Transcript Drugs - PHARMACEUTICAL REVIEW

Pharmacology
By
Prof. Dr. Amany Ibrahim El-Brairy
Professor of Pharmacology
H107
Why we study Pharmacology?

Drug information : knowledge, skills,
and attitude

Rationale and safe prescribing in dental
practice throughout the dental graduate
career

Self and continuous learner
The following scheme is used in discussion of a
drug
Name Of The Drug
1- Definition
2- Pharmacokinetics = What the BODY does
to the DRUG = A. D. M. E.
a- Absorption: Oral and/or Other
b- Distribution: Binding to plasma proteins,
Blood Brain Barrie & Placental barrier.
c- Metabolism: Hepatic and/or other
d- Excretion: Renal and/or other e.g. Milk
3- Pharmacodynamics = What the DRUG does to the BODY
a- Mechanism of action
b- Pharmacological actions:
- Desirable = Therapeutic effects = Uses
- Undesirable = Adverse effects
= Side effects and toxicity
4- Pharmacotherapeutics:
a- Therapeutic uses = Indications
b- Dosage
5- Side effects and toxicity:
a- Manifestations
b- Management
6- Contraindications
7- Drug interactions.
Types of drug names
Chemical:
e.g. acetyl salicylic acid.
Generic (scientific):
e.g. aspirin.
Commercial (Trade):
e.g. Rivo, Aspocid, Rhonal..etc.
PHARMACOKINETIC
What the Body dose to the Drug?
Absorption,
Distribution,
Metabolism ,
Excretion
ADME
Absorption
Bound Drug
Free Drug
Excretion
Metabolite/s
Distribution
Site of Action
Site of storage
Metabolism
The study of pharmacokinetics is important to:
1- Design a proper dosage schedule
(dose, route, frequency of administration)
2- Determine the drug’s bioavailability.
* Bioavailability:
1- The fraction (%) of administered drug that
reaches the systemic circulation in an
unchanged form.
2- Bioavailability is 100% after I.V. & most
variable after oral administration
Absorption
Rate & Efficiency = Bioavailability
Oral
GIT
Liver
Systemic
Circulation
pH &
Enzymes
I.V.
Oral
I.V.

Bioavailability of a Route =
Area under the curve (AUC) of the route
x100
Area under the curve (AUC) of I.V. route
Trans-membrane Movement of Drugs
Passage of Drugs Across Biological
Membranes
Cell membrane is formed
mainly of bimolecular LIPID
sheet, interrupted by
protein macromolecules
(receptors, carriers, etc.),
water-filled pores & ion
channels
Lipid
Protein
Water
Ions
* Types of Passage of drugs
A) Passive Transfer :
1- Simple Diffusion:
a- Mostly across the LIPID phase of cell membrane.
b- Water & water-soluble small M.W. drugs pass
across the water-filled pores.
* Characteristics:
Lipid
1- Along concentration gradient.
No Carrier
2- NO carrier.
No Energy
3- NO energy.
Factors & Forces:
1-Gradient (Concentration of drugs )
Higher gradient = Higher rate of passage
across the membrane.
2-Molecular weight & size:
The smaller is the faster.
*Passive Diffusion (cont.)
3-Solubility in water is a must.
4-Oil (lipid) / Water (O/W) partition coefficient.
The higher is the better.
A 10 g B
Oil
H2O
9
2
/
/
1
8
9
1/4
*Passive Diffusion (cont.)
5-Ionization:
 It depends upon pH of the medium & pKa of the
drug (pH at which 50% of drug is ionized)
 Low Ionization = High lipid solubility = Better
passage.
 Drugs are non-ionized when they are present in
a similar medium (Acidic drugs in acid medium
and basic drugs in alkaline medium).
*Effect of pH on Oral Absorption & Renal
Excretion of Drugs:
-For weak base and acid drugs:
a- The unionized (non-polar) form is lipid
soluble and easily absorbed.
b -Ionized (polar) form of drugs is lipid
insoluble and not easily absorbed but easily
excreted.
 Weak acid drugs are more unionized in acid
& more ionized in alkaline media.
 Weak base drugs are more unionized in
alkaline & more ionized in acid media.





When drugs are present in a reverse medium
→ Ionized → not lipid soluble → not
absorbed → Excreted.
Aspirin is better absorbed in acid medium
e.g. Stomach.
Alkalinization of urine by sodium acetate, or
citrate   its urinary excretion.
Ephedrine is better absorbed in alkaline
medium e.g. Intestine.
Acidification of urine by ammonium chloride
  its urinary excretion.
2- Filtration:
Passage of drugs through Capillary endothelium
& Glomeruli
* Characteristics:
 Along hydrostatic and osmotic gradients
Circulation
No
carrier
No energy
2- Filtration )cont.)
* Factors & Forces:
1- Molecular weight
2- Not bound to plasma proteins
3- Hydrostatic and osmotic gradients
4- Blood flow
B) Special Transfer:
1- Facilitated Diffusion:
Along concentration gradient
Needs Carrier  Site for Saturation
No energy
Carrier
Example: Glucose uptake
No Energy
B) Special Transfer (cont.)
2- Active Transport:
Against concentration gradient
Needs Carrier  Site for Saturation &
Competition (Interaction)
Energy & Enzymes
Example: Na+/K+ pump &
Renal tubular excretion of penicillins
Carrier
Energy
B) Special Transfer (cont.)
3- Pinocytosis (Cell Drinking):
Energy dependent
Example: Absorption of Vit B12 + Intrinsic
factor by terminal ileum
Characteristics
1- Gradient:
2- Carrier:
3- Saturation &
competition:
4- Energy:
5- Example:
Simple Diffusion
Facilitated
Diffusion
Active Transport
Along
NO
NO
Along
Yes
Yes
Against
Yes
Yes
NO
Lipid soluble drugs
NO
Glucose
Yes
Na/+K +pump
I- Absorption

Transfer of drugs from their site of
administration to the systemic
circulation
*Factors Affecting Absorption:
A) Factors Related to the Patient
1-Route of Administration: I.V. > I.M. > S.C. >
Oral > Skin
2-Absorbing Surface:
a-Vascularity: Alveoli > Skeletal muscle >
Subcutaneous
b-Surface area: Alveoli > Intestine > Stomach
c-State of health: Diarrhea & mal-absorption
inhibit Oral absorption
3-Systemic circulation: Shock & Heart failure 
Absorption
4-Specific factors: Intrinsic factor for Vit B-12
5-Presence of other drugs & food:
 a-Adrenaline S.C . V.C . Absorption of
Local anesthetics Long duration of action
 b-Milk (Calcium)   Oral absorption of
Tetracyclines (Antibiotic)
B )Factors Related to the Drug:
1-Water and lipid solubility:
Drugs MUST be Water soluble as well as Lipid
soluble.
Drugs must be completely dissolved in water to
be absorbed.
Drugs insoluble in water e.g. Barium
chloride (BaCl2) are NOT absorbed.
More lipid solubility  High Lipid/Water
partition coefficient  Better absorption
2-Ionization :
Non-ionized drugs are more lipid soluble 
Better absorption
Depends on pKa of the drug & pH of the
medium.
Tertiary amines Non-ionized  Better
absorption.
Streptomycin has high pKa  Always ionized
Not absorbed
Sulfaguanidine Not ionized yet  not lipid
soluble  Poor absorption
3- Valency: Ferrous iron (Fe2+) is better absorbed
than Ferric Iron (Fe3+).
4- Nature: Inorganic (small molecules) > Organic
(Big molecules)
5- Pharmaceutical Preparation:
a- Dosage form: Solution > Suspension >Tablet
b- Shape & size of particles and rates of
disintegration & dissolution of tables:
Rapid with paracetamol & propranolol
Slow with digoxin
c- Excepient (Filler)e.g. CaCO3 & Ca Phosphate
  Absorption of Tetracyclines.
Routes of Administration


Enteral
1- Buccal e.g. Sublingual
2- Oral
3- Rectal
Others
1- Parenteral e.g. Injection
2- Inhalation
3- Topical
Effect Of Administered Drug:
1-Systemic (General):
If drug is absorbed and distributed
2-Local (Topical):
If drug is not absorbed nor distributed
Enteral Route
1-Sublingual  Absorbed directly Systemic
circulation  Good Bioavailability
 2-Oral  Stomach & Intestine  pH changes &
enzymes  Portal circulation  Liver metabolism
 Systemic circulation  Most variable
Bioavailability
 3-Rectal (Suppository) 
a-Upper rectum  Portal circulation  Liver
metabolism  Systemic circulation
b-Lower rectum  Systemic circulation

1- Oral Route
Characteristics:
1- Suitable:
a- Small amount or volume
b- Palatable: If bad taste 
- Dilute with milk or fruit juice
- Use sugar coated or effervescent form
b- Non-irritant: If Mild irritant 
- Take after meal
- Use enteric coated form: Covered with acid
resistant coat
Advantages:
Convenient (Safe, easy & economic)
Disadvantages:
1-NOT in emergency  Delayed onset
2-NOT in uncooperative patients e.g. coma, insane or very
young
3-NOT in vomiting or severe diarrhea
4-NOT in very irritant drugs e.g. Emetine HCl
5-NOT in unabsorbed drugs when systemic effect is wanted
6-NOT for drugs with extensive First Pass Effect (Metabolism):
a-pH changes: Benzyl penicillin is destroyed by gastric
acidity
b-Digestive enzymes: Insulin
c-Hepatic enzymes: Nitroglycerin
D) Factors Affecting Oral Absorption:
1- State of Health of G.I.T. Mucosa e.g. Mal-absorption
Syndrome.
2- Specific Factors e.g. Intrinsic Factor for Vit B12
Absorption.
3- Gastric Emptying:
a- Metoclopramide (Primperan, Anti-emetic)  Emptying 
-  Absorption of Paracetamol (Rapid rates of
Disintegration & Dissolution).
-  Absorption of Digoxin (Slow rate of Disintegration &
Dissolution)
b- Atropine   Emptying  The REVERSE Effects.
4- Gut Motility: Marked alterations (e.g. Morphine)  
Absorption.
5- pH
a- Gastric Acidity   Absorption of Salicylates &
Barbiturates
b- Intestinal Alkalinity   Absorption of Ephedrine &
Amphetamine.
6- Presence of FOOD & Other DRUGS:
a- Bad  Food dilutes Drugs & may compete with them
for absorption e.g. amino-acids compete for the same
carrier of L-DOPA
b- Good  with IRRITANT drugs e.g. aspirin & iron.
c- Milk (Ca2+) & Anti-acids  Interfere with Tetracycline
absorption.
d- Tea (Tannic Acid) & Tetracycline   Iron absorption.
e- Cholestyramine & Activated Charcoal   Absorption
of Most Drugs.
7- First Pass Effect (Pre-Systemic Metabolism):
 Bioavailability
a- Gut First Pass Effect:
- Gastric Acidity: Benzyl Penicillin.
- Digestive Enzymes: Insulin & Pituitary hormones
- Mucosal enzymes: Tyramine, L-DOPA, -Methyldopa
&Chlorpromazine
- Flora: Histamine
c- Hepatic First Pass Effect:
- Extensive: Nitroglycerine, Lidocaine & Natural sex hormones.
- Partial: Propranolol & Morphine.
- Minimal: Atenolol, Nadolol & Barbitone.
d- How to OVERCOME Hepatic First Pass Metabolism?
- Increase the oral dose of the drug e.g. Morphine & Propranolol
- Use other routes (NOT ORAL) e.g. Sublingual “Nitroglycerine”.
8- Factors related to the DRUG e.g. Lipid Solubility.
2-Sublingual (Pellet or Linguat)
*Example: Isoprenaline & Nitroglycerine.
*Advantages:
1- Easy.
2- Escape gut and hepatic first pass effect 
Good bioavailability.
3- Rapid onset.
4- Proper control of dose by either spitting or
swallowing excess of the drug.
3-Rectal:
1- Solid (Suppository): Drug (Aminophylline) in a
cone of gelatin or cocoa butter.
2- Fluid (Enema):
a- Evacuant (Cleansing) enema e.g. for
constipation:
-Large volume (1 liter)
-High head pressure
-Mild irritant (chamomile)
b- Retention enema e.g. Nutrient:
-Small volume (1/4 liter)
-Low head pressure
-Non-irritant
B) Advantages:
a- Escape gut & hepatic first pass effects
b- Useful in patients with vomiting
c- Useful in uncooperative patients e.g.
coma & young children
d- Useful in mild irritant drugs e.g. aspirin
and aminophylline
e- Useful in large volume drugs
Parenteral Routes
All drugs must be STERILE and PYROGEN-FREE
A)Subcutaneous Pellet Implantation:
Sterile pellet under the skin  Fibrosis 
Slow absorption  Long duration e.g. some
hormones (Contraceptives).
B)Intradermal Injection (I.D.): e.g. Sensitivity
tests & Vaccinations.
C)Subcutaneous Injection (S.C.):
1-Drugs should be:
a- Non-irritant
(If irritant or oily  Inflammation)
b- Aqueous Solution or fine suspension.
2-Absorption can by Enhanced by:
a- Use a solution
b- Massage of injection area
c- Application of heat d- Add hyaluronidase enzyme
3-Absorption can be Slowed by:
a- Use a suspension
b- Application of cold
c- Add adrenaline (V.C.) to local anesthetics
d- Add gelatin to heparin
D) Intramuscular (I.M.):
1- Drugs can be: Solution, suspension, oily, nonirritant or mild irritant.
2- Better absorption than S.C.
3- Some drugs (Diazepam & Phenytoin)  Bound
to muscle proteins  Irregular absorption.
E) Intravenous (I.V.):
Either SLOW bolus injection or Infusion
(Drip) method.
 Water solution ONLY.
 Advantages:
Useful in Emergencies
a- 100% bioavailability
b- Immediate onset
c- High plasma concentration
d- Useful for Irritant & Large volume drugs

Disadvantages:
MOST DANGEROUS ROUTE
a- If Allergy  Anaphylactic shock
b- If Very Irritant  Thrombophlebitis
c- If Extravasation of irritant drug  Severe
pain and inflammation
d- If Rapid I.V.  Velocity reaction 
Cardiac problems (Aminophylline)
e- Pyrogenic reaction by phospho-lipo-protein
of microorganisms
f- Transmission of diseases e.g. Viral
Hepatitis C & AIDS.

F) Other Injections:
1- Intra cardiac e.g. Adrenaline in cardiac resuscitation
2- Intra-umblical = I.V. in new born e.g. Lobeline in
neonatal asphyxia
3-Intra-bone marrow = I.V.
4- Intra-arterial e.g. Angiography and cancer
chemotherapy
5- Intra-peritoneal as substitute for Hemodialysis
6- Intra-thecal (CSF) e.g. spinal anesthesia, antibiotics
in meningitis & Radiography
7- Intra-articular e.g. Steroids in osteoarthritis
8- Intra-cameral (Into aqueous humor)
Inhalation
- Inhaled drugs may be in the form of:
a-Gas e.g. Oxygen & Nitrous oxide
b-Vapor of Volatile liquid e.g. Halothane
(General anesthesia)
c-Solution e.g. Salbutamol (B2-agonist in
Bronchial asthma)
d-Powder e.g. Di-sodium-cromoglycate
(Mast cell stabilizer in Bronchial asthma)
- Excellent
absorption because of:
a-Wide surface area
b-High vascularity
c-Thin porous membrane of the alveoli
Topical e.g. Skin & M.M.
1-Usually  Local effect.
However highly lipid soluble drugs can be absorbed
from the skin.
2-Skin absorption can be enhanced by:
a-Iontophoresis by the aid of galvanic electric
current e.g. Methacholine in P.V.D.
b-Inunction by the aid of rough rubbing.
c-Transdermal Drug Delivery System (TDDS) e.g.
Skin patch of nitroglycerine
- Prolonged blood level with minimal fluctuations
- Better patient compliance
- Avoid gut & hepatic first pass effect
3-Usually skin absorption is not wanted and
harmful:
a-Estrogen hormone in females  Cancer
breast.
b-Cortisone in infants  Moon face.
c-Insecticides  Toxicity.
II-Distribution
Patterns Of Distribution:
Total Body Fluid
Extra-cellular
Intra-vascular
Intra-cellular
Interstitial
Free fraction
Bound Fraction
High M.W. (Poly) & Bound
Cells
Low M.W.
Low M.W.
NOT lipid soluble
Lipid Soluble
A) Binding To Plasma Proteins:
A fraction of Most drugs binds Reversibly to
plasma proteins Mainly albumin .
The Bound fraction of the drug 
 NOT Active
 NOT Filtered
 NOT Metabolized
 NOT Excreted  Depot Form.
 More binding = More Depot = Longer duration.

The Free fraction of the drug 
 Active,
 Metabolized
 Excreted.
 There equilibrium between the bound
& the free fractions of the drug.
Drugs extensively bound to plasma
proteins e.g. Thiopentone (I.V.
Anesthesia) have to be injected rather
Rapidly I.V.
 Drugs have specific binding sites on
plasma proteins = Non-functioning
receptors  Site for competition &
drug interactions.

Site for Drug Interactions:
 Aspirin (NSAID) & Sulfa drugs
displace:
1- Oral Anti-coagulants e.g. Warfarin
 Hemorrhage.
2- Oral Hypoglycemics e.g.
Tolbutamide  Hypoglycemia.
3- Bilirubin in neonates  Jaundice &
Kernictrus.

B) Patterns Of Distribution:
1- Intra-vascular (Single Compartment):
Drug is retained in the blood compartment.
Drugs that can NOT filtrate through capillary
endothelium.
Examples High MW > 500 e.g. Polypeptides
(Plasma proteins & Drugs bound to
plasma proteins) & Polysaccharides
(Heparin & Dextrans).
2- Extra-cellular (Two compartments =
Intra-vascular + Interstitial):
Drugs that can filtrate (Small MW) but
can NOT pass cell membrane (Not
lipid soluble).
Ionized form of drugs (Neostigmine),
Mannitol, Na+, Cl- & SO4.
3- All over the body (Multi-compartment
= Intra + Extra-cellular):
Drugs that can filtrate (Small MW) &
Can pass cell membrane (Lipid
soluble).
Non-ionized form of drugd
(Physostigmine), Alcohol, Aspirin &
Barbiturates.
4- Tissue Reservoirs:
a- Hair: Arsenic
b- Thyroid: Iodine
c- Heart: Digitalis
d- Liver: Vit B12 & Chloroquine
e- Fat: Thiopentone
f- Bone: Ca2+
5- Blood Brain Barriers:
Lipid cellular barrier composed of Brain Capillary
Endothelium (Which lacks the water channels)
and the adjacent Glial tissue.
Only lipid soluble Non-ionized drugs can pass
B.B.B. along their concentration gradient.
Inflammation (Meningitis) increases permeability
of B.B.B.
Penicillins can pass inflamed meninges but NOT
normal ones.
6- Placental Barrier:
Lipid cellular barrier composed of Epithelium of
Fetal Villi & Capillary endothelium.
Rich in enzymatic activity e.g. M.A.O.
Drugs that pass placental barrier may cause:
 During pregnancy  Teratogenicity e.g.
Thalidomide & Tetracyclines
 During Labor  Neonatal asphyxia e.g.
Morphine & Barbiturates.
Metabolism (Biotransformation)
Chemical alteration of the drug
AIMING to convert: Drugs (Active,
Non-ionized & Lipid soluble) 
Metabolite (Inactive, Ionized & water
soluble)  Easily excreted in urine &
bile.
* Types of Metabolism:
A) Phase-I (Non-Synthetic) 
Oxidation, Reduction & Hydrolysis
1- Oxidation:
- Phenacetin (Active)  Paracetamol
(Active)
2- Reduction:
- Chloral hydrate (Active)  Tri-chloroethanol (More active)
3- Hydrolysis:
- Di-acetyl-morphine (Heroin)  Acetic acid
+ Morphine (Active)
B) Phase-II (Synthetic, Conjugation):
- Usually leads to inactivation
- May lead to activation e.g. Morphine 
Morphine-6-Glucoronoid (More active)
- Types:
1- Glucuronic acid  Aspirin, Paracetamol,
Morphine & Chloramphenicol.
2- Acetic acid (Acetylation)  Isoniazide,
Sulfonamides & Hydralazine.
3- Methylation  Noradrenaline ( Active
Adrenaline) & Histamine.
4- Glycine  Aspirin
* Site Of Biotransformation:
 Organs:
a- Liver (Hepatic) is the main site for
biotransformation
b- Lung  Nicotine, Prostaglandins &
Angiotensin (ACE).
c- Kidney  Vitamin D
d- G.I.T. & Gut flora  Tyramine & Histamine
e- Skin  Vitamin D
f- Plasma (Cholinesterase)  Succinylcholine
* Factors Affecting Hepatic
Microsomal Enzymes
A) Hepatic Microsomal Enzyme Inducers
(Activators):
Examples: Phenytoin, Carbamazepine,
Rifampicin, Testosterone, Cortisol & Tobacco
smoking.
They  Metabolism of other drugs e.g. Oral
anti-coagulants, Oral hypoglycemics & Oral
contraceptives   Their duration of action.
They  Their own metabolism (Auto-induction)
 Tolerance.
B) Hepatic Microsomal Enzyme Inhibitors:
Specific: Grapefruit, Estrogen, Cimetidine,
Chloramphenicol, Erythromycin &
Ciprofloxacin.
Non-specific (General):
a- Hepato-toxic drugs: Carbon monoxide,
Carbon tetrachloride & Ozone.
b- Drugs  Hepatic blood flow: -Blockers
(Propranolol) & H2-Blockers (Cimetidine)
C) Age:
H.M.E. Activity is inhibited in extremities of age.
Premature neonate can NOT conjugate
chloramphenicol  Fatal Grey Baby
Syndrome.
D) Liver disease, Starvation & Cancer  
H.M.E. Activity
E) Genetic Abnormality (Idiosyncrasy): Favism
& Abnormal Pseudo-Ch.E.
Excretion
A) Renal:
Non-volatile drugs and metabolites are
excreted in the urine.
The clearance of some drugs depends mainly
on renal excretion (Little or no metabolism)
e.g. Atenolol, Nadolol, Barbitone & Gallamine
 Caution in Renal patients.
Renal excretion is the result of glomerular
filtration
and active tubular secretion & reabsorption
Passive Glomerular filtration for water
soluble Non-bound drugs with M.W. <
500 e.g. Mannitol.
 Active Tubular Excretion (Saturable &
Site for competition & Drug Interaction):
Weak acid drugs e.g. Penicillin,
Frusemide, Uric acid & Probenecid.
Weak base drugs e.g. Digoxin &
Quinidine





Changes in urinary pH  Affect excretion of
weak Acid & Base drugs:
Alkalinization of urine (Na or K Acetate,
Bicarbonate ) 
 Renal excretion of weak Acid drugs e.g.
Aspirin
Acidification of Urine (NH4Cl or “Vit C”) 
 Renal excretion of weak Base drugs e.g.
Ephedrine & Amphetamine.
B) Lung
Gases (CO2) & Volatile Liquids (Halothane)

C) Alimentary Tract:
1- Saliva (pH = 8): Morphine & Aspirin
2- Stomach  Morphine.
3- Bile  Intestine  Either:
a- Excreted in large intestine
b- Reabsorbed  Entero-Hepatic Circulation e.g.
Morphine& Indomethacin,
c- Some anti-microbials are excreted in bile in an
active form e.g. Ampicillin & Rifampicin  Useful in
treatment of Cholecystitis & Typhoid carrier.
4- Large Intestine: Either via the bile or unabsorbed
oral drugs.
D) Skin Glands:
1- Sweat  Vit B-1, Hg, As & Rifampicin 
Red discoloration of sweat.
2- Milk  May affect suckling baby e.g.
Morphine, nicotine, Purgatives, Tetracyclines
& Chloramphenicol.
PHARMACODYNAMICS
(What the DRUG does to the BODY)


This science deals with Mechanism &
pharmacological Actions of drugs.
Drugs are chemical substances that modify
increase or decease already present cell
function but do not create a new one.
However, genetic engineering and gene
therapy may change this concept.
* Types of Drug Action:
1- Local or Topical Action:
NO Absorption from site of administration 
NO Distribution  NO Systemic actions.
The drug acts at site of application.
Examples: Most of eye & ear drops, intraarticular injections & skin ointment.
2- Systemic or General Action:
The drug is absorbed and distributed from site
of administration.
Examples: Oral aspirin, Subcutaneous (SC)
adrenaline & Sublingual (SL) isoprenaline.
3- Reflex or Remote Action:
The drug acts at a site to provoke an effect
away from its site of action.
Examples : SC Camphor  Irritation  Reflex
 Respiratory center = Reflex Analeptic.
* Mechanism of Drug Action:
1- Physical:
a- Adsorption: Kaolin & Activated charcoal in diarrhea.
b- Osmotic: MgSO4 as a purgative.
c- Demulcent: Liquorice as an anti-tussive.
d- Astringent: Tannic acid mouth wash in gingivitis
2- Chemical:
a- Neutralization:
- NaHCO3 (Antacid) + HCl in treatment of hyperacidity.
b- Chelation: Organic compound + Heavy metal  Nontoxic easy excreted complex.
- Dimercaprol (British Anti-Lewisite) for Mercury (Hg)
3- Interference with Cell Division: Anti-cancer
drugs e.g. Nitrogen mustard.
4- Interference with Metabolic Pathway:
Sulfonamides compete with PABA in bacteria
  Synthesis of folic acid.
5- Inhibition of Enzymes: Physostigmine (
Cholinesterase) &
Aspirin ( Cyclooxygenase, COX).
6- Action on Ion Channel:
Local anesthetics block Sodium (Na+)
channels.
Calcium channel blockers (CCB) e.g.
Verapamil block L-type of voltage gated
calcium channels of heart & blood vessels.
Some pharmacologists consider ion channels
as an especial type of receptors.
7- Action on Receptors:
A Receptor is a chemo-sensitive & chemoselective cellular macromolecule that reacts
specifically with a Ligand (drug, transmitter or
hormone) to produce a biological response:
Affinity (Ka)
Efficacy or
Drug + Receptor
Drug/Receptor Complex
Response
(Kd)
Intrinsic Activity
1- Affinity = Ability of a drug to fit onto a receptor to
form Drug/Receptor complex.
2- Efficacy or Intrinsic Activity = Ability of D/R
complex to evoke a response.
3- Ka = Association constant with the receptor
4- Kd = Dissociation constant from the receptor
* Types of Ligands
A) Stimulants = Agonists:
These drugs stimulate the receptors directly
and produce their effects by their own. They
should have:
1- Affinity.
2- High intrinsic activity or efficacy to stimulate
the receptors.
3- Rapid rates of association (Ka) &
dissociation (Kd).
Examples: Adrenaline ( &), A.Ch. (M & N) &
Morphine ( &).
B) Blockers:
These drugs produce their effects indirectly by
blocking the receptors and blocking the actions of
internal chemical transmitters and/or hormones.
They are:
1- Antagonists: They should have:
a- Affinity.
b- No = Zero efficacy  No dose/response curve
c- Slow dissociation from receptors.
They block the action of agonists.
Examples: Prazosin, propranolol, atropine & naloxone
2- Partial Agonists = Dualists: They should have:
a- Affinity.
b- Low intrinsic activity = Weak efficacy
 Less maximum response (Emax) than agonists.
c- Moderate rates of association & dissociation.
They produce initial stimulation then block of the receptor
If used alone  Weak stimulation of the receptor 
Weak response
If used in presence of an agonist  Block the action of
the agonist.
Examples: Ergotamine ( + 5-HT), Oxprenolol (),
Nicotine (NN) & Succinylcholine (NM).
* Types of Block:
A) Competitive Block:
- Antagonists bind REVERSIBLY with the receptors.
- Antagonists can be DISPLACED by excess agonists 
Surmountable
-They produce PARALLEL shift of the curve to the RIGHT  
Potency.
They produce NO effect on the maximum response (E-max) =
Same Efficacy.
Examples: Propranolol, atropine & naloxone.
B) Non-Competitive Block:Response
- Antagonist is NOT displaced by agonist  Nonsurmountable
- Non-Parallel shift of cure to the Right =  Potency.
- Decrease maximum response (E-max) =  Efficacy.
- Types of Non-Competitive Block :
a- REVERSIBLE :
- The antagonist binds REVERSIBLY to the receptor.
- The block ends by the Metabolism of the blocker.
- Usually of Short duration of action.
Examples : succinylcholine.
b- IRREVERSIBLE :
- The antagonist binds COVALENTLY to the receptor.
- The block ends by Resynthesis of new receptors.
- Usually of Long duration of action.
- Examples: organophosphorus compounds.
:Types of Ligands *
Characteristics
1-Affinity
2-Efficacy
3-Ka & Kd
4-Effect
Stimulant
=Agonist
+++
+++
Rapid
Stimulation
Blocker
Antagonist
Partial Agonist
= Dualist
+++
No = Zero
Slow
Block
+++
Moderate
Moderate
Stimulation
then Block
Competitive
Non-Competitive
1-Blocker is displaced by excess
agonist = Surmountable
2-Parallel shift of curve to right 
 Potency
3-Same Emax = Same Efficacy
4-Example: Atropine & Propranolol
1-Blocker is not displaced by excess agonist
=Non-surmountable
2-Non-parallel shift of curve to the right  
Potency
3-Decreased Emax   Efficacy
4-Types: Reversible & Irreversible
Reversible
Irreversible
1-Block ends by
metabolism of the
blocker
2-Short acting
3-Example:
Succinylcholine
1-Block ends by
resynthesis of new
receptors
2-Long acting
3-Example:
Phenoxybenzamine
NB )Chronic Use of Drugs Affects the No. &
Sensitivity of Receptors:
Long use of Agonists   No. & Sensitivity
of Receptors Down Regulation.
Long use of Antagonists or drugs that
transmission   No. & Sensitivity of
Receptors  Up Regulation.
Doses of Drugs (Posology)
1- Therapeutic Dose: Average dose calculated for an
Adult, Male, 20-60 year old & 70 Kg body weight.
2- Initial Dose; Initial large dose aiming to reach the
therapeutic plasma concentration
3- Maintenance Dose: Small daily dose required to
replace eliminated drug from the body to maintain
the achieved therapeutic plasma concentration.
4- Maximal Tolerated Dose; Highest dose without toxic
effects.
5- Lethal or Fatal Dose: Dose that kill the patient or an
experimental animal
6- Therapeutic Index:
Ratio = LD50 / ED50
LD50 = Lethal dose in 50% of animals
ED50 = Effective dose in 50% of animals
A good guide to determine & compare SAFETY
of drugs
The Higher the therapeutic index  The Safer
the drug
Factors Affecting The Dose &
Action of Drugs
1.
2.
Biological variation Range of dose. Start by minimal effective
dose then increase the dose gradually as needed.
Age Decrease the dose in extremities of age.
A.
B.
Geriatrics (Elderly > 60 years):
a. They have exhausted drug-elimination mechanisms
(metabolism & excretion).
b. Use 2/3 or 3/4 of the adult dose.
Pediatrics (Young < 12 years):
a. They have immature drug-elimination mechanisms
(metabolism & excretion).
b. Calculate the dose by:
- Infant (< 1 year) dose (Clark’s Formula) = Adult dose X
(Weight of infant in Pounds/150)
- Child (1 – 12 year) dose (Young’s Formula) = Adult dose X
[Age in years / (Age + 12)]
or (Dilling’s Formula) = Adult Dose X (Age in Years / 20)
or = Adult Dose X (wt of child in Kg / 70)
Factors Affecting The Dose & Action of Drugs (cont.)
3.
Body Weight & Surface Area:
a.
b.
c.
4.
Skeletal muscle weight is more important than fat or edema.
Surface area =  Height in cm X weight in Kg / 3600
Surface area is more accurate in calculating doses for children & infants.
Sex:
a.
b.
Males need higher doses than females:
 Males have bulky muscle tissue & Androgens (HME Inducers)
 Females have bulky fat tissue & Estrogen (HME Inhibitor)
Some drugs are contraindicated in Females during physiological periods:
 Menstruation: Aspirin & Cathartics   Bleeding
 Pregnancy: Sex hormones, Oxytocics (Ergotamine) & Teratogens
(Phenytoin)
 Labor: Barbiturates & Morphine  Neonatal asphyxia
 Lactation: Drugs excreted in milk eg Purgatives, Tetracyclines &
Chloramphenicol
Factors Affecting The Dose & Action of Drugs (cont.)
5.
Route & Time Of Administration:
Affect the dose: usually I.V. dose < Oral dose
Affect the effect: Mg SO4
After meal  No effect
Orally  Empty stomach  4 g  Cholagogue
15 g  Saline purgative
I.V.   CNS,  Smooth, Skeletal & Cardiac muscle
Retention Enema  Dehydrating agent e.g. in brain edema
If drug is irritant  Use after meals
If drug is sedative  Use at bed time
6.
Commutation:
a.
Occurs with zero-order kinetics when the rate of intake > rate of
elimination.
b.
Examples: Digitalis, Aspirin L.D., Phenytoin L.D. & Ethanol L.D.
c.
To avoid cumulation either  The dose or  Frequency of
administration.
Factors Affecting The Dose & Action of Drugs (cont.)
7. Psychological Effect:
Some patients improve by Psychological (Suggestion)
rather than Pharmacological effect of the drug (Placebo
effect).
Placebo (Dummy medication) is an inert substance
(Lactose, starch, etc.) used in a dosage form (Tablet,
capsule, etc). Useful in:


Treatment of patients by psychological
suggestion
As a comparison when testing new drugs
Factors Affecting The Dose & Action of Drugs (cont.)
8.
Pathological Condition:
a.
Some drugs act ONLY in presence of disease:


b.
Pathology may cause supersensitivity:


c.
Aspirin acts as an antipyretic ONLY in fever
Digitalis acts as a diuretic ONLY in heart failure
a- Adrenaline in thyrotoxicosis
b- -Blockers in bronchial asthma
Pathology may affect drug kinetics: Achlorhydria  
Intrinsic factor   Absorption of Vit B-12  Pernicious
anemia.
Liver and/or kidney disease may affect the dose of some
drugs.
Factors Affecting The Dose & Action of Drugs (cont.)
Idiosyncrasy (Pharmacogenetics)  Abnormal
response
9. Supersensitivity (Intolerance)   Dose of the
drug
10. Tolerance   Dose of the drug
11. Drug interactions  Summation, Synergism,
Antagonism & Reversal.
8.