1. Pharmacology Department
General pharmacology
(Pharmacokinetics; drug administration and absorption, distribution and biovailbility Revision)
Dr.Ishfaq Bukhari
Pharmacology Department

2. What is Pharmacology? From the Greek pharmakon (drug),
and legein (to speak or discuss)
Broadly defined as the study of how chemical agents affect living processes.
e.g Hormones, Neurotransmitters and drugs

3. Some Pharmacology Definitions and Areas of Study
Pharmacokinetics
Study the fate of drugs once ingested. It covers , How the body absorbs, distributes,
metabolizes, and excretes drugs (what the body does to a drug?)
Pharmacodynamics
Study the mechanisms by which drugs work ,Also study endogenous agents (what the drug does to the body?)

4. Recommended books
Lippincott’s illustrated reviews (Pharmacology) by Howland and Mycek
Basic and Clinical Pharmacology by by Katzung

5. Routes of drug administration

6. Routes of drug administration

7. Oral administration Self use Safe convenient - cheap
Disadvantages
Advantages
- Slow effect
No complete absorption
- Destruction by pH and enzymes
- GIT irritation
- Food - Drug interactions
Drug-Drug interactions
First pass effect
(low bioavailability).
Not suitable for
vomiting & unconscious patient
emergency & bad taste drugs
- Easy
Self use
Safe
convenient
- cheap
- No need for sterilization

8. Factors affecting absorption from GIT
GIT motility changed by drug / diseases
Presence of food
Blood flow/surface area
GIT juices
pH of GIT fluids
Chemical/drug interactions
dosage form of a drug
Most of the drug is absorbed with in 1-3 hours,mostly it occurs in small intestine ,rate of absorption depends on lipid solubility ,ionization and pH.

9. First pass Metabolism
Metabolism of drug in the gut wall or portal circulation before reaching systemic circulation
So the amount reaching system circulation is less than the amount absorbed
Where ?
Liver
Gut wall
Gut Lumen
Results ?
Low bioavailability.
Short duration of action of drugs (t ½).

11. Stomach pH
The low pH of the gastric contents (pH 1–2) may influence. e.g, the weak base diazepam will be highly Ioninized in the gastric juice, and absorption will be slow.
weak acid drug, acetaminophen will exist mainly in its unionized form and can more readily diffuse from the stomach into the systemic circulation.

12. Small intestine
The small intestine, with its large surface area and high blood perfusion rate, has a greater capacity for absorption than the stomach.
Conditions that shorten intestinal transit time (e.g., diarrhea) decrease intestinal drug absorption and vice versa

13. Oral Dosage Forms (oral formulations)
Tablets (enteric coated tablets)
Capsules (hard and soft gelatin capsules)
Syrup
Suspension
Emulsion

14. Spansule
Tablets
Soft- gelatin capsule
Hard- gelatin capsule

15. Sublingual Disadvantages Advantages Not for - irritant drugs
- Frequent use
Rapid effect (Emergency)
No first pass metabolism.
High bioavailability
No GIT destruction
No food drug
interaction
Dosage form: friable tablet

16. Rectal administration
Disadvantages
Advantages
Irregular absorption & bioavailability.
Irritation of rectal mucosa.
Suitable for
children
Vomiting or unconscious
patients
Irritant & Bad taste drugs.
less first pass metabolism
(50%)
Dosage form:
suppository or enema

17. Parenteral administration
Intradermal (I.D.) (into skin)
Subcutaneous (S.C.) (under skin)
Intramuscular (I.M.) (into muscles)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)

19. Intravenous administration
Disadvantages
Advantages
Infection
Sterilization.
Pain
Needs skill
Anaphylaxis
Expensive.
Not suitable for oily solutions or poorly soluble substance
Rapid action (emergency)
High bioavailability
No food-drug interaction
No first pass metabolism
No gastric irritation
Suitable for
Vomiting &unconsciousness
Irritant & Bad taste drugs.
Dosage form:
Vial or ampoule

20. Injection Special Utility Limitations
I.D.
Minute volume (0.1 ml)
Suitable for vaccinations
& sensitivity test
Not suitable for large volumes
S.C.
0.1 ml – 1 ml
Suitable for some poorly soluble suspensions and for instillation of slow-release implants e.g. insulin zinc preparation
I.M.
larger volume 3-5 ml Suitable for moderate volumes, oily vehicles, and some irritating substances
Not suitable for irritant drugs
I.V.
Suitable for large volumes and for irritating substances
Not suitable for oily solutions or poorly soluble substances
Must inject solutions slowly as a rule

21. Drugs are mainly applied topically to produce local effects
Drugs are mainly applied topically to produce local effects. They are applied to
Skin (percutaneous) e.g. allergy test, topical antibacterial and steroids prep and local anesthesia
Mucous membrane of respiratory tract (Inhalation) e.g. asthma
Eye drops e.g. conjunctivitis
Ear drops e.g. otitis externa
Intranasal, e.g. decongestant nasal spray
Topical application

22. Only few drugs can be used
Inhalation
Disadvantages
Advantages
Only few drugs can be used
Mucous membrane of
respiratory system
Rapid absorption
(large surface area)
Provide local action
Minor systemic effect
Less side effects.
No first pass effect
Dosage form: volatile gases (anesthetics), aerosol, nebulizer for asthma

23. Nebulizer Atomizer

24. Transdermal patch
a medicated adhesive patch applied to skin to provide systemic effect (prolonged drug action)
e.g. the nicotine patches (quit smoking)
Scopolamine
(vestibular depressant)

25. Drug absorption
Is the passage of drug from its site of administration to its site of action through various cell membranes.
Except for intravenous administration, all routes of drug administration require that the drug be transported from the site of administration into the systemic circulation.

26. Sites of Administration Sites of action
Drug absorption
Is the passage of drug from its site of administration to its site of action through cell membranes.
Cell membrane
Sites of
Administration
Sites of
action

27. Mechanisms of drug absorption
The transport of drugs across membranes occurs through one or more of the following processes:
Simple diffusion = passive diffusion.
Active transport.
Facilitated diffusion.
Pinocytosis (Endocytosis).

29. Simple or passive diffusion
water soluble drug (ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane.
Lipid soluble drug (nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.

31. Simple diffusion
Low conc
High conc

32. Simple diffusion Characters Occurs along concentration gradient.
common.
Occurs along concentration gradient.
Non selective
Not saturable
Requires no energy
No carrier is needed
Depends on lipid solubility.
Depends on pka of drug - pH of medium.

33. Simple diffusion
Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium.
Drug ionized form + nonionized form
Only nonionized form is absorbable.
Nonionized / ionized fraction is determined
by pH and pKa
As general basic drugs are more ionized and less diffusible in a relatively acidic medium, on the contrary basic are more lipid soluble and more diffusible in a relatively alkaline medium

34. PKa of the drug
(Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized.
The lower the pKa value (pKa < 6) of the acidic drug the stronger the acid e.g aspirin (Pka= 3.0 ),
The higher the pKa value (pKa >8) of a basic drug, the stronger the base e.g propranolol ( pKa= 9.4)

35. Affects ionization of drugs.
PKa of the drug
(Dissociation or ionization constant):
pH at which half of the substance is ionized & half is unionized.
pH of the medium
Affects ionization of drugs.
Weak acids  best absorbed in stomach.
Weak bases  best absorbed in intestine.

36. Which one of the following drugs will be best absorbed in stomach (pH=3)?
Aspirin pka=3.0
warfarin pka=5.0
Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine (pH=7.8)?
Propranolol pka= 9.4

37. Active Transport Relatively unusual.
Occurs against concentration gradient.
Requires carrier and energy.
Specific/selective
Saturable.
eg.
Sugar, amino acids and Iron absorption.
Uptake of levodopa by brain.

39. Carrier-mediated Facilitated Diffusion
Occurs along concentration gradient.
Requires carriers
Selective.
Saturable.
No energy is required.

41. against concentration gradient along concentration gradient
Active transport
Passive transport
against concentration gradient
(From low to high)
along concentration gradient
(From high to low)
Needs carriers
No carriers
saturable
Not saturable
Selective
Not selective
energy is required
No energy

42. Carrier-mediated facilitated diffusion Active transport Needs carriers
along concentration gradient
(From high to low)
Against concentration gradient
(From low to high)
Needs carriers
saturable
Selective
No energy is required
Energy is required

43. Mechanisms of drug absorption

44. Factors modifying drug absorption
GENERAL FACTORS
lipid solubility
Degree of ionization
Drug solubility (aqueous sol better than oily,susp,sol)
Dosage forms (depending on particle size and disintegration)
Concentration of drugs
Circulation at site of absorption
Area of absorbing surface (small intestine has large surface area)
Route of administration.

45. Bioavailability I.V. provides 100% bioavailability.
Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action
I.V. provides 100% bioavailability.
Oral usually has less than I.V.

46. By the end of the lectures, students should be able to define the following:
Major body fluid compartments
Concept of compartments.
Apparent volume of distribution (vd).
Plasma protein binding.
Tissue binding.

47. Bioavailability Bioavailability (F) = AUC (oral) X 100 AUC (I.V.)
Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action (therapeutic effect)
Bioavailability (F) = AUC (oral) X 100
AUC (I.V.)

48. Bioavailability
I.V. provides 100% bioavailability i.e. F= 1.
Subcutaneous, intramuscular, oral, rectal, and other extra vascular routes of administration require that the drug be absorbed first, which can reduce bioavailability.

50. Absolute bioavailability
The bioavailability of a drug after administration by any route is compared to its intravenous standard formulation.

51. Relative bioavailability
is determined when two products are compared to each other, not to an intravenous standard.
This is commonly calculated in the drug industry to determine that the generic formulation is bioequivalent to another formulation.
e.g Tylenol (paracetamol 500 mg) compared to panadol (paracetamol 500 mg).

52. Relative bioavailability
is important to get an idea of how different formulations or routes of administration differ in their bioavailability.
dosage adjustment is required when changing formulations or routes of administration.

53. Bioequivalence
Two drug products are considered to be bioequivalent when the rates and extents of bioavailability of the two products are not significantly different under suitable test conditions.
Rate and extent means the amount of drugs and the time required reaching the systemic circulation.

54. Factors affecting bioavailability:
are the same factors controlling drug absorption
GENERAL FACTORS
lipid solubility
Degree of ionization
Drug solubility (aqueous sol better than oily,susp,sol)
Dosage forms (depending on particle size and disintegration)
Concentration of drugs
Circulation at site of absorption
Area of absorbing surface (small intestine has large surface area)
Route of administration.

55. Distribution

56. Distribution
Is the process by which drugs leave blood circulation and enters the interstitium and/or the cells of the tissues.

57. Absorption & distribution
Elimination
Sites of
Administration

58. (70% of body weight in 70-kg individual)
Total body fluids
(70% of body weight in 70-kg individual)
Plasma (4 L)
Interstitial fluids (10 L)
Intracellular volume ( 28 L)
Total body
Fluids
(42 Liters)

59. Apparent Volume of Distribution (Vd)
is the ratio of drug amount in the body to the concentration of drug in blood
Vd (L)= Dose of the drug (mg)
concentration in blood (mg/L)
Large Vd = means long duration of action

60. FACTORS AFFECTING DISTRIBUTION
1.Cardiac output and blood flow.
2. Physiochemical properties of the drug.
Molecular weight
Pka.
Lipid solubility.
3. Capillary Permeability
4. Plasma protein binding
5. Tissue binding.

61. Blood flow to organs
The greater the blood flow to tissues, the more distribution that occurs from plasma to interstitial fluids.
Drugs distribute more rapidly to brain, liver and kidney > more than skeletal muscles & fat.

62. Physiochemical properties
Most lipid soluble drugs cross biological membranes
Hydrophilic drugs do not readily cross membranes but go through slit junctions

63. Volume of Distribution (Vd)
Drugs with high Vd
Have higher concentrations in tissues than in plasma.
Low molcular weight
Relatively lipid soluble.
Distributed intracellularly
Not efficiently removed by haemodialysis.
e.g. phenytion, morphine, digoxin

64. Volume of Distribution (Vd)
Drugs with low Vd
confined to plasma & interstitial fluid.
distributed in extracellular compartments.
Polar comp or lipid insoluble drugs. e.g. Carbenicillin, vecuronium, gentamycin.
High MW e.g. heparin – insulin.
High plasma protein binding e.g. warfarin.
Do not cross BBB or placental barriers.

65. Blood brain barrier (BBB):
Only lipid soluble drugs or actively transported drugs can cross BBB.
Hydrophilic drugs (ionized or polar drugs) can not cross BBB.
Inflammation as in meningitis increase permeability to hydrophilic drugs
e.g. penicillin & gentamycin
Placental barrier
Lipid soluble drugs can cross placental barrier and enter the fetal blood.

68. Binding of Drugs
Plasma proteins binding.
Tissue proteins binding.

69. Plasma Proteins
Albumin
Has affinity for acidic drugs as warfarin, phenytoin, aspirin

70. Plasma protein binding
Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein)
Drugs exist in two forms bound and unbound forms in equilibrium
Unbound drug (free) bound drug

71. Tissues Binding Drugs can bind to specific tissue
Tetracycline bind to bone
Iodides accumulate in salivary & thyroid glands

72. Bound form of drug
non diffusible form
can not combine with
receptors
inactive
not available for metabolism & excretion
has long duration of
action (t ½).
Unbound form of drug
diffusible form
combine with receptors
active
available for metabolism & excretion
has short duration of
action (t ½).

73. Binding of drugs and its effect on drug action
Usually reversible.
determines volume of distribution (vd)
Slows drug metabolism & excretion.
Prolongs duration of drug action (t1/2).
Result in clinically important drug interactions.

74. PHARMACOKINETICS:
Pharmacokinetics:It is the study of what the body does to the drug i.e ADME
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
of the drug
Note: Pharmacodynamic is what the drug does to our body