1. Dr Nasim Ullah Siddiqui
General Pharmacology
Dr Nasim Ullah Siddiqui

2. What is Pharmacology? Pharmacology:
Pharmacon (drugs) + Logos (studies)
The study of drugs

3. Drugs & Medicines Drugs:
Any substance that, when absorbed into the body of a living organism, alters (changes) normal body function
Examples:
aspirin,
Antibiotics,
Nicotine,
alcohol,
Marijuana….

4. Drugs & Medicines Medicines:
In pharmacology, a drug is a chemical substance used in the:
treatment, cure, prevention, or diagnosis of disease
Or used to enhance physical or mental well-being

5. Drugs & Medicines
Drug is called medicine when used in proper dosage form for safe administration
All medicines are drugs but all drugs are not medicines

6. Clinical / Experimental
Clinical Pharmacology
deals with the study of drug effects in humans beings, i.e. healthy volunteers and patients
Experimental Pharmacology
deals with the study of drug effects in laboratory animals
In vitro – Isolated tissue
In vivo – Intact organism

7. Definitions Toxicology: Pharmacogenetics:
deals with adverse (undesired) reactions of drugs & their treatment
Pharmacogenetics:
How genetics influence the mode of drug actions (e.g.. Metabolism) and biological variations of drug responses

8. Definitions
Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing response to drugs.
Pharmacogenetics refers to genetic differences in metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.

9. Definitions Pharmacokinetics: Pharmacodynamics:
How the body handles the drug
Includes absorption, distribution , biotransformation, and elimination
Pharmacodynamics:
How drug handles the body
Deals with the biochemical and physiological effects of drugs on man

10. Receptors Definitions
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand (such as a hormone or drug).
Receptors can be membrane-bound, occurring on the cell membrane of cells, or intracellular, such as on the nucleus or mitochondrion. Binding occurs as a result of noncovalent /covalent interaction between the receptor and its ligand, at locations called the binding site on the receptor.

11. Definitions
Potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
A highly potent drug (e.g., morphine) evokes a larger response at low concentrations.
while a drug of lower potency (acetylsalicylic acid) evokes a small response at low concentrations
It is proportional to affinity and efficacy

13. Definitions Affinity is the ability of the drug to bind to a receptor.
Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.
The response is equal to the effect(E), and depends on both the drug binding and the drug-bound receptor then producing a response; thus, potency depends on both affinity and efficacy.

14. Definitions
The agonist (ligand, drug or hormone) that binds to the receptor and initiates the response.
The less the concentration of a drug is required to produce 50% of maximum effect and the higher the potency.

15. Definitions
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.
The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally-defined binding sites on receptors.
Antagonists have affinity but no efficacy for their receptors, and binding will disrupt the interaction and inhibit the function of an agonist at receptors.

16. Antagonist
Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist receptor binding.
Physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by β-adrenergic receptor activation.

17. Definitions
Tachyphylaxis : Rapidly developed tolerance is tachyphylaxis, is a medical term describing a decrease in the response to a drug due to previous exposure to that drug.
Caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect, or by the depletion of receptors available for the drug or neurotransmitter to bind to. Examples: Amphetamine, ephedrine (indirectly acting drugs)
Tachyphylaxis is characterized by the rate sensitivity i.e, a high-intensity prolonged stimulus or often-repeated stimulus may bring about a diminished response also known as desensitization.

18. Definitions
Physiological tolerance or drug tolerance is a subject's reaction to a drug (such as an opiates painkiller, benzodiazepine drug) is reduced at a later time even though the dose or concentration at the effect site is the same.
This means that larger doses are required to achieve the same effect.
Drug tolerance can involve both psychological & physiological drug tolerance factors.
It is reversible
Physiological tolerance occurs after repeated exposure .

19. Definitions
Idiosyncrasy (idiosyncratic drug reaction) denotes a non-immunological hypersensitivity to a substance, without connection to pharmacological toxicity.
Is an individual based on a specific condition of the one who suffers it. Most commonly, this is caused by an enzymopathy, congenital or acquired.

20. Drugs actions Drug actions are mediated by 3 ways:
Acting on somatic or psychic processes or functions
Correction of deficiencies
Toxic action on pathogenic microorganism

21. Ideal drug effects Drug effects should be: Selective Temporary
Dose-related (controllable)
Show close relationship with bioavailability

22. Drug Responses How are drug responses produced?
By interaction with active binding sites called RECEPTORS
Drug may be agonist or antagonist for the receptors

23. Nature of drugs Physical: Chemical structure: Solid (aspirin)
Liquid (nicotine, ethanol)
Gas (nitrous oxide)
Chemical structure:
Protein, lipid, carbohydrate
To be weak acid or weak base
Amine (primary, secondary, tertiary, ..)

24. Sources of drugs Natural from: Semi-synthetic Synthetic Bio-synthetic
Plants
Animals / Humans
Micro-organisms
Minerals
Inorganic metals
Semi-synthetic
Synthetic
Bio-synthetic

25. Sources of drugs Natural from Plants:
Active principles are found in roots, leaves and seeds in 2 forms:
Glycoside, e.g
Cardiac glycoside Digoxin ( from the Foxglove plant)
Alkaloid, e.g
Morphine (from Poppy capsules),
Atropine (from Belladonna leaves)
Quinine (from bark of Cinchona tree)
Castor oil (from castor seed)

26. Sources of drugs Natural from animals / humans: Hormones:
Heparin from Pig or Ox liver,
Insulin from Pig or Ox pancreas
Gonadotrophins from urine of pregnant women
Plasma or serum from blood
Thyroxin from Pig or Ox thyroid gland
Cod Liver Oil from Cod fish Liver

27. Sources of drugs Natural from micro-organisms: Antibiotics:
Penicillin from Penicillium notatum,
Streptomycin from Streptomyces griseus,
Bacitracin from Bacillus

28. Sources of drugs Minerals:
Calcium, Magnesium, Aluminium, Sodium, Potassium & Iron salts,
Liquid paraffin from petroleum.
Inorganic metals:
Iodine,
Lithium,
Radioactive elements: I131

29. Sources of drugs Semi synthetic drugs:
Prepared by chemical modification of natural drugs in labs.
Ampicillin from Penicillin-G,
Semisynthetic cephalosporin's from 7-amino cephalosporinic acid

30. Sources of drugs Synthetic Drugs:
Prepared by chemical synthesis in pharmaceutical laboratories
Sulphonamides
Salicylates
Barbiturates
Benzodiazepines

31. Sources of drugs Bio-Synthetic Drugs:
Prepared by cloning of human DNA into bacteria like E.Coli.

32. Sources of drugs Bio-Synthetic Drugs:
Technique is called Recombinant DNA technology or Genetic Engineering
Cells from animals or human that produce active substance
Isolation of DNA
Transfer to bacteria (E-coli) by plasmids (Gene cloning)
A new E-coli synthesizes the new substance
Cloning of ‘new’ E-Coli means production of identical subjects like parent

33. Sources of drugs Bio-Synthetic Drugs:
Examples: Human Insulin's, Human Growth Hormones, Human BCG vaccine , Human Hepatitis B Vaccine

34. Criteria for drug classification
Chemical structure:
Cholinesters,
Organophosphates,
Catecholamine's
Location of action:
Cardiac glycosides,
Autonomic drugs

35. Criteria for drug classification
Purpose of medication:
Antihypertensive
Diuretic
Antiemetic
Analgesic
Name of plant:
Opium alkaloids
Cardiac glycosides
Belladonna alkaloids

36. Prescription / Over the counter
Drugs fall into two distinct categories:
1)Those that require a physician’s prescription to obtain (Rx)
2)Those that can be purchased over-the counter (OTC)
both are regulated by the regulatory authorities

37. Pharmacotherapy
Employment of drugs for the prevention and treatment of diseases
Its scope:
Indications
Contraindications
Drug interactions
Therapy:
Radical (full healing)
Symptomatic (treatment of symptoms only)
Prophylactic (e.g. contraception, vaccine)

38. Therapeutic Index Therapeutic Index (TI):
Toxic dose / Effective dose
Indicates the relative safety of a drug
Examples:
Acetominophen : 27
Valium: 3
Methotrexate, vincristine: 1
Narrow TI indicates the need for frequent blood tests to monitor drug levels

39. Mechanism of Action Agonist: Antagonist:
drug mimics an endogenous substance that would normally stimulate a receptor
Antagonist:
drug which binds a receptor site, doesn't stimulate it, but blocks other substances from stimulating it

40. Drug Nomenclature Most drugs have at least three names: Chemical name
Generic name (Official, Approved)
Proprietary name (Trade name, Company name)

41. Drug Nomenclature
Chemical name
The chemical composition and structure

42. Drug Nomenclature Generic name (Official, Approved)
is usually the abbreviated form of the chemical name
this name is used and chosen by official bodies

43. Drug Nomenclature Proprietary name (Trade name, Company name)
the name given by the company which markets the drug
It is the commercial property of a pharmaceutical company
It indicates a particularly formulation of a particular substance by a particularly manufacturer

44. Drug Nomenclature
Since several companies market the same drug under different proprietary names, unnecessary confusion may arise
Whenever possible drugs should be prescribed by their approved names
Chemical name:
Acetyl-p-aminophenol
Official name:
Paracetamol
Proprietary name:
Panadol, Calpol, Adol, Fevadol

45. Routes of Drug Administration

46. Routes of Drug Administration
Factors Deciding Choice of Route
Type of described effect, systemic or local
Physiochemical properties, solid or insoluble
Rapidity of effect, oral, intramuscular (IM), intravascular (IV)
Condition of patient, conscious or unconscious, vomiting

47. Topical Application - Mucous Membrane
Conjunctiva, nasopharynx , oropharynx, vagina, urethra, urinary bladder, ear, nose, anal canal for local / systemic effects
Absorption rapid
Local anesthetic for local effects rapidly absorbed, produce systemic toxicity
Types:
ointment, cream, drops, jelly, powder, tablet, suppository, pessary

48. Topical Application - Skin
Absorption- depends on
surface area, lipid solubility
Few drugs readily penetrate skin
Burned, denuded, abraded, inflamed skin increase systemic absorption
Toxicity by highly lipid soluble insecticides
Controlled- release by topical patches

49. Topical Application - Injection
Intra articular (in joint)
hydrocortisone
Intra thecal into subarachnoid space of L2-3 or L3-4,
Local anaesthetics
Subcutaneous (under skin)
Intra arterial
anticancer drugs in limbs cancer

50. Systemic Routes Enteral through GIT Parental Orally
Buccal or sublingual
Rectal
Parental
Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC)
Transdermal Therapeutic system (TTS)
Inhalation

51. Oral Ingestion /Swallowing
Tablets, capsules, powder, syrup, mixture suspension or emulsion
Absorption variable
Most conventional, economical, more safe and acceptable to patient
Absorption delayed, reduced after food
Not good for some drugs:
Gentamicin not absorbed
Insulin destroyed in gut

52. Oral Ingestion /Swallowing
Absorption from stomach and upper intestine is affected by:
Surface area,
Blood flow to site of absorption,
Physical state: (solid, solution, suspension),
Water solubility,
Concentration at the site of absorption,
Rate of dissolution,
Rate of disintegration,
Particle size

53. Sublingual Good, readily available Systemic effect Quick
Example of a clinically useful drugs:
Nitroglycerine

54. Rectal Administration
Used when recurrent vomiting or unconscious
50% absorbed drug bypass liver
Absorption incomplete, irregular in lower rectum by external haemorrhoidal veins
Example:
indomethcin, steroids, soap water & barium sulphate as enema
Inconvenient & embarrassing
Rectal inflammation occurs

55. Intravenous Advantages: Disadvantages / Precautions Example:
Rapid reach and response
Life-saving in critical conditions (Blood, IV fluids)
Disadvantages / Precautions
Careful of too quick infusion
Anaphylactic shock
Can not withdraw medication once given
Example:
Blood transfusion, Antibiotics for rapid effect

56. Intramuscular Advantages: Disadvantages / Precautions Example:
Quick absorption and response
Easy to learn
Disadvantages / Precautions
Possible infection, or injury to nerve
Could not retrieve
Painful
Example:
Pain killer (Pethidine)

57. Subdermal Advantages: Disadvantages / Precautions Example:
Slow control release
Easy accessibility
Less painful
Disadvantages / Precautions
Not very effective
Not good if circulation not effective
Collapsed hypotensive patients
Example:
Insulin (bypasses digestion)

58. Inhalation Drug Administration
Most common types:
Volatile liquids, gaseous anaesthetics and therapeutics gases
Metered dose aerosol inhaler
e.g. salbutamol
Compressed air driven nebulised solution inhaler

59. Inhalation Drug Administration
Pulmonary Absorption
Important route for drugs abuse
Access to circulation rapid
large surface area of lungs
Fine drug droplets in air (aerosol ) inhaled
Instantaneous absorption
Avoids hepatic first-pass loss
Local application at the desired site of action in pulmonary disease
Treatment of bronchial asthma Aerosol Delivery

60. Inhalation Drug Administration
Only 2-10 % dose deposited in lungs
90 % dose is swallowed

61. Pharmacokinetics Pharmacokinetics deal with the quantitative study of:
Absorption
Distribution
Biotransformation and
Excretion of drugs

62. Pharmacokinetics Absorption:
is the process by which a drug is transferred from its site of entry to the volume of distribution
The rate of absorption affects the
Onset,
Duration, and
intensity of drug action

63. Factors affecting drug absorption
Drug-related factors:
Physical state
Particle size
Concentration
Dosage form (preparation)
Solubility (lipid and water solubility)
Degree of ionization

64. Factors affecting drug absorption
Host-related and other factors:
Transport (absorption) of drug
Passive transport (e.g. simple diffusion)
Specialized transport (e.g. active transport)
Circulation at the site of absorption
Area of absorbing surface
Presence of other agents

65. Drug Distribution
The process by which a drug leaves the blood stream and enters the extracellular fluid and or cells of the tissues
Depends on:
Capillary permeability,
Degree of drug to plasma and tissue proteins,
Relative hydrophobicity of the drug

66. Bioavailability
Bioavailability of a drug = availability of biologically active drug
Is the proportion of the active drug that reaches the systemic circulation (site of action) after administration
Helps in choosing “best drug” and “best route” of administration

67. Bioavailability
The bioavailability of a drug may vary from one dosage form to another and for the same dosage form it may vary according to the pharmaceutical formulation.
The bioavailability is of great importance in therapeutics specially in the case of life saving drugs, antibiotics and drugs with a narrow margin of safety e.g. anticoagulants.
Differences in the rate of absorption may cause patients to be overmedicated or under medicated.

68. Factors Affecting Bioavailability
Quality Control in Manufacturing and formulation
First pass metabolism
Factors affecting absorption of drugs from GIT
- These are pH of GIT fluids, area of absorbing surface, functional integrity of GIT, presence of food and other substances in stomach, blood flow, physiochemical properties of the drug.

69. Biotransformation
Chemical alteration which a drug undergoes within a living organism
Most of the substance (taken exogenously or produced endogenously) need a change in their forms, which changes their activity (increased, decreased or become inactive) and make them available for elimination from liver and kidney

70. Biotransformation Metabolism of drugs may may change them from:
Inactive to active
Active to:
Less active
More active
Inactive

71. Biotransformation Metabolism of drugs takes place in various organs:
Liver (most important)
Epithelial cells of GIT
Lungs
Kidneys
skin
brain

72. Drug metabolism Extrahepatic microsomal enzymes
(oxidation, conjugation)
Extrahepatic microsomal enzymes
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)

73. Drug metabolism Factors affecting drug metabolism: Age Sex
Genetic differences
Nutrition
Pathological conditions
Route of administration
Effect of drug on metabolism

74. Drug elimination The removal of drugs from the body may occur from
Kidneys (most important),
Bile,
Intestine,
Lung,
Breast,
Skin

75. MAJOR
MINOR

76. Concept of “Half-Life”
Time required to metabolize 1/2 of the original dose of the drug
Use of this terms helps in determining how long a drug will remain in the body

77. Concept of Critical Threshold
Defined as the minimum level of drug concentration needed for the desired therapeutic effect to be present.

78. Elimination Zero order: First order:
Constant rate of elimination irrespective of plasma concentration.
First order:
Rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.
Rate of elimination ∝ Amount
Rate of elimination = K x Amount

79. Zero order elimination
1000 C
Plasma Concentration (mg/l)
100
C/2 10
t1/2 1 1 2 3 4 5 6
Time (hr)
t½ is the time for the plasma concentration to reach half the original, i.e., the half-life of elimination.

80. First Order EliminationC
t1/2
Plasma concentration
t1/2
C/2
C/4

81. Drug elimination
Elimination of drugs from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).

82. First Order Elimination
Clearance: volume of plasma cleared of drug per unit time.
Clearance = Rate of elimination ÷ plasma conc.
Half-life of elimination: time for plasma conc. to decrease by half.
Useful in estimating:
Time to reach steady state concentration
Time for plasma concentration to fall after dosing is stopped.

83. The time to reach steady state is ~ 4 t1/2’s
Plasma concentration
Concentration due to repeated doses (infusion)
Concentration due to a single dose
The time to reach steady state is ~ 4 t1/2’s

84. Plasma concentration Drug concentration in plasma
Should be maintained within the specific drug therapeutic range

85. Plasma concentration Drug concentration in plasma
Should always be maintained above the drug sub-therapeutic level

86. Plasma concentration Drug concentration in plasma
Should always be maintained below the specific drug lethal dose level

87. Plasma concentration

88. Adverse Drug Reactions
Unwanted or unexpected effects of drug
Quite common but in most of the cases they are not serious
Occasionally they could be so serious as to endanger life e.g.
Acute anaphylactic shock with penicillin,
Severe hypoglycemia after excessive insulin administration

89. Adverse Drug Reactions

90. Adverse Drug Reactions

91. Adverse Drug Reactions

92. Adverse Drug Reactions
Adverse drug effects can be divided into two groups:
Predictable Reactions
Withdrawal symptoms or rebound responses

93. Adverse Drug Reactions
Predictable Reactions:
Due to excessive pharmacological activity of the drug
They are liable to occur with CNS depressants cardio-active drugs, hypotensive agents and hypoglycemic drugs
All patients are at risk of developing this type of reaction if high doses are given
Patients with renal disease, liver disease and extreme of ages are particularly susceptible

94. Adverse Drug Reactions
Predictable Reactions:
Withdrawal symptoms or rebound responses after discontinuation of treatment
Crisis may be precipitated by sudden stoppage of corticosteroid therapy
Withdrawal symptoms occur after narcotic analgesics, barbiturates and drugs liable to cause addiction
These drugs should be gradually withdrawn to avoid such mishaps.

95. Adverse Drug Reactions
Unpredictable Reactions:
They occur usually infrequently, and are not dose dependent. They are of following types:
Drug allergy: (e.g. to Penicillin)
Genetically determined: ( e.g. patients with G6PD deficiency may develop acute hemolytic anemia after anti-malarial drugs)
Idiosyncrasy: (unusual, unexpected, unexplained)

96. Almost ALL DRUGS ARE POISONS
Summary: Concept no 1
Almost ALL DRUGS ARE POISONS
The only thing that determines if a drug provides a benefit or kills a patient is how we administer it

97. Concept II : Our Therapeutic Goal
To achieve drug concentrations at the site of action (target tissue)…that are sufficiently high enough…to produce the intended effect without producing adverse drug reactions (or with minimal adverse reactions)

98. What happens after drug administration?
Summary
What happens after drug administration?
Drug at site of
administration
2. Distribution
1. Absorption
Drug metabolites
in tissues
Drug in plasma
3. Metabolism
Drug metabolites
In urine, feces, bile
4. Elimination