2. Learning Objectives
• Define terminologies used in Pharmacology.
• Know about nature, sources and nomenclature of
drugs.
• Understand pharmacokinetics like absorption,
distribution, metabolism and excretion (ADME) of
drugs.
• Understand theoritical pharmacokinetics like half-life,
order of kinetics, steady state plasma concentration.
3. I. Introduction to Pharmacology
Terms
• Pharmacology
• Drugs
• Pharmacokinetics
• Pharmacodynamics
4. Chemical nature of drugs
Sources of drugs
• Drugs are obtained from various sources.
1. Natural drugs
A/ Plants E.g. .Digoxin from Digitalis purpurea
.Atropine from Atropa belladonna
.Quinine from Cinchona officinalis
B/ Animals E.g.. Insulin from pig
.Cod liver oil from Cod fish liver.
C/ Minerals E.g.. Iron, Iodine, Potassium salts.
D/ Micro – organisms E.g. .Penicillin from penicillium
notatum..Chloramphenicol from Streptomyces
venezuelae (Actinomycetes).
Acidic; Aspirin, barbiturates...etc- Basic or alkaline; Morphine,
Atropine, Alkaloids...etc- Neutral; Steroids...etc
5. 2. Synthetic drugs
- prepared by chemical synthesis in pharmaceutical
laboratories E.g.. Sulphonamides, quinolones,
barbiturates
3. Semisynthetic drugs
- prepared by chemical modification of natural drugs.
E.g.. Ampicillin from penicillin G.
.Dihydroergotamine from ergotamine.
4. Biosynthetic drugs
- prepared by cloning of human DNA in to the bacteria
like E.coli.
E.g.. Human insulin.
6. Drug names
Every drug has at least three names
Chemical Name
• Gives the complete description of the molecule (using
the laws of organic chemistry).
• It is often extremely long and complex and describes
the atomic or molecular structure of the drug.
Inappropriate for everyday use
7. • Generic Name
– Assigned by an official body to a drug
– generic names for drugs of a particular type (class)
usually have the same ending
• Example, beta-blockers- end with "lol.“
• Each drug has only one generic name. E.g. aspirin
• Less complex than chemical but more complex than
trade name
• It is strongly recommended
Advantages of generic prescription
• Avoids confusion (Only one generic name used only for one
products).
• Generic products are cheaper than brand product.
8. Brand /Trade Name
• The name given to a particular product by the company
that makes it.
Big problems with Brand/Trade Names
- A single drug can have different TN
• Creates confusion
-Same trade name can be used for different products
9. Drug Groups
• Understanding what group a drug belongs to is also useful
• Broadly, drugs are classified by therapeutic group—that is, by
what disorder or symptom they are used to treat
• For example, drugs used to treat
– high blood pressure are called antihypertensive and
– drugs used to treat nausea are called antiemetic (emesis is
the medical term for vomiting).
Within each therapeutic group, drugs are categorized by classes
– Some classes are based on how the drugs work in the body to
produce their effect.
For example
– diuretics, calcium channel blockers, beta-blockers, and
angiotensin-converting enzyme (ACE) inhibitors are all classes
of antihypertensives that work differently
10. Mechanisms by which Drugs Cross Biological
Membranes
Passage of drug across membrane
(a) Passive transfer
i) Simple diffusion
ii) Filtration
(b) Specialized transport
i) Facilitated diffusion
ii) Active transport
iii) Endocytosis.
11. 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
12. Carrier-mediated
(facilitated diffusion)
Active transport
along concentration
gradient
(From high to low)
Against concentration gradient
(From low to high)
Needs carriers Needs carriers
saturable saturable
Selective Selective
No energy is required Energy is required
13. Endocytosis and Exocytosis
• For large molecules.
• Substance is engulfed by the cell membrane and
carried into the cell by pinching off of the newly
formed vesicle inside the membrane.
• The substance can then be released inside the
cytosol by breakdown of the vesicle membrane.
• Iron and vitamin B12 across the gut wall.
• Exocytosis is a reverse process for the excretion of
some substances outside the cell
15. Ionization of weak acids and weak bases
• Ionization of drug may decrease their ability to permeate
membranes since the drug becomes more water soluble when
ionized.
• Non-ionized molecules are usually lipid soluble and can diffuse
across membrane
Henderson-Hasselbalch Equation
is clinically important when it is necessary to accelerate the excretion
of drugs by the kidney – in the case of an overdose
• Henderson-Hasselbalch Equation
– pH = pKa + log (salt)/(acid)
– pH = pKa + log (ionized form of
drug)/(unionized form of drug)
– pH = pKa + log (B)/(A)
– pH refers to the environment (GI, blood, urine) of where the drug
currently is available
– pKa is the pH at which the concentrations of the ionized and unionized
forms of the drug are equal
16. Henderson-Hasselbalch Equation…
Can manipulate drug excretion by the kidney by
changing the pH of the urine
– When a patient takes an overdose of a weak acid
drug, its excretion may be accelerated by alkalinizing
the urine – giving bicarbonate I.V.
» Acidic drug is in the lipid soluble form at acidic pH
– Excretion of a weak base may be accelerated by
acidifying the urine - giving ammonium chloride I.V.
» Basic Drug is in the lipid soluble form at alkaline
pH
17. • Route of administration is determined primarily by
– The properties of the drug and
water or lipid solubility, ionization
– The therapeutic objectives;
for example, the desirability of
rapid onset of action
need for long-term treatment or
restriction of delivery to a local site
19. Enteral Routes…..
The Oral (PO):-The most common route
• Some drugs are absorbed from the stomach However, the
duodenum is the major site of absorption.
Advantages of the Oral Route
• Most convenient (Easily self-administered),Safe, Economical and
no need for sterilization
Disadvantages of the Oral Route:
• Needs patient cooperation
• Some drugs may become destroyed
• GIT irritation and bad taste drugs(needs coating)
• Food - Drug interactions or Drug-Drug interactions
• First pass effect limits efficacy of some drugs e.g.
Nitroglycerine
• Presence of GIT diseases may limit absorption
• Slow effect(slow onset of action)
• No complete absorption
20. Enteral Routes……
• Buccal and sublingual route :drugs are administered by placing
them in the mouth, either under the tongue (sublingual) or
between the gum and the cheek (buccal).
Advantages Disadvantages
Rapid effect (Can be used in
emergency)
High bioavailability
No first pass effect.
No GIT irritation
No food drug - interaction
Dosage form: friable tablet
Not for
- irritant drugs
- Frequent use
21. Enteral Routes……
Rectal Route:
• 50% Bypasses portal circulation
• Good absorption
• Prevents drug destruction by low pH of the stomach and
intestinal enzymes
• Good for drugs that might induce vomiting if given orally and
if the patient is vomiting (commonly used to administer
antiemitics)
• May be used for unconscious patients
Parenteral Routes
• Used for drugs poorly absorbed from the GIT (heparin)
• Used for drugs unstable in the GIT (insulin)
• Used for treatment of unconscious patients
• Used in circumstances that require rapid onset of action
22. Intravenous Route (IV):
• The most common parenteral route
• May be used inject large volumes like iv fluids
• May be used to administer drugs over a long period of time
Advantages Disadvantages
Rapid action (emergency)
High bioavailability
No food-drug interaction
No first pass metabolism
No gastric irritation
Suitable for
Vomiting & unconscious
Irritant & Bad taste drugs.
Dosage form:
Vial or ampoule
Only for water soluble drugs(Not
suitable for oily solutions or poorly
H2O soluble substance)
Infection
Sterilization
Pain
Needs skill
Expensive
Possibility of adverse reactions
by too rapid delivery of high
drug concentrations
23. Parenteral Routes……
Intramuscular Route (IM) :
• Used for depot preparations (oily preparations, or special
non-aqueous vehicles such as ethylene glycol).
• Irritant drugs may be given IM.
Subcutaneous Route (SC) :
• Only used for drug not irritating to tissues.
• May be used for:
– depot drugs (implants; silastic capsules containing the
contraceptive levonorgestrel)
– or sustain release drugs
• Absorption may be controlled through co-administration of
a vasoconstrictor (Epinephrine)
24. Parenteral Routes…Cont
Intra-arterial (IA):
• Occasionally used when a drug effect is intended to be localized
in a particular organ or tissue (treatment of liver cancer;
diagnostic agents)
Intrathecal:
• Used for injection of certain drugs directly in the cerebrospinal
fluid (CSF) when rapid and localized effect is intended in the
meninges or the cerebrospinal axis:
methotrexate in acute leukemia
treatment of brain tumor
spinal anesthesia
acute CNS infections
25. Other Routes of Drug Administration
Inhalation:
• Provides rapid delivery of drugs over the large surface
area of the mucous membranes of the respiratory tract
and pulmonary epithelium
• For Drugs which are gases (general anesthetics), or as
aerosols.
• Convenient for patients with respiratory complaints
such as asthma.
• Rapid onset of effect (as the IV)
26. Advantages Disadvantages
rapid absorption (large
surface area)
provide local action
limited systemic effect
less side effects.
no first pass effect
Dosage form: aerosol,
nebulizer
Not suitable for irritant
drugs
Only for some drugs as
inhalation anesthetics &
bronchodilators
27. Other Routes of Drug Administration
Topical application
1. Mucous membranes:
Drugs are applied on the mucous membranes of the
conjunctiva, nasopharynx, oropharynx, vagina, urethra,
urinary bladder to produce a local effect
Good absorption to sites of action
2. Eye:
Used for ophthalmic drugs to produce local effects on
the eye
28. Other Routes of Drug Administration
Topical application:
3. Skin:
Drugs applied directly on the skin.
Used when a local effect is desired.
Absorption through the skin can be enhanced by
preparing the drug in a cream or as an oily preparation.
May be used for sustain release preparations (dermal
patches) to achieve systemic effects.
29.
30. II. Pharmacokinetics
Drug absorption and Bioavailability
• Absorption: is the process by which the drug enters in to the
systemic circulation from the site of administration through
biological barrier.
• Bioavailability : the fraction of the dose of a drug (F) that enters
the general circulatory system,
F= amt. of drug that enters systemic circul.
Dose administered
• Bioavailability (F)= Amount of drug absorbed
after oral dose/ amount of drug absorbed
after I.V. dose
32. Factors affecting drug absorption and bioavailability
a) Physico-chemical properties of drug
b) Nature of the dosage form
c) Physiological factors
d) Presence of other agents
e) Pharmacogenetic factors
f) Disease states
33. a) Physico-chemical properties of drug
i) Physical state:
• Liquids are absorbed better than solids.
ii) Lipid or water solubility:
• Drugs in aqueous solution mix more readily than those in oily
solution.
• However at the cell surface, the lipid soluble drugs penetrate into
the cell more rapidly than the water soluble drugs.
iii) Ionization:
• Most of the drugs are organic compounds. Unlike inorganic
compounds, the organic drugs are not completely ionized in the
fluid.
• Unionized component is predominantly lipid soluble and is
absorbed rapidly and an ionized is often water soluble component
which is absorbed poorly.
34. a) Physico-chemical properties of drug…
Acidic drugs:
• rapidly absorbed from the stomach e.g. salicylates and
barbiturates.
Basic drugs:
• Not absorbed until they reach to the alkaline environment i.e.
small intestine when administered orally e.g. pethidine and
ephedrine.
b) Nature of dosage forms:
i) Particle size:
• Small particle size is important for drug absorption.
• Drugs given in dispersed or emulsified state are absorbed better
e.g. vitamin D and vitamin A.
ii) Disintegration time and dissolution rate.
• Disintegration time: The rate of break up of the tablet or capsule
into the drug granules.
• Dissolution rate: The rate at which the drug goes into solution.
35. b) Nature of dosage forms
iii) Formulation:
• Usually substances like lactose, sucrose, starch and calcium
phosphate are used as inert diluents in formulating powders or
tablets.
• Fillers may not be totally inert but may affect the absorption as
well as stability of the medicament.
• Thus a faulty formulation can render a useful drug totally
useless therapeutically
36. c) Physiological factors:
i) Gastrointestinal transit time:
• Rapid absorption occurs when the drug is given on empty
stomach.
• However certain irritant drugs like salicylates and iron
preparations are deliberately administered after food to
minimize the gastrointestinal irritation.
• But some times the presence of food in the G.I tract aids
the absorption of certain drugs e.g. griseofulvin,
propranolol and riboflavin.
ii) Area of the absorbing surface and local circulation:
• Drugs can be absorbed better from the small intestine than from
the stomach because of the larger surface area of the former.
• Increased vascular supply can increase the absorption.
37. c) Physiological factors:
iii) Metabolism of drug/first pass effect:
• Rapid degradation of a drug by the liver during the first
pass (propranolol) or by the gut wall (isoprenaline) also
affects the bioavailability.
• Thus a drug though absorbed well when given orally may
not be effective because of its extensive first pass
metabolism.
d) Presence of other agents:
• Vitamin C enhances the absorption of iron from the G.I.T.
• Calcium present in milk and in antacids forms insoluble
complexes with the tetracycline antibiotics and reduces
their absorption.
38. e) Pharmacogenetic factors
• Individual variations occur due to the genetically
mediated reason in drug absorption and response.
f) Disease states:
• Absorption and first pass metabolism may be affected
in conditions like malabsorption and liver cirrhosis
40. Distribution of drugs
Definition: Penetration of a drug to the sites of action through the
walls of blood vessels from the administered site after
absorption.
Volume of Distribution
Relates the amount of drug in the body to the concentration of
drug (C) in blood or plasma
Vd= amount of drug in the
body/plasma concentration “c”
41. Vd cont’d
• Drugs with very high Vd have much higher concentrations in
extra vascular tissue than in the vascular compartment.
• Volume of distribution indicates the extent of distribution but
not the tissues or fluids into which the drug distributes.
• Two drugs can have the same volume of distribution ,but one
may distribute primarily into muscle tissues, whereas the other
may concentrate in adipose tissues
42. Factors affecting drug distribution / Vd
• Physicochemical properties of the drug: Lipid soluble and
unionized form of drugs readily cross the cell membrane and are
widely distributed
e.g.. lignocaine, propranolol, tricyclic antidepressants etc.
Drugs like heparin (strongest acid in the body) is confined only to
intravascular compartment as it exists in ionized form.
• Degree of plasma protein binding: Drugs highly bound to plasma
proteins have a low volume of distribution.
• Tissue storage(uptake): - Certain drugs can get sequestrated in
some tissues. Such drugs have a large Vd eg. digoxin is
sequestrated in heart, muscle, liver etc. and has a Vd of 66L/kg.
• Disease states:
Eg: In CHF, the Vd of some drugs can increase due to increase in
ECF volume or it could decrease due to reduced perfusion of
tissues.
• physiological barrier:
43. Redistribution
• Highly lipid soluble thiopentone → IV administration
immediately gets distributed to areas of high blood flow -
brain → general anaesthesia.
• In few minutes, it re crosses the BBB gets distributed to less
perfused tissues such as muscle, adipose tissue →
termination of action Thiopentone
44. Biotransformation of drugs
Definition: chemical alteration/change of the drug in
the body.
– Generates more polar (water soluble) compound
– Readily excreted from body
– Hydrophilic drugs (eg. Streptomycin, neostigmine,
decamethonium) are not biotransformed and
excreted unchanged.
– Metabolites may still have potent biological
activity (or may have toxic properties)
45. biotransformation can result in:
A) Inactivation: most drugs & their active metabolites are
rendered inactive or less active.
E.g- pentobarbitone, morphine, CAF
B) Active metabolites from active drug: drug can be
converted to one or more active metabolites.
E.g-diazepam-to-desmethyl diazepam, oxazepam;
digitoxin-to-digoxin; codiene-to-morphine
C) Activation of inactive drugs: prodrugs to active
metabolites.
E.g- L-dopa to dopamine, enalapril to enalaprilat, ά-
methyldopa to ά-methylnorepinephrine.
49. INHIBITORS (Drugs that inhibit the production of Cyt-
P450 enzymes)
• Acute Alcohol in take
• Chloramphenicol
• Cimetidine
• Erythromycin
• Grapefruit juice
50.
51. INHIBITORS of Cyt-P450 enzymes...
Ciprofloxacin
Inhibits Cytochrome P450 hepatic enzymes
Reduced metabolism of Theophylline
Raised plasma levels
Toxicity
53. INDUCERS (Drugs that increase the production of Cyt-
P450 enzymes)
• Phenobarbitol,
• Phenytoin,
• Carbamazepine
• Glucocorticoids
• Chronic Alcohol
54.
55. INDUCERS of Cyt-P450 Enzymes...
• Rifampicin (Rifampin)
Induces
Cytochrome P450 hepatic enzymes
Increased metabolism of Estrogens
Contraceptive failure
56. Factors Affecting Biotransformation of drugs
Physiochemical properties of the drug
Presence of other chemical factors
Age differences
Disease states
57. Excretion of drugs
• Excretion is defined as the process where by drugs or metabolites are
irreversibly transferred from internal to external environment through
renal or non renal route.
• The principal organ of excretion are kidneys.
Glomerular filtration
It is non selective , unidirectional process
Ionized or unionized drugs are filtered, except those that are bound to
plasma proteins.
Active tubular secretion
This mainly occurs in proximal tubule.
It is carrier mediated process which requires
energy for transportation of compounds against conc. gradient
Active secretion is unaffected by change in pH and protein
binding.
58. Tubular reabsorption
It occurs after the glomerular filtration of drugs.
99% of glomerular filtrate is reabsorbed.
TR can be active or passive processes.
Reabsorption results in increase in the half life of the drug.
Active Tubular Reabsorption:
Its commonly seen with endogenous substances or
nutrients that the body needs to conserve e.g. electrolytes,
glucose, vitamins.
Passive Tubular Reabsorption:
It is common for many exogenous substances including drugs.
The driving force is Conc. Gradient.
59. Reabsorption…
Changes in urinary pH affect tubular reabsorption of drugs
that are partially ionized-
• Weak bases ionize more and are less reabsorbed
in acidic urine.
• Weak acids ionize more and are less reabsorbed
in alkaline urine.
This principle is utilized for facilitating elimination of the drug
in poisoning, i.e. urine is alkalinized in barbiturate and
salicylate poisoning.
Though elimination of weak bases (morphine, amphetamine)
can be enhanced by acidifying urine.
60. Factors affecting renal excretion
Physicochemical properties of drug
Biological factor
Disease state
61. Non-renal route of drug excretion
Various routes are
Biliary Excretion
Pulmonary Excretion
Salivary Excretion
Mammary Excretion
Skin/dermal Excretion
Gastrointestinal Excretion
62. Clinical pharmacokinetics
• Clinical pharmacokinetics is study of the time course
of a drug’s movement through the body.
• Primary goals of clinical pharmacokinetics Enhancing
efficacy and Decreasing toxicity of a patient’s drug
therapy.
• pharmacological effect of most drugs is produced by
forming a complex with a drug receptor.
63. Kinetics of elimination
• The knowledge of kinetics of elimination of drug provides the
basis to devise rational dosage regimens and to modify them
according to individual needs.
• Drug elimination is the sum total of metabolic inactivation and
excretion.
Clearance (cl)
• Ability of organs of elimination (e.g. kidney, liver) to “clear”
drug from the bloodstream.
• Theoretcal volume of plasma from which the drug is
completely removed per unit time.
• Units are in L/hr or L/hr/kg
• Clearance varies with body weight.
• Also varies with degree of protein binding.
64. Clearance con…
• Rate of elimination = kel D,
– Remembering that C = D/Vd
– And therefore D= C Vd
– Rate of elimination = kel C Vd
• Rate of elimination for whole body = CLT C
Combining the two,
CLT C = kel C Vd and simplifying gives:
CLT = kel Vd
65. Types of Kinetics
• First Order Kinetics : Elimination of the Drug is directly
proportional to its plasma Concentration. It is dependent on
its Half life. First order implies that No matter How much
concentration of the Drug u give it will be eliminated 50% by
its First Half- life. E.g most drugs
• Zero Order Kinetics :
The rate of elimination remains constant irrespective of drug
concentration or a constant amount of the drug is eliminated
in unit time, e.g. ethyl alcohol.
67. Comparison
– [drug] decreases linearly with
time
– Rate of elimination is
constant
– Rate of elimination is
independent of [drug]
– No true t 1/2
First Order Elimination
– [drug] decreases
exponentially w/ time
– Rate of elimination is
proportional to [drug]
– Rate of elimination is
dependent on [drug]
– t 1/2 is constant regardless of
[drug]
Zero Order Elimination
68. Half-Life
Half-life is the time taken for the drug concentration to fall to
half of its original value. E.g.
• Digoxin 40 hr, Penicillin –G 30 min
• Digitoxin 7 days Aspirin 4hr
• Phenobarbitone 90 hr
The elimination rate constant (k) is the fraction of drug in the
body which is removed per unit time.
• t1/2 = ln2/k
• t1/2 = 0.693/k
• K=cl/v
• Therefore t1/2 = 0.693 x v/cl
69. Steady-State
• Steady-state occurs after a drug has been given for
approximately five elimination half-lives.
• At steady-state the rate of drug administration equals the
rate of elimination.
• Rate in = Rate Out
Loading Dose calculation
• Loading Dose (LD) = A dose of drug sufficient to produce a
plasma concentration of drug that would fall within the
therapeutic window after only one or very few doses over
a very short interval.
• Loading Dose (LD) = Cp(Target) x Vd
Vd is a theoretical Volume and determines the loading dose.
70. Question
• What is the loading dose required for drug A if;
• Target concentration is 10 mg/L
• Vd is 0.75 L/kg
• Patients weight is 75 kg
71. Maintenance dose calculation
• Maintenance Dose (DM) = The dose needed to maintain the
concentration within the therapeutic window when given
repeatedly at a constant interval.
• Maintenance Dose = CL x CpSSav
• CpSSav is the target average steady state drug concentration
• The units of CL are in L/hr or L/hr/kg
• Maintenance dose will be in mg/hr so for total daily dose will
need multiplying by 24
72. Question
• What maintenance dose is required for drug A if;
• Target average SS concentration is 10 mg/L
• CL of drug A is 0.015 L/hr/kg.
• Patient weighs 75 kg
