped
They are more effective than astringent, styptics or sympathomimetics
in controlling capillary oozing & surface bleeding

137. Types of mechanical haemostatics
1- Absorbable gelatin (Gel Foam)
* Advantages of absorbable gelatin
It does not interfere with the followings:
Thrombin
Epithelization
Bone regeneration
2- Oxidized cellulose (Oxycel &Novocel)
It has high affinity to haemoglobin & it is form of gauze of cotton pellets
It is more effective than Gelfoam
It interfere with followings:
- Epithelization & bone regeneration (not suitable for packing in bone fracture
Inactivates thrombin

138. 3- Oxidized regenerated cellulose (Surgicel) Advantages
- It does not interfere with epithelization
-Therefore , it is suitable for surface dressing
Disadvantages
- It interferes with bone regeneration
- Inactivates thrombin
3- Microfibrillar collagen hemostat (Avitene)
It is in the form of powder & used to control bleeding after oral surgery
* Advantages
- It does not interfere with:
* epithelization
* bone regeneration
* activity of thrombin
Disadvantage: it is source of animals which may transfere diseases

139. SYSTEMIC HAEMOSTATICS
HAEMOSTATIC SYSTEMS
1- Formation of fibrin via clotting factors
2- Fibrinolysis
3- Platelets aggregation
4- Blood vessels (PGE12)

140. Examples of systemic haemostatic agents
VITAMIN K
Role of vitamin K in clotting system
- Vit K is necessarly for final stage of clotting factors synthesis such as prothrombin ,factor vii, ix &x
Premature Mature clotting factor
Clotting factors

141. CAUSES OF VIT K DEFICIENCY
1- Obstructive jaundice
2- malabsorption
3- Reduced GIT flora
-Rarely after broad spectrum antibiotics
CLINICAL USES OF VITK
1-Reverse bleeding induced by oral anti-coagulant
2- Inadequate vit k availability
3- new born baby

142. Menadiol sodium phosphate (vitk3)
VIT K Preparations
vit k1 (phytomenandione) konakion
- it is lipid soluble and injected in new born baby
onset within 12 hours
Menadiol sodium phosphate (vitk3)
it is water soluble
onset 24 hrs
prefered in malabsorption or obstructive jaundice
It has tendency to induce hemolytic anemia

143. TRANEXAMIC ACID 1- MECHANISM OF ACTION 2- Clinical uses
Prevents plasminogen not to attach to fibrin
resulting in inhibition fibrinolysis
inhibits the proteolytic activity of plasmin
2- Clinical uses
Use as Mouthrinse 4.8% to prevent bleeding in hemophiliac & patient under warfarin due to dental extraction
ORAL: 25 MG/KG FOR 2-8 DAY in haemophiliac
Hereditary angioedema & menorrhagia
Thrombolytic over dose

144. 3- pregnancy Risk factor B 3- Adverse effects
TRANEXAMIC ACID
3- pregnancy Risk factor B
to prevent bleeding in hemophiliac & patient under warfarin due to dental extraction
3- Adverse effects
If taken orally
GIT Disturbances such as diarrhea
Hypotension
Thrombosis
Blurred vision requires regular eye examination
-Regular liver function tests in long term oral use for hereditary angioedema

145. AMINOCAPROIC ACID 1- Mechanism of action 2- Clinical uses
Inhibits the activation of plasminogen to plasmin
2- Clinical uses
Treatment of excessive bleeding from fibrinolysis
5-30 g/day in divided dose at 3-6 hrs interval

146. 3- pregnancy Risk factor C 4- Adverse effects
AMINOCAPROIC ACID
3- pregnancy Risk factor C
4- Adverse effects
Hypotension
bradycardia
Arrhythmia
Myopathy
GIT irritation

147. APRPTONIN (Trasylol) CLINICAL USES
It is inhibitor of plasmin (plasmin causes fibrin lysis)
CLINICAL USES
- Over dose of thrombolytic drugs such streptokinase
- Hyperplasminia as a result of mobilization and dissection of malignant tumor
SIDE EFFECTS
Hypersensitivity
-localized thrombophlebitis

148. ETHAMSYLATE OR ETAMSYLATE DICYNENE®
1- Mechanism of action
CORRECT ABNORMAL PLATELETS ADHESION
2- Clinical uses
Short term use in blood loss in menorrhagia(500mg tablets four times daily during menses
Prophylaxis and treatment of periventricular haemorrhage in low birth weight infants (i.v. or i.m.)
3- Clinical uses
- Rashes , Nausea and Headache

149. DESMOPRESSIN ACETATE(Stimate®)
1- Mechanism of action
Enhance reabsorption of water in kidney
Increase Von Willebrand factor & factor viii
2- Clinical uses
Control bleeding in mild hemophilia & Von Willebrand disease during dental extraction
Diabetes insipidus
Nocturnal enuresis
CAUTION : Avoid overhydration (it has ADH activity)

150. 3- pregnancy Risk factor B 4- Adverse effects
DESMOPRESSIN ACETATE
3- pregnancy Risk factor B
4- Adverse effects
Facial flushing
Dizziness
Nasal congestion
hyponatremia
Water intoxication

151. 1- Anti-hemophilic factor (Kogenate®)
BLOOD PRODUCTS
1- Anti-hemophilic factor (Kogenate®)
It is factor viii derived from recombinant DNA
- CLINICAL USES
- Control bleeding in hemophilia A
- Life threatening haemorrhage
2- FACTOR VIIa (NovoSeven®)
It is recombinant DNA
CLINICAL USES:
* PATIENT WITH INHIBITORS TO FACTORS VIII & IX

152. 3- FACTOR IX (Replenine®)
BLOOD PRODUCTS
3- FACTOR IX (Replenine®)
- CLINICAL USES
- it indicated in patient with factor ix deficiency (Hemophilia B)
- CAUTION : Risk for thrombosis

153. FIBRIN GLUE (Beriplast)
1- Composition
Two separate solutions
a- fibrinogen
b- thrombin & calcium
It is completely reabsorb within 2 –4 weeks
Some products contain
tranexamic acid or aprotonin
2- Effective in preventing bleeding in bleeding disorders

154. Management of patient under warfarin
1- Minor surgery
Use tranexamic mouth rinse
without adjustment of anticoagulation if INR is less than 4
2- Major surgery
Stop warfarin preoperative
use low molecular weight heparin

155. Intrinsic Pathway Extrinsic Pathway Blood Vessel Injury Tissue Injury
Tissue Factor
XII
XIIa
Thromboplastin XI
XIa IX
IXa
VIIa
VII X Xa X
Prothrombin
Thrombin
Factors affected
By Heparin
Fibrinogen
Fribrin monomer
Fibrin polymer
Vit. K dependent Factors
Affected by Oral Anticoagulants
XIII

156. 1- Drugs inhibit vit k actions (oral anticoagulant)
ANTI-COAGULANTS
1- Drugs inhibit vit k actions (oral anticoagulant)
By prevents maturation of the clotting factors
slow onset (3 days)
2- Drugs directly acting on the clotting factors
- Rapid onset (Heparin)
3- Drugs inhibit platelets aggregation
4- Fibrinolytic drugs (dissolve clot)

157. ORAL ANTI-COAGULANTS WARFARIN (Coumadin®)
1- CLINICAL USES OF WARFARIN
Prophylaxis and treatment of venous thrombosis such as :
- Deep vein thrombosis (DVT)
- Atrial fibrillation
- prosthetic cardiac valves with antiplatelets
- thromboembolic disorders such post MI or Stroke and embolism

158. ORAL ANTI-COAGULANTS WARFARIN (Coumadin®)
2- MOA OF WARFARIN
Warfarin interferes with hepatic synthesis of vit K-dependent factors (ii, vii, ix, x)
PREVENT RECYCLING OF VIT K by inhibiting reductase enzyme which convert epoxide vit K to vit K
3- ONSET OF WARFARIN
Within hours

159. Mechanism of action WARFARIN Reduced Vitamin K Oxidized Vitamin K
Descarboxy Prothrombin
Prothrombin
Reduced Vitamin K
Oxidized Vitamin K
NAD
NADH
WARFARIN

160. ORAL ANTI-COAGULANTS WARFARIN (Coumadin®)
4- MONITORING ITS EFFICACY
Prothrombin time expressed by :
International Normalized Ratio (INR) determined daily initially then at longer intervals depends on the response
INR For prophylaxis of DVT, AF, Cardioversion, dilated cardiomyopathy, MI, Rheumatic valve disease
INR 3.5 For recurrent DVT , pulmonary embolism and mechanical prosthetic heart valve

161. ORAL ANTI-COAGULANTS WARFARIN (Coumadin®)
4- ADVERSE EFFECTS OF WARFARIN
The main is hemorrhage
Skin necrosis in patient with protein c & s deficiency
5- PREGNANCY
AVOID RISK FACTOR D
REPLACED BY HEPARIN

162. ORAL ANTI-COAGULANTS WARFARIN (Coumadin®)
6- DRUG INTERACTION
INCREASE EFFECTS:
- NSAIDs
- Sulfa drugs
- cimetidine
Decrease effects
liver enzyme inducer such as:
-phenobarbitone, rifampicin, phenytoin

163. HEPARIN 1- RAPID ONSET, inject only S.C. OR I.V. 2- CLINICAL USES
Preventive and treatment of thromboembolic disorders such as DVT, MI, pulmonary emobolism
patient undergoin general surgery (low dose)
orthopedic surgery
unstable angina & Pregnancy
Extracorporeal circuits such as hemodialysis & cardiopulmonary bypass

164. HEPARIN A- Post-operative & MI 5000 units s.c. every 8-12 hrs
3- DOSES OF HEPARIN
PROPHYLAXIS DOSE
A- Post-operative & MI units s.c. every 8-12 hrs
B- pre-surgery units 2 hours before surgery
C- Pregnancy ,000 units every 12 hours (REQUIRED APTT monitoring

165. HEPARIN 5- MONITOR THE EFFICACY Prophylaxis dose does NOT require
4- MECHANISM OF ACTION OF HEPARIN
Heparin enhances the activity of anti-thrombin
It inhibits factor X in small dose
5- MONITOR THE EFFICACY
Prophylaxis dose does NOT require
APTT (Activated partial thromboplastin)
APTT should be in the ranges

166. Heparin mechanism of action
Antithrombin III
Thrombin

167. HEPARIN 6- ADVERSE EFFECTS 7- ANTIDOTE OF HEPARIN
Bleeding if APTT more than 3 or
- impaired hepatic or renal functions
Thrombocytopenia
Osteoporosis (long term use)
skin necrosis & hypersensitivity
It may induce hyperkalemia by inhibition of aldosterone secretion
7- ANTIDOTE OF HEPARIN
- Protamine sulfate 100mg neutralizes 100 unit

168. LOW MOELCULAR WEIGHT HEPARIN
1- EXAMPLES:
Enoxaprin , Dalteparin & Ardeparin
2- Advantages
A- Do not required APTT monitoring
B- because it has little effects on antithrombin but it potent inhibition on factor Xa
C- Long duration (once daily)

169. HEPARINOID 1- EXAMPLES: DANAPAROID 2- MOA : inhibits Xa & IIa factors
3- Advantages
A- Low incidence of thrombocytopenia
* therefore it can be used in patient had history of thrombocytopenia due to heparin
4- Disadvantage : not effectively antagonized by protamine sulfate

170. ANTIPLATELETS AGGREGATION
1- EXAMPLES:
Aspirin
Clopidogrel
Dipyridamole
Ticlopidine
Abciximab
Eptifibatide
Tirofiban

171. ANTIPLATELETS AGGREGATION
2- THEY DECREASE PLATELETS AGGREGATION and inhibit thrombus formation in the arterial circulation where anti-coagulants have little effects.
3- General Clinical uses
cerebral vascular diseases such as Transient ischemic attack (TIA)
Unstable angina
Post MI
Coronary artery bypass surgery & Angioplasty

172. ASPIRIN 1- CLINICAL USES OF ASPIRIN (small dose)
Prophylaxis for MI (75mg- 81mg mg)
Transient ischemic episode & stroke (600 mg twice daily)
Following coronary bypass surgery
percutaneous transluminal coronary angioplasty
Eclampsia in small dose ? Unlabelled
2- MOA : Irreversibly inhibits COX (cyclooxygenase) leading to inhibit thrombane A2 in platelets

173. ASPIRIN 3- ADVERSE EFFECTS OF ASPIRIN GIT upset may develop ulcer
May precipitate bronchial asthma in patient has histry of bronchial asthma
Some patient develop subcutaneous hemorrhage (as spots)
4- contraindication
* children under 12 years and breast feeding mother
* active peptic ulcer
* bleeding disorders
5- Caution:
* asthma , pregnancy

174. CLOPIDOGREL (PLAVIX) 1- CLINICAL USES
*Reduces atherosclerosis events such as MI, Stroke & peripheral artery diseases
Prevent of thrombotic complications after coronary stenting
Acute coronary syndrome such as unstable angina or non-Q-wave MI
It can be used instead of aspirin if patient allergic to aspirin
2- MOA
It blocks the ADP receptors in platelets which prevent fibrinogen binding to platelets leading to reduce platelets aggregation.

175. CLOPIDOGREL (PLAVIX) 3- ADVERSE EFFECTS
Bleeding (GIT & Brain) & leukopenia
GIT upset such as gastritis (less than aspirin)
4- CONTRAINDICATIONS
Active bleeding avoid first few days after MI & 7 days after stroke
Not recommend for angioplasty
Stop it 7 days before surgery
Liver impairment
Breast feeding

176. TICLOPIDINE (TICLID) 1- CLINICAL USES
It is reserved for patients who are intolerant to ASPIRIN
Prophylaxis of major ischemic events in patient with a history of ischemic stroke
Adjuvant therapy with aspirin following coronary stent to reduce stent thrombosis
2- MOA
Similar to plavix

177. TICLOPIDINE (TICLID) 3- ADVERSE EFFECTS Bleeding
Neutropenia , agranulocytosis & pancytopenia
Thrombotic thrombocytopenic purpura
Increases liver enzymes
Jaundice
hyperlipidemia

178. DIPYRIMADOLE (PERSANTIN)
1- CLINICAL USES: Maintains patency after surgical grafting include coronary artery bypass
Used with Warfarin to decrease thrombosis in patient after artificial heart valve replacement
Use with ASPIRIN to prevent thromboembolic disorders
It can be given 2 days prior open heart surgery
2- MOA: Inhibits adenosine deaminase & phosphodiesterase leading to accumulation of:
Adenosine , adenosine nucleotides These inhibit platelets aggregation
cAMP this causes vasodilation

179. DIPYRIMADOLE (PERSANTIN)
3- ADVERSE EFFECTS
Hypotension
Headache
Increased bleeding during or after surgery
Worsening symptoms of coronary heart disease
4- CAUTIONS
Rapidly worsening angina
Aortic stenosis
Recent MI
CHF & Migraine

180. ABCIXIMAB(REOPRO) 1- CLINICAL USES
Adjunct to percutaneous transluminal coronary angioplast
Prevention of acute ischemic complications in patients at high risk for abrupt closure of treated coronary vessels
Use with heparin in unstable angina
2- MOA
It binds with platelets iib/iiia receptors preventing their aggregation

181. FIBRINOLYTIC DRUGS 1- EXAMPLES
Alteplase (recombinant DNA tissues plasminogen activator)
Reteplase
Streptokinase
tenecteplase

182. ALTEPLASE (ACTIVASE) 1- CLINICAL USES Management of acute MI
& pulmonary embolism for lysis of thrombi
2- MOA
* It initiates local fibrinolysis by binding to fibrin in clot and converts entrapped plasminogen to plasmin

183. ALTEPLASE (ACTIVASE) 3- adverse effects Multiple emboli
Arrhythmia due to cardiac reperfusion
bleeding

184. ANTICOAGULANT DRUGS TO TREAT THROMBOEMBOLISM
Drug Class Prototype Action Effect
Anticoagulant
Parenteral
Heparin
Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin
Decrease synthesis of
Clotting factors
Prevent venous
Thrombosis
Prevent arterial
Thrombosis
Antiplatelet
drugs
Aspirin
Decrease platelet
aggregation
Breakdown of
thrombi
Thrombolytic
Drugs
Streptokinase
Fibinolysis

185. ORAL PROTECTIVE AGENTS
1- CLINICAL USES :Protectives are used for non-specific mouth ulceration such as aphthus ulcer
It is usually combines with local anesthetic and antiseptics such as [ORAL B®] composed of:
-lidocaine, cetylpyridinium, menthol & cineole
2- examples of oral protectives
Carmelose gelatin (ORABASE®)
Choline salicylate dental gel (BOJELA®)
Benzdamine (DIFFLAM®)

186. ANTI-SEPTIC MOUTH RINSE
1- Chlorhexidine
2- Cetylpyridinium chloride & Triclosan
3- phenols
4- Hexitidine (oraldene mouth rinse)
5- Domiphen bromide (Bradoral lozenges)

187. CHLORHEXIDINE 0. 2% CORSODYL® & Hexidine®
1- PROPERTIES OF CHLORHEXIDINE
* It is used in 0.2% as mouth rinse
* It is the most effective mouth rinse
It Reduces gingival pathogen
The anti-microbial last several hours
it is effective in gingivitis associated with bleeding & PUS
it cause permanent stain of restorative
But reversibly stains natural teeth & dorsum of the tongue

188. CHLORHEXIDINE 0. 2% CORSODYL® & Hexidine®
2- MOA
It broad spectrum antiseptic
its bacterial action exerts by disruption of bacterial membrane of both gram positive & negative bacteria
3- CLINICAL USES
Oral hygeine especially if there heavy plaque
Inhbition of plaque formation
Gingival infection
It may help in recurrent aphous ulcer

189. CHLORHEXIDINE 0. 2% CORSODYL® & Hexidine®
4- ADVERSE EFFECTS
Reversible brown staining of natural teeth
Irreversible brown staining of artificial teeth (restorative)
Idiosyncratic Epithelial irritation of oral cavity
Rarely parotid gland swelling
Inflammation of salivary glands
It may mask periodontitis

190. CETYLPYRIDINIUM CHLORIDE0.5% SCOPE®
1-PROPERTIES
It is surface active agent
It is ineffective in present of bleeding, sputum & pus
It is weak antibacterial
2- MOA
It acts as detergent which help removal of bacteria & Disrupts the membrane of bacteria

191. PHENOLS CHLORASEPTICS®
It contains phenol
Available as spray , mouth rinse & lozenges
2- ADVERSE EFECTS OF PHENOL
Nephrotoxicity if exceeds the dose
It inhibits polymerization of resin restoration
It damage the cavity liner

192. Agents used in dental procedures
1- HYDROGEN PEROXIDE
It is used for root canal irrigation
Its action is mediated by releasing nascent oxygen which kills bacteria
2- SODIUM HYPOCHLORITE 5%
It is used to irrigate root canal
It is irritant to mucous membrane of oral cavity

193. Agents used in dental procedures
3- OBTUNDANTS
A- DEFINTION OF OBTUNDANT
Chemical precipitates cellular protein of nerve fiber
Causing paralysis of nerve fiber which leads to diminish sensation of dentine
B- IDEAL PROPERTIES OF OBTUNDANTS
Acts without initial pain
Does not stain teeth, dentine or enamel
It penetrates quickly through the dentine but not too deep otherwise it may lead to inflammation of the pulp

194. Agents used in dental procedures
C- MOA OF OBTUNDANT
It precipitates cellular protein of nerve fiber
Causing paralysis of nerve fiber which leads to diminish sensation of dentine
D- CLINICAL USES
Obtundants allow painless excavation

195. EXAMPLES OF OBTUNDANTS
1- Eugenol
It causes initial stimulation followed by paralysis of nerve
2- Zinc chloride
It stains teeth and has poor penetration
3- Absolute Alcohol
It requires the oral cavity to be dry
4- Cresote

196. Agents used in dental procedures
4- MUMIFYING AGENT
A- Definition of mumifying agents
It is a chemical causes aseptic dryness and hardness of pulp tissues and root canal
They have astringent and antiseptic properties
All mumifying agents are obtundant but not all obtundants are mumifying agents
B- CLINICAL USES
* They applied when pulp or content of the root can NOT be removed

197. EXAMPLES OF MUMIFYING AGENTS
1- Iodinated cresol
2- beta-naphthol 1% in alcohol
3- iodoform
4- Ammonical silver nitrate (it stains teeth)
5- Forlmaldehyde

198. FLOURIDE PREPARATIONS
1- NATURAL SOURCE OF FLOURIDE
Water (1PPM iseffective cincentration)
Fish (20 PPM)
Tea (100 PPM)
2- METABOLISM & ABSORPTION OF FLOURIDE
Calcium and magnesium decrease flouride absorption
Flouride concentrates in bone & teeth
In children, the flouride concentrates in bone and teeth than elderly

199. FLOURIDE PREPARATIONS
3- MECHANISM OF ACTION OF FLOURIDE
Flouride converts hydroxyapatite to FLOUROAPATITE which leads
Makes the apatite structure more stable which improve CRYSTALLINITY of the structure
FLOUROAPATITE is less soluble in acid
FLOURIDE inhibits bacteria enzymes

200. EXAMPLES FLOURIDE PREPARATIONS
1- ACIDULATED PHOSPHATE FLOURIDE (APF)
It contains flouride between 10,000 to 20,000 PPM
It is the preparation of choice for professional flouride application
It benefits last 2-3 years after application on the teeth
Contact time upon application is (1-4 minutes) depends on the type of preparation.

201. EXAMPLES FLOURIDE PREPARATIONS
ACIDULATED PHOSPHATE FLOURIDE (APF)
A- Advantages of APF
Stable in solution
Not irritant to gingiva
Agent of choice for professional application
B- Disadvantages of APF
APF is acidic solution may affect CEMENTUM
Not suitable for dentrifrices

202. EXAMPLES FLOURIDE PREPARATIONS
2- SODIUM FLOURIDE
It is available in tablets such as Zymaflour® 1mg
0.25 MG (1/4 Tablet) per day required for 5-16 years old
A- Advantages of sodium flouride
Stable in solution
Neutral solution (Ph 7.0)
B- Disadvantages of sodium flouride
It is NOT compatible with many abrasives in
tooth-paste because:
- it reacts with CALCIUM & PHOSPHATE
- and becomes insoluble compound
- Not absorb into circulation (not effective)

203. EXAMPLES FLOURIDE PREPARATIONS
MOUTH RINSE CONTAINS SODIUM FLOURIDE
It is more effective than MFP present in tooth-paste
but combination of sodium flouride mouth rinse with dentrifrices are more effective than either product alone
Mouth rinse containing FLOURIDE 100 PPM recommend to use it twice daily
Mouth rinse containg 250 PPM used once daily
mouth rinse contains 1000 ppm used once weekly or every other week

204. EXAMPLES FLOURIDE PREPARATIONS
3- SODIUM MONOFLOUROPHOSPHATE (MFP)
It is commonly used in tooth-paste
A- Advantages of (MFP)
Stable in various pH
It is compatible with tooth-paste abrasives
B- Disadvantages of (MFP)
It is weak flouride source
Efficacy is questionable

205. EXAMPLES FLOURIDE PREPARATIONS
4- STANNOUS FLOURIDE
A- Advantages of STANNOUS FLOURIDE
Both cation & anion are effective
B- Disadvantages of STANNOUS FLOURIDE
Unstable in solution
Stain teeth
bitter taste

206. TOXICITY OF FLOURIDE A- ACUTE TOXICITY
It is common during applying APF IN CHILDREN
Fatal dose mg/kg
Symptoms of toxicity
- Nausea, vomiting
- Abdominal pain
- Sweating
- Convulsion
- Death

207. TOXICITY OF FLOURIDE B- CHRONIC TOXICITY
It is occurs at concentration ranges between 2-8 ppm consumed in drinking water
Flourosis occurs when the crown of permanent teeth are forming
DEFINITION OF FLOUROSIS
- Is hypoplastic defect resulting from disturbance in the function of AMELOBLAST (enamel) during teeth development
Symptoms of chronic toxicity
- endemic flourosis is associated with
- mottled enamel & deformed teeth

208. DENTRIFERICES Clean Polish Prevent bacterial fermentation
1- It is a pharmaceutical preparations are used locally on the teeth & oral cavity to perform the followings:
Clean
Polish
Prevent bacterial fermentation
Prevent gingivitis
Prevent dental caries

209. EXAMPLES OF DENTRIFERICES
TOOTH PASTE
POWDER
LIQUID IN FORM OF SOLUTION

210. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 1- Abrasive
It is am inert , insoluble and finely powdered
Examples of abrasives
- calcium pyrophosphate
- dicalcium phosphate
Main action of abrasive
- it cleans and polish
- removes stain and plaque

211. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 2- Flavouring agents
They have the following properties:
good odor
mild antiseptic
mild local anesthetic
counter irritant
Examples of flavouring agents
- peppermint
- cinnamon
- clove oil
- menthol

212. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 3- SWEETNER
Examples of sweetner
- Saccharin
- aspartame
- glycerin

213. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 4- HUMICTANT
FUNCTIONS OF HUMICTANTS:
- Keep moisture of the tooth-paste
- prevents dryness of the tooth paste
- it gives plasticity to the tooth-paste
- it has demulcent action on the gum
Examples of sweetner
GLYCERIN
SORBITOL

214. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE
5- DETERGENT & FOAMING AGENTS
FUNCTIONS OF HUMICTANTS:
- they lower surface tension(emulsifying agents)
- emulsify fatty materials
- Promote good penetration and mixing of constituents of the tooth-paste
- they assists in removal mucous deposit and debris
- Help to dissolve plaque

215. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE EXAMPLES DETERGENT
& FOAMING AGENTS
Examples of detergent and foaming agents:
- sodium lauryl-sulfate
- magnesium lauryl-sulfo-acetate
- monoglyceride
- dioctyl-sodium-sulfo-succinate

216. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 6- THICKENING AGENTS
FUNCTIONS
- Improve & maintain the consistency of the paste
- they prevent separation of the tooth-paste contents under extreme temperatures (high & low)
Examples of thickening agents:
- glycerin starch
- carboxy-methyl-cellulose
- sodium alginate
- methyl-cellulose

217. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 7- PRESERVATIVES FUNCTIONS
- prevent bacterial , fungal growth which prevents fermentation of the tooth-paste
Examples of preservatives:
- methylparaben 0.15%
- propylparaben 0.15%

218. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 8- FLOURIDE FUNCTIONS
- It is anti-cariogenic agent and significantly reduces caries
- it is commonly used sodium-mono-flouro-phosphate (MFP) because :
* it is stable at various Ph
* compatible with many abrasives

219. TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 9- DESENSITIZING AGENTS
Not present in most of tooth-paste
examples of desensitizing agents
- Potassium nitrate
- Potassium oxalate

220. GLUCOCORTICOIDS
Adrenal steroids are synthesised from zona fasciculata of adrenal cortex as needed
It is stimulated by ACTH which is release from pituitary gland
ACTH is regulated by CRF in hypothalamus
Glucocorticoids is synthesised from chlosterol
Stress also stimulate glucocorticoids

221. Adrenal Gland

223. Glucocorticoids

224. MECHANISM OF ACTION
Glucocorticoids bind with specific receptors in the cytoplasms
The complex binds with DNA which leads to:
* prevent transcription such as
- COX-2
- Block Vit D3 –mediated induction of
osteocalcin
* or induce particular gene
- Such as LIPOCORTIN-1 & Tyrosine hydroxylase

225. MECHANISM OF ACTION
Glucocorticoids bind with specific receptors in the cytoplasms
The complex binds with DNA which leads to:
* prevent transcription such as
- COX-2
- Block Vit D3 –mediated induction of
osteocalcin
* or induce particular gene
- Such as LIPOCORTIN-1 & Tyrosine hydroxylase

226. Direct effects come from receptor binding
CBG
albumin
HSP70 IP
HSP70 IP
HSP90
HSP90
transcription
GRE GRE
GRE GRE
Altered cellular function
protein

227. Example of indirect inhibition of gene induction
Cytokines
COX-2
NOS-2
NF-  B
NF-  B
TNF- 
TNFR
NF-  B I  B 
GCR GC I  B  I  B 
GCR
GLUCORTICOIDS

228. Phospholipase A2
(PAF)

230. Pharmacological action of glucocorticoids
1- General effects on metabolism
- Water, edlectrolyte balance and organ systems
2- Negative feedback on Pituitary & Hypothalamus
3- Anti-inflammatory and immunosuppressive

231. GENERAL METABOLIC & SYSTEMIC EFFECTS
1- Carbohydrate and protein metabolism
2- Decrease glucose utilization
3- increase gluconeogenesis which may induce hyperglycemia
4- Decrease in protein synthesis breakdown
5- It has permissive effects on the lipolytic response to catecholamines

232. GENERAL METABOLIC & SYSTEMIC EFFECTS
6- Redistribute fat in large dose
7- It has some mineralocorticoids activities
8- Increase calcium secretion & decrease its absorption
9- Reduce function of osteoblast
10- and Increase the activity of osteoclast (Digest bone)
* by hypocalcemia-induced parathyroid hormone secretion
* These lead to osteoporosis

233. NEGATIVE FEEDBACK EFFECTS
1- Both endogenous and exogenous glucocorticoids have a negative feedback on CRF & ACTH
2- The inhibitory effects of endogenous glucocorticoids due to exogenous steroids is prolonged (months)
3- lipocortin-1 play negative feedback on hypothalamus and pituitary
3- and leads to atrophy of adrenal cortex

234. Atrophy due to negative feedback inhibition of ACTH
3rd
vent
( - )
( + )
CRF neuron
IL-1
IL-2
IL-6
TNF-
( - )
( + )
immune
system
ACTH
( + )
( - )
Adrenal d
Cortisol
administered glucocorticoid

236. Anti-Inflammatory
1- Inhibit production of prostaglandins due to decrease the expression of COX-2
2- inhibit early and late manifestation of inflammation
3- Which leads to prevent chronic inflammation
4- Decrease fibroblast which leads to inhibition of chronic inflammation (less fibrosis) and wound healing and repair

237. Arachidonic acid which is the precursor for:
Continue anti-inflammatory effects
5- Inhbits Phospholipase A2 by inducing lipocortin which leads to:
Decrease production of PAF
Arachidonic acid which is the precursor for:
* Production of prostaglandins
* Leukotrienes (slow reacting substance of anaphylaxis

238. 6- Decrease histamine release 7- decrease production of nitric oxide
Continue anti-inflammatory effects
6- Decrease histamine release
7- decrease production of nitric oxide
8- Decrease production of PAF
9- Decrease the production of GM-CSF which is essential for production of:
-platelets
-Monocyte, neutrophil & eosinophil
-RBCs

239. IMMUNOSUPPRESSIVE EFFECTS
* Drug binds only to certain targets
Supress initiation generation of immune response
It is non-selective
** Supress cellular immunity
** and Humeral
* It induces apoptosis of lymphocyte

240. ADVERSE EFFECTS OF GLUCOCORTICOIDS
Adverse effects occur after prolonged used
or large dose
1- Supress response to infection or injury
2- Impair wound healing
3-Slight incidence of peptic ulcer
4- Cushing’syndrome
5- Osteoporosis
6- Hyperglycemia

241. ADVERSE EFFECTS OF GLUCOCORTICOIDS
7- Muscle wasting
8- Inhibit growth in children
9- Euphoria & Psychosis
10- decrease blood supply to bone leading to necrosis the head of the femur
inhalation

242. ADVERSE EFFECTS OF GLUCOCORTICOIDS
11- cataract
12- glaucoma
13- increase in intracranial pressure
14- disorder of menestrual cycle
15- oral thrush especially when taken by inhalation
16- Adrenal insufficiency
* It may take two months or more up to 18 months

243. GUIDELINES FOR GLUCOCORTICOID THERAPY
1- It should based on the severity of diseases
2- Dosage, frequency, duration & preparation influence the response and adverse reactions
3- Administered locally when possible inorder to minimize the adverse effects & efficacy
4- The pharmacological dose should be tapered in order to avoid adrenal crisis

244. CLINICAL USES OF GLUCOCORTICOIDS
1- Replacement therapy (Addison’disease
2- Asthma
3-Topically in various inflammatory condition
skin , eye, nose
4- Post neurosurgery &head and spinal injury
5- Autoimmune diseases
-Inflammatory bowel disease
- haemolytic anemia

245. CLINICAL USES OF GLUCOCORTICOIDS
6- Anti-cancer with other cytotoxic agents
7- Autoimmune diseases
8- Inflammatory diseases
- haemolytic anemia
- organ transplant with other immunosuppressants
9- Anti-emetic in conjunction with other anti-emetic

246. GLUCOCORTICOIDS USES IN DENTAL PRACTICE
10- Temporary relief of sympton associated with
Oral inflammation and ulcerative lesion such as
A- Recurrent aphthus stomatitis
Triamcinolone acetonide (Kenalog orabase)
B- Erosive lichen planus
-- Dexamethasone
C- Major aphthae
- Kenalog orabase

247. CLASSIFICATION OF GLUCOCORTICOIDS
DURATION OF ACTION
Pregnancy Risk
Potency
Short (8-12hrs)
- Hydrocortisone
- Cortisone C D 1
0.8
Intermediate (18-36)
- Methylprednisolone
- Prednisolone
- Prednisone
- Triamcinolone B 5 4

248. CLASSIFICATION OF GLUCOCORTICOIDS
Duration of action
Pregnancy Risk
Potency
Long acting (36-54)
- Betamethasone
- Dexamethasone C 25
25-30

249. INHALER GLUCOCORTICOIDS
DRUG
Pregnancy
Risk
Potency
Compare to dexamethasone=1
Fluticasone C
1200
Budesonide
(Pulmicort, Rhinocort)
980
Beclomethasone
(Beconase, Beclovent)
600
Triamcinolone
330

250. SEE YOU NEXT TIME

251. Thank you