General Part I

General Pharmacology
By Biruk S. (Bpharm., MSc. in Pharmacology)

Department of Pharmacy, Pharmacology and Toxicology
Unit
Objectives:
 Upon completing this chapter, students will be able to
describe:
 Definition, Branches of Pharmacology, Sources of
drugs, Routes of drug administration

 Pharmacokinetics
 Dosage and dosage regimen
 Pharmacodynamics
 Factors modifying drug effects
 Drug interactions
 Adverse drug reactions
General Pharmacology By: Biruk S. 2

What is pharmacology?
 The term pharmacology comes from the Greek words:
 “Pharmakon” ( drug) and “logos” (study)
 Is the study of interaction of drugs with living
organisms.
 It also includes study of history, source,
physicochemical properties, dosage forms, methods of
administration, absorption, distribution, mechanism of
action, biotransformation, excretion, clinical uses and
adverse effects of drugs.

Pharmacology…
 The concept of drugs dates back to the origin of human
history
 Pharmacology though is quite young!!
 Born around the mid-19th century following advances
in biology and chemistry; then, physiology and

biochemistry…..genetics, biotechnology…..molecular
medicine

Drug Vs Medicine
Drug:
 Derived from Drouge (French word) = A Dry Herb
 Is any substance or product that is used or intended to be
used to modify or explore physiological system or

pathological states for the benefit of the recipient
 Aim of Drugs: To improve quality of life

Drug Vs Medicine…
 Basic use of drugs
 Diagnosis: BaSo₄ → GIT lesion
 Prevention: Vaccine, Contraceptives
 Suppression/Control: Insulin for DM, Anti-
hypertensive drugs.
 Treatment: Antibiotics for infection, Diuretics for
edema, analgesic for pain

Drug Vs Medicine…
Paracelsus (1493-1541)
 Swiss renaissance scientist
 All drugs are poisons
 “All substances are poisons; there is none that is not a
poison. The right dose differentiates a poison and a

remedy”
 Drugs taken in excess of recommended doses are
harmful

Drug Vs Medicine…
Medicine
 Medicine: (Medicament; Medication)
 Chemically formulated form of a drug(s)
 May contain more than one drug
 Medicine = Drug(s) + Additives (excipients)
 Medicine = a compound with therapeutic value
 Drugs are formulated into medicines

Drug Vs Medicine…
Paracetamol/Acetaminophen
1. Acetaminophen ( Active ingredient)
2. Maize Starch (Binder)
3. Croscarmellose (Desintegrant)
4. Nipagin/Methyl Paraben (Preservative)
5. Purified Water
6. Talc (antisticking)
7. Silicon Dioxide Colloidal (antiadherent)
8. Magnesium Stearate (Lubricants)

Pharmacology: Too interdisciplinary
 Full understanding of pharmacology demands knowledge of
 Physiology
 Biochemistry
 Genetics/Genomics
 Pathology
 Microbiology and Parasitology
 Biotechnology
 Clinical medicine
 Pharmaceutical sciences
 Others related disciplines
 Veterinary medicine, Epidemiology, Health economics,
Biostatistics
Branches of pharmacology
 Clinical pharmacology
 Pharmacological principles and methods towards
patient care and outcomes

 Neuropharmacology
 Effects of medication on central and peripheral nervous
system functioning
 Psychopharmacology
 Effects of medication on the psyche; how molecular
events are manifested in a measurable behavioral form

Branches of pharmacology…
 Pharmacogenetics
 The study or clinical testing of genetic variation that
gives rise to differing response to drugs

 Pharmacoepidemiology
 Effects of drugs in large numbers of people.
 Toxicology
 Harmful or toxic effects of drugs, the adverse effects of
any chemical substance in excess (including those

beneficial in lower doses)
 Posology: How medicines are dosed. It also depends
upon various factors like age, climate, weight, sex, and so
on.

Naming of drugs
 Several names throughout its development, production
and use
 3 types of naming systems
1. Chemical name
 Tells the exact chemical make up of the drug
 Unique for a drug, but too complex for common use
 Chemical name for Erythromycin:
3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-
(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-14-
ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-
methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,7,9,11,13-
hexamethyl-1-oxacyclotetradecane-2,10-dione

Naming of drugs…
2. Brand/Trade name
 Coined by the sole manufacturer and can’t be used by
others
 A drug produced by many manufacturer has several brand
names
  is added at the end of brand names
 E.g. Erythromycin has the following brand names (not
exclusive)
 Erythrocin, Ery-Tab, E-Mycin, EryPed
 Brand named drugs are usually more expensive
 Are confusing for use … are not promoted for prescription

Naming of drugs…
3. Generic name (International nonproprietary name)
 One universal name for one drug…..to be accepted
internationally
 Not-protected by trademark, patent or copyright
 Designated by the WHO
 Avoids confusion
 The difference b/n generic product and brand product
is only the additives but not active ingredient

Sources of drugs
 Drugs can be found from
 Plants
 Digoxin from Digitalis lanta (Foxglove)
 Atropine from Atropa belladona (Nightshade)
 Animals
 Insulin from sheep pancreas
 Anticoagulants from snake venom
 Gonadotropins from a woman’s urine (Menotropin)
 Minerals
 Iron sulfate, magnesium trisilicate

Sources of drugs…
 Micro-organisms
 Penicillin from the fungus penicillium
 Cephalosporins from cephalosporium
 Synthetic and semi-synthetic drugs

 Aminopenicillins, fluoroquinolones
 Products of DNA recombination

 Vaccines, insulin, hormones, many other peptides

Dosage forms
 Drugs are not usually administered as pure chemical
substances
 Dosage forms are formulations into which the drug is
made for administration
 Drugs are formulated in to dosage forms for
 Keeping the stability of the drug
 Ease of administration
 User appeal / Organoleptic effect
 Ease for packaging, labeling, transporting and storage

Dosage forms…
Types of dosage forms
 A single drug can be prepared in several dosage forms
 Based on physical property
 Solid dosage forms: Tablets, capsules (powder filled),
powders, pessaries (vaginal tabs)

 Semi-solid dosage forms: Creams, lotions,
suppositories
 Liquid dosage forms: Suspensions, solutions, liquid
filled capsules
 Gaseous dosage forms: Inhalations

Dosage forms…
 Based on site of application
 Dosage forms for systemic use: Injections, tablets,
solutions, suspensions, inhalations, syrups

 Dosage forms for topical use: Creams, lotions,
shampoos, soaps, sprays

Posology: Deals with dosage of drug
 Dose: amount of drug or medicinal substance to be
administered at one time
 Dosage: determination of the amount , frequency and
number of dose for a patient
 Maximum dose: largest dose of drug that is safe to
administration and produce no toxic effect
 Minimum dose: smallest dose of drug that will be
effective
 Therapeutic dose: dose required to produce the optimal
therapeutic effect.
 The dose b/n maximum and minimum dose

Classification of drugs based on safety
 Prescription drugs
 Drugs with potentially harmful outcomes unless used
under the supervision of professionals

 Authorized prescription is required to obtain
 Majority of the drugs in the market are prescription
drugs.
 E.g. Cardiac glycosides
 Non-prescription/Over-The-Counter drugs
 Can be taken without the supervision of professional
but as directly as recommended

 Relatively safer than prescription drugs
 E.g. Paracetamol, Aspirin, diclofenac

Classification of drugs…
 Controlled drugs (Narcotics, Psychotropics, …)
 High potential for abuse and cause addiction, and
dependence
 The most strictly monitored of all drugs
 Sale and distribution are controlled by law
 Are further classified in to 5 “Schedules”/categories
 Schedule I to V

Fate of administered drug
 Most drugs after administered to the body they undergo
two major process.
 Principles of pharmacology!!!
 Pharmacology is the study of pharmacokinetics and

pharmacodynamics of drugs
 What does the body do to the drug?
 Pharmacokinetics
 What does the drug do to the body?
 Pharmacodynamics

Pharmacokinetics
 Pharmakon=drug, Kinetics=movement
 Is the study of the processes through which the drug
passes after administration
 The processes include:
 Absorption
“A D M E”
 Distribution
 Metabolism
 Excretion Elimination

The Pharmacokinetic process…
 PK affects concentration and time course of a drug at its
site of action and thus the quality and intensity of its
effects
 All the pharmacokinetic processes involve passage of
drug through membranes

A. Absorption
 The passage of dissolved drug molecules through an
epithelial membrane
 Movement of drug from site of administration to the
systemic circulation
 Occurs after dissolution of a solid drug or administration
of liquid drugs

Absorption…
Mechanisms of drug absorption
 The passage of drug molecules from the site of absorption
to the systemic circulation can take place in different

mechanisms
 There are 4 mechanisms by which drug molecules cross
the cell membrane/absorption/

 Pore transport (Filtration)
 Passive diffusion
 Carrier mediated transport
 Facilitated diffusion
 Active transport
 Bulk transport mechanisms
Absorption…
1. Filtration (pore transport)
 Is passage through the water filled pores across
membranes
 It is accelerated by the hydrodynamic flow of water
occurring under hydrostatic or osmotic pressure gradient
 Drug should be water soluble and of smaller molecular
size than the diameter of the pores.

Absorption…
2. Passive diffusion
 The major means of drug
transportation
 Needs no energy to proceed, no
carrier protein
 Is unsaturated and non-competitive
 Moves along concentration gradient
 Molecules move from a region of
high concentration to a region of

low concentration

Absorption…
 Factors affecting passive diffusion
 The size of molecule
 Lipid solubility
 Polarity
 Degree of ionization
 The drugs which are unionized, low polarity and higher

lipid solubility are easy to permeate membrane.
 The drugs which are ionized, high polarity and lower
lipid solubility are difficult to permeate membrane.

Absorption…
Influence of pH on passive diffusion:
 Most drugs are either weak acids or weak bases that
are present, as both non-ionized and ionized species.

 The trans-membrane distribution of a weak electrolyte
usually is determined by its pKa and the pH gradient

across the membrane.
 The dissociation constant (pK ) of the drug
a
 The pH of the absorption site

Absorption…

Absorption…
3. Carrier-mediated transport systems
 Involves binding of the drug to specific receptors on the
membrane for translocation into the cytoplasm

 Characteristics of carrier mediated transport
 Selectivity
 Competitive inhibition by chemical congeners
 Saturability
 Two types of carrier-mediated transport
 Facilitated diffusion
 Active transport

Absorption…
A. Facilitated diffusion
 Diffusion is facilitated by carrier proteins
 Needs no energy to carry on
 Goes along concentration gradient but is much faster
than passive diffusion

 Is saturable
 Is competitive
 Example: GLUT4 …carries glucose across

muscle cell membranes

Absorption…
B. Active transport
 When movement is against concentration gradient
 Needs expenditure of energy to proceed
 Needs carrier protein/carrier mediated/
 Only few drugs are absorbed this way
 Is competitive
 Is saturable
 Na+/K+ ATPase

Absorption…
4. Bulk transport systems
 Process by which molecules are engulfed by cell
membrane forming a vesicle & releases them

intracellularly.
 Endocytosis: Phagocytosis and Pinocytosis
 Transport of exceptionally large drugs
 E.g. Protein, toxin, Vitamin B12.

Absorption…

Absorption and Bioavailability
 Bioavailability (BA):- is a measure of the fraction (F) of
administered dose of a drug that reaches the systemic
circulation in the unchanged form.
 E.g. Bioavailability of Paracetamol is 50%. It means if
a patient orally takes 500 mg of Paracetamol, only

250mg (50%) of drug will reach to the systemic
circulation
 Drugs with good absorption – have better BA.

Absorption and BA…

Absorption and BA…

Factors affecting absorption of drugs
 Rate and extent of absorption is affected by;
 Physicochemical properties of the drug
 Molecular shape
 Particle size
 Degree of ionization
 Lipid solubility
 The PH of the environment such as: fluid of body, fluid
in cell, blood, urine

 Route of drug administration
 Patient conditions
 Presence/absence of food vs GI absorption

 Massaging affects the absorption of IM injected
drugs
Factors affecting absorption of drugs…
1. Physiochemical properties
 Lipid solubility
 Lipid soluble drugs can easily cross the semi-
permeable lipid bilayer /plasma membrane/

 Highly polar/poorly lipid soluble drugs/ are poorly
absorbed across the cell membrane

 Non-ionized form of a drug is more lipid soluble than
ionic form and thus cross the plasma membrane easily

 Degree of ionization
AB A + + B+
 Drugs that exist in unionized form are more easily
absorbed
 Acidic drugs exist in more of their nonionic form in
lower pH areas and in more of their ionic form in areas

of high pH (basic environment.)
 Weak acids are absorbed better from regions of lower
pH while weak bases are better absorbed from regions

of higher pH
 Acidic drugs are largely unionized in stomach and
absorbed faster while basic drugs are absorbed faster

in intestines
2. Blood flow to the absorption site
 Because blood flow is much greater in the intestines than
the stomach, absorption is greater in the intestines.

3. Total surface area available for absorption
 Intestines have large surface area

4. Contact time at the absorption surface
 Absorption is affected by changes in gastric motility (e.g.
diarrhea)
 Anything that delays the transport of the drug from the
stomach to the intestine delays the rate of absorption of

the drug

5. Expression of P-glycoprotein
 Drug transporter in liver, kidney, brain, intestines
(reduces absorption)
 High expression of p-glycoprotein reduces absorption
 It is expressed throughout the body
 E.g.
 In the liver: transporting drugs into bile for elimination
 In kidneys: pumping drugs into urine for excretion

6. Route of administration
 For IV drugs, absorption is complete
 (100% bioavailability)
 Drug administration by other routes may result in partial
absorption and lower bioavailability

Routes of drug administration
 Drugs are administered for either their action in the
locality of their administration or for general systemic
purpose.
 There are two major routes of drug administration:
 Enteral - means to do with the gastrointestinal tract
and
 Parenteral - all other means of drug administration.

Routes of drug administration…
1. Enteral Administration
 The enteral routes of administration are those in which
the drug is absorbed from the gastrointestinal tract

 These include the sublingual, buccal, oral, and rectal
routes.

2. Parenteral Administration (Par-beyond, enteral-
intestinal)
 This refers to administration by injection which takes the
drug directly into the tissue fluid or blood without having

to cross the intestinal mucosa.
 The most important and most frequently used parenteral
routes are I.V. (intravenous), IM (intramuscular) and SC

(subcutaneous) routes respectively.

3. Topical application:
 Topical administration
 Application could be on mucous membranes, skin or the
eye.

Enteral route
I. Oral: (per os= PO, Latin "through the mouth" or "by
mouth". )
 Administration by mouth mostly, for systemic effect.
 Is the most common method of drug administration
 Site of absorption:
 Stomach
 Small intestine
 Involve many step before absorption (disintegration,
dissolution).

Enteral route…
Oral route…
 Advantages
 Safe, more convenient and economical
 Often painless, need no assistance for administration
 Both solid dosage forms and liquid dosage forms can
be administered
 Reverse of dose management is easily done

Enteral route…
Oral route…
 Disadvantages
 Slower action and thus not suitable for emergencies
 Unpalatable drugs difficult to administer
 Not suitable for uncooperative /unconscious/ vomiting
patients
 Certain drugs are not absorbed sufficiently (drug-food
interactions)
 Irritant effect of some drugs
 Some drugs are destroyed by digestive juice or liver
enzymes (first pass metabolism)

Enteral route…
 First pass effect (First pass metabolism)
 The elimination of a drug by liver (main) and GI wall
as it passes from the GIT into the circulation.

Enteral route…
 First pass effect…
 A drug given via the oral route may be extensively
metabolized by the liver before reaching the systemic

circulation (high first-pass effect)
 The same drug - given IV- bypasses the liver,
preventing the first-pass effect from taking place, and

more drug reaches the circulation

Enteral route…
Factors affecting absorption of drugs from GIT
Factors related to the drug Factors related to the Patient
 Size of the molecules  pH of the absorbing site
 Polarity  Health of GIT mucosa
 Lipophilicity of the drug
 Stability of the drug  GIT motility
 Pharmaceutical  Food
Formulation  Presence of other drugs in
GIT
 Intestinal FPM

Enteral route…
II. Sublingual
 Keeping drug under the tongue
 Site of absorption: oral cavity
(sublingual mucosa)
 Faster absorption than PO and skin
 Requires drug to be palatable
 i.e. require sweetening agent
 Examples of commonly prescribed
sublingual tablets include

nitroglycerin, loratadine

Enteral route…
II. Sublingual…
Disadvantages Advantages
 Not for irritant  Rapid effect (Emergency)
drugs,  No first pass metabolism
 Not for frequent  High bioavailability
use
 No GIT destruction
 No food drug
interaction

Enteral route…
III. Buccal route
 Between cheek and gum
 Requires drug to be palatable
 Advantages:
 Avoid first pass metabolism
 Rapid absorption
 Drug stability
 Disadvantages:
 Inconvenience
 Advantages lost if swallowed
 Small dose limit

Enteral route…
IV. Rectal
 Insertion of the drug into the rectum
 Drugs absorbed in lower part of the rectum do not pass

through the liver before entry into systemic circulation
 Certain irritant and unpleasant drugs can be put into the
rectum as suppositories for systemic effect.

Enteral route…
Rectal…
 Advantage
 For certain irritant and unpleasant drugs
 In patients who are unconscious, uncooperative, and
incapable of swallowing (elderly and pediatrics)

 In the presence of vomiting
 FPE is minimal by 50% from PO

Enteral route…
Rectal…
 Disadvantage
 Unreliable and unpredictable absorption
 Uncomfortable/not convenient and embarrassing

 Absorption is slower
 Irritation of rectal mucosa

Parenteral route
 Par = beyond and enteral = intestine
 Drug directly introduced into tissue fluids or blood
without having to cross the intestinal mucosa.
 Usually refers to injections
 Intradermal (I.D.) (into dermis of the skin)
 Subcutaneous (S.C.)
 Intramuscular (I.M.)
 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)

Parenteral route…
 Advantages
 Action faster (hence valuable in emergencies)
 Employed in unconscious/uncooperative/vomiting
patients
 No interference of food or digestive juice and first pass
effect is bypassed to a certain extent

 High bioavailability

Parenteral route…
 Disadvantages
 Preparation is costly
 Need of assistance by others during administration
 Infection
 Pain at injection site
 No recall of drug

Parenteral route…
Intravenous route (IV)
 Drug injected as a bolus or infused slowly over hours in
one of the superficial veins

 Fast action – suitable for emergencies
 The drug directly reaches into the blood stream and
effects are produced immediately

 Dose required is smallest as F=100%
 Only solutions can be injected
 Even large volumes can be infused through this route

Parenteral route…
Intravenous…
 Better for drug with irritation effect
 Difficult to terminate action or to manage dose dumping
 Pain, not convenient (difficult for self administration)
 Expensive
 Only sterilized solution is used
 It is the most risky route
 Cellulitis or abscess formation, necrosis, nerve injury,
prolonged pain…

Parenteral route…
II. Intramuscular (IM)
 Administration into skeletal muscle
 Such as deltoid, triceps, gluteus maximus
 Muscle is less richly supplied with sensory nerves and
(mild irritants can be applied) and is more vascular

(absorption is faster)
 Absorption depends on rate of blood flow to the site
of injecting
 Massaging, heating, exercise increases absorption

Parenteral route…
 Advantages  Disadvantages
 Permits use of poorly  Inconvenient
soluble drugs  Painful
 Permits use of depot  Potential for injury
(Oily/suspension)  Local tissue injury

preparations  Nerve damage
IM; Gluteal injection site

IM; Deltoid injection site

Parenteral route…
III. Subcutaneous, SC (under skin)
 Injection under skin
 Absorption is slower but constant
 The drug is deposited in the loose SC tissue
 Is richly supplied by nerves (unsuitable for irritant drug
administration) but is less vascularized (slow

absorption)
 Self injection is simple
 Oily solution or aqueous suspensions can be injected for
prolonged action
 Solid pellets can be implanted for longer effect, e.g.
contraceptive implants (Implanon)

Parenteral route…

Topical routes
 Application could be on mucous membranes, skin or the
eye
 Mucous membranes
 Drugs are applied on the mucous membranes of the
conjunctiva, nasopharynx, oropharynx, vagina and

colon usually for their local effects.
 Absorption through mucous membranes occur readily
to cause systemic effects

Pulmonary/inhalation route
 Suitable for gaseous and volatile drugs
 Used for both local action (asthma), and systemic action
(general anaesthetic)
 Rapid absorption due to large surface area
 Advantage: Rapid absorption, avoidance of hepatic first
pass loss, local application to the pulmonary system.
 Disadvantage: Poor ability to regulate the dose and
irritation of the pulmonary mucosa

Factors governing choice of route
 Physico-chemical property of the drug (solid/ liquid /gas;
solubility, stability, PH, irritancy, etc.…)
 Site of desired action (localized or generalized effect)
 Rate & extent of absorption of the drug from d/t routes
 Effect of GI & first pass effects
 Rapidity with which the response is required (routine use
or emergency)
 Status of the patient

Factors governing choice of route…
 Decreasing order of rate of absorption:
 Inhalation → Sublingual → Rectal → intramuscular →
subcutaneous → oral → transdermal

B. Distribution
 Is a random movement drug molecules out of the central
compartment /systemic circulation/ in to the different
body tissues /fluid compartments
 The major compartments are: plasma, interstitial fluid,
intracellular fluid, transcellular fluid and fat

 Involves the delivery of drugs from the blood in to the
target sites

Distribution…
 The human body is about 60% water in
adult males and around 55% in adult
females
 The total amount of water in a 70 kg man
is approximately 42 liters (57%) of his
total body weight.
 Intracellular fluid (2/3 of body water)

Distribution…
 Extracellular fluid (1/3 of body water)
 Plasma (1/5 of extracellular fluid)
 Interstitial fluid (4/5 of extracellular fluid)
 Transcellular fluid
 GIT, cerebrospinal, peritoneal, and ocular fluids

Distribution…
 Possible modes of drug distribution:
 Following its uptake into the body, the drug is
distributed in the blood (1)

 And through it, the drug may be restricted to the
extracellular space (plasma volume plus interstitial

space) (2)
 Or it may also extend into the intracellular space (3)
 Certain drugs may bind strongly to tissue structures (4)

Distribution…
 Drug retained in the

vascular system [1]
 Drug distributed b/n
the blood and ECF
[2]
 Drug distributed b/n
the blood, ECF and
ICF [3]
 Drug strongly
bound to specific
tissues [4]

Factors affecting drug distribution
 There are factors governing the distribution of a drug
into tissues of the body.
 Physico-chemical properties of drugs
 Lipid solubility of the drug
 pKa of the drug
 Degree of plasma protein binding
 Physiological factors
 Rate of blood flow/Tissue perfusion
 Tissue uptake
 Presence of barriers
 BBB, placental barrier, testicular barrier

Factors affecting drug distribution…
1. Drug - plasma protein binding
 After entering the blood stream, drugs exist in two forms
[protein bound & unbound form]

 The major plasma proteins that bind drugs are
 Albumin
 α-acid glycoprotein
 Lipoproteins, globulin, hormone-binding factors
 Drug-Plasma protein binding is a reversible process and
in dynamic equilibrium.
 As free drugs leave the systemic circulation the bound
drug dissociate
D + P ↔[DP] ↔ D + P

 The extent of plasma protein binding is affected by;
 Drug’s affinity to plasma proteins
 Availability binding sites on binding proteins
 Since drug binding is saturated process --- ↑ in site of
binding --- ↑ binding

 Concentration of the drug
 Concentration of plasma proteins in the blood
 Presence of other chemicals that are bound to the same
site

 The extent of this binding will influence the drug’s
distribution and rate of elimination b/c only the unbound
drug can:
 Diffuse through capillary and cell membrane
 Produce pharmacological effect
 Produce toxic effect
 Be metabolized
 Be excreted

1. Albumin
 Most drug binding glycoprotein
 Mainly acidic and hydrophobic drugs bind
 Albumin has the strongest affinity for anionic drugs
(weak acids ) & hydrophobic drugs.

 Example: Phenytoin, salicylate
 Some factors affect the binding of drugs with albumin
 Age and Pregnancy
 Disease state: Hyperalbuminemia,
hypoalbuminemia, liver disease

2. α1 –acid glycoprotein
 Binding site mainly for basic drug.
 It is an important binding protein for weak basic drugs
such as quinidine, lidocaine & propranolol.
 Serum plasma level ↑ in situation such as:
 Stress, injury, trauma
 Rheumatoid arthritis
 Surgery

Examples of highly PPB drugs
Bound to Albumin
Bound to alpha1 – acid GP
 Barbiturates
 Beta-blockers
 Benzodiazepines
 Bupivacaine
 NSAIDs
 Lidocaine
 Valproic acid
 Disopyramide
 Phenytoin
 Imipramine
 Penicillins
 Methadone
 Sulfonamides
 Prazosin
 Tetracyclines
 Quinidine
 Tolbutamide
 Verapamil
 Warfarin

Clinically significant implications of PPB :
1) Highly PPB drugs are largely restricted to vascular
compartment. Protein binding restricts drug
distribution and elimination.
2) Protein bound drug is pharmacologically inactive (i.e.
pharmacological activity is mediated only via the free
drug).
3) High degree of PPB generally makes the drug long
acting as the bound form is not available for
metabolism &/or excretion.
4) Age, hepatic disease, renal failure, and pregnancy
decreases plasma protein concentration.
5) One drug can bind to many sites on the albumin
molecule ….more than one drug can bind to the same
binding site which may lead to drug interaction.
 Drug bound with higher affinity will displace the drug
with lower affinity leading to drug interactions.
 Ex. Tolbutamide is normal 95% bound to albumin &
5% is free (active part). If a sulfonamide is

administered it will displace tolbutamide from
albumin → ↑free particle of tolbutamide → adverse
effect

2. Tissue uptake (tissue-affinity of drugs )
 Drugs will not always be uniformly distributed to and
retained by body tissues
 Some drugs have strong affinity to a particular body
tissue
 Tetracycline prefers to accumulate in teeth and bone
 Fat soluble drugs like thiopental prefer to accumulate
in the adipose tissue

 Decrease therapeutic activity
 Cadmium, lead, mercury accumulate in the kidney –
toxicity
 Chloroquine distributes to the eye and the liver

3. Physiologic barriers
I. Blood Brain Barrier
 The BBB limits the entrance of some drugs in to the brain
tissue
 Molecules/drugs/ that are allowed to cross the BBB are:
 Unionized
 Small in size
 Unbound to plasma proteins
 Drugs that are ionized, large in size and/or bound to
plasma proteins are not allowed to cross in to the brain

II. Placental barrier
 Blood vessels of the mother separated from the fetus by
PBB
 Highly polar and ionized drugs do not cross placenta
readily
 Placental barrier protects the fetus from exposure to
some drugs
 However, some lipid soluble drugs can cross the
placenta and cause unwanted effects to the fetus

 Tetracycline causes parti-colored teeth & weak bones
 Chloramphenicol causes gray baby syndrome

4. Tissue perfusion
 Refers to the rate and amount of blood that reaches each
organ and tissue

 Organs and tissues that get more of the blood pumped by
the heart get more of the drug in the plasma too.

 Highly perfused tissue: heart, lung, brain, liver, kidney
 Intermediate perfused tissue: skeletal muscle
 Poorly perfused tissue: skin, bone, nail, fat
 Generally the distribution of drugs to body compartment
determine by Vd

 Volume of distribution (Vd )
 V is the hypothetical fluid volume that would be
d
required to contain all the drug in the body at the same
concentration measured in the blood or plasma
 Relates the amount of drug in the body to the
concentration of drug in blood or plasma (expressed as:

in Litres)

 The conc. (c) of a solution corresponds to the amount (D)
of substance dissolved in a volume (V);
Thus, c = D/V
 If the dose of drug (D) and its plasma concentration (c)
are known, a volume of distribution (Vd) can be
calculated from:
 V = [D]/[C]
d
 [D] = total concentration of the drug in the body
(dose administered)
 [C] = concentration of the drug in the plasma


• Vd is not a real volume, small volume indicates
extensive plasma protein binding, but large volume
indicates extensive tissue binding.
• Vd is increased by increased tissue binding, decreased
plasma binding and increased lipid solubility.

 Drugs with small Vd are confined in the plasma
 Drugs with intermediate Vd are probably distributed in to
the interstitial compartment
 Drugs with large Vd are distributed in to all fluid
compartments including the intracellular fluid
 Drugs with very large Vd above the total body fluid
volume may be sequestered in some tissue

Drug Elimination
 Drugs are eliminated from the body via two basic
mechanisms:
 Biotransformation (metabolism) and
 Excretion.
 Metabolism involves enzymatic conversion of one

chemical entity to another within the body
 Excretion involves removal of chemically unchanged
drug or its metabolites from the body
 These processes are initiated as soon as the drug reaches
the systemic circulation.

C. Metabolism/ Biotransformation
 What is BT?
 A chemical change (transformation) of drugs usually
by body enzymes.
 Why BT?
 To facilitate excretion of drugs by changing to more
water soluble form.

 Lipophilic → → Hydrophilic
 Where BT?
 Metabolism of drug occur in all body parts
 Liver, GI (enzymes and microflora), kidney, lung,
blood…
 But mainly take place in liver ; b/c it contains large
amount of metabolizing enzymes

Metabolism…
 Consequence of BT:
 Inactivation of parent drug - loss of pharmacological
activity (for most drugs)

 E.g. Phenobarbital
 Conversion of drug to its toxic metabolite
 E.g. Paracetamol is changed into a toxic metabolite
called N-acetyl-p-benzoquinone imine (NAPQI)

 Maintenance of activity- Some drugs remain active
(even more active) after metabolism

 E.g. Diazepam→ Oxazepam, Codeine → Morphine

Metabolism…
 Consequence of BT…
 Conversion of inactive drug (prodrug) to more active
drug
 Pro-drugs:
 Are pharmacologically inactive drugs that are
administered in inactive forms to be activated by
metabolism
 E.g. levodopa to dopamine.
 Enalapril to enalprilat (active)

Metabolism…
 How BT?
 Metabolism in liver-the major drug metabolizing
organ
 Involve 2 steps/phases of reaction
 Phase I
 Phase II

Metabolism…
1. Phase I (Non-synthetic) reactions
 Also called functionalizing reaction due to the addition
and/or formation of new functional groups on to the

parent drug
 Result in more reactive and hydrophilic metabolites
 Introduction or unmasking of functional group by:
 Oxidation
 Reduction
 Hydrolysis
 Most (not all) phase I reactions are catalyzed by a family
of microsomal enzymes called CYP 450 which are found

in the liver

Metabolism…
I. Oxidation
 It is the addition of oxygen and/or the removal of
hydrogen.
 Accounts for a large proportion of drug metabolism.
 It is mediated primarily by mixed function oxygenases
(monooxygenases) located in endoplasmic reticulum,

which include :
 Majorly Cytochrome P-450 family of enzymes
 Others: Flavin monooxygenases family of enzymes
and hydrolytic enzymes

Metabolism…
Oxidation…
 The cytochrome P-450 (officially abbreviated CYP) is
large and diverse group of enzymes

 Present in liver, small intestine, lungs and brain
 The function of CYP enzymes is to catalyze the
oxidation of organic substances (endogenous steroidal

hormones, vitamins FAs)
 Accounts for over 80% of drug oxidation.

Metabolism…
Oxidation…
 Most common are:
 CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2,
CYP2A6, CYP2E1.
 CYP enzymes can be inhibited (slowed) or induced
(speed up)
 Enzyme induction: ↑ synthesis of microsomal enzyme 
↑ metabolism  ↑excretion
 Enzyme inhibitor: ↓liver enzyme function 
↓metabolism ↓excretion  toxicity

Metabolism…

Metabolism…
II. Reduction
 Add a hydrogen or remove oxygen
 Reduction rxns can be performed by the body tissues or
intestinal microflora.
 Reduction quantitatively accounts for a much smaller
proportion of drug metabolism; however, it is involved in

biotransformation of some common drugs with low
therapeutic indices.
 Examples: Warfarin → hydroxywarfarin
Cortisone → hydrocortisone

Metabolism…
III. Hydrolysis = Hydration reactions
 Involves addition of water to the drug molecule
 Hydrolysis is mediated by enzymes such as hydrolases
and esterases.
 Intestinal flora can hydrolyse many drugs.
 Examples:
 Succinylcholine → Succinic acid + choline
 Acetyl choline → acetic acid + choline

Metabolism…
2. Phase II reactions
 Also called conjugation reactions=addition of
endogenous macromolecules to drug molecules

(substrates)
 Functional group or metabolite formed by phase I is
masked by conjugation with natural endogenous

constituent
 Add a polar group, such as glucuronide, glutathione,
acetate, or sulfate, to the drug molecule (Conjugation)

by covalent bonds to (OH, NH2, SH).
 Drug + endogenous polar compound

Metabolism…
 Phase II reactions make the products of phase I reaction
more polar and water soluble so that they can easily be
excreted
 Usually Follow the phase I reaction (not always true)
 Some drugs may undergo phase II reaction before
undergoing phase I reaction

 Isoniazid is first acetylated (phase II) and then is
hydrolyzed to isonicotinic acid (phase I)

Metabolism…
 Most phase II products are pharmacologically inactive
 There are exceptions: E.g. morphine, codeine
 Morphine-6-glucoronide is even more
pharmacologically active than morphine, the parent

drug
 Phase II reactions are saturable as the conjugating
macromolecules can be exhausted

Metabolism…
Types of phase II reactions:
A. Glucuronide conjugation (Glucuronidation)
 Faster than phase I
 Is the most common and most important conjugation
reaction
E.g. Diazepam, chloramphenicol, morphine.
 Enzymes UDP- glucuronyl transferase (microsomal)
 Endogenous substances conjugated by this system:
steroids, bilirubin
B. Acetyl conjugation (acetylation)
 Involve N-acetyl transferase.
 E.g. Isoniazid (INH), hydralazine

Metabolism…
 The rate of acetylation is mainly affected by the
existence of genetic polymorphism
 Two acetylators phenotypes:
 Slow acetylators: tend to accumulate higher blood
conc. of un-acetylated drugs….toxicity

 E.g. isoniazid…peripheral nerve damage and liver
damage
 60-70% Indians, Egyptians, Jews
 Fast acetylators: eliminate drugs rapidly--- outcome
of therapy
 E.g. Japanese
 Ethiopians living in Ethiopia (39% rapid, 61%
slow)

Metabolism…
C. Sulphate conjugation (Sulfation)
 Use sulfotransferase enzyme
 E.g. Steroids
D. Methyl conjugation (Methylation)

 Use methyl transferase
 E.g. Catecholamine, Histamine
E. Glutathione conjugation
 Use glutathione transferase
 Glutathione protect cells from reactive electrophilic
compounds
 E.g. Acetaminophen

Metabolism…
Order of the phases
 Drugs usually enter phase I first, then enter phase II for
conjugation.
 Some drugs enter phase I only
 Some drugs which have polar groups and so enters phase
II only, directly without entering phase I

 Some drugs have a reversed order of the phases i.e. Enter
phase II first then enter phase I

 Isoniazid is firstly acetylated (conjugation) and then
hydrolysed to isonicotinic acid + acetyl hydrazine

(phase I reaction)

Metabolism…
Factor affecting drug metabolism/ BT
 Genetic make up: N-acetyl transferase Vs Isoniazid
 Diet: e.g. grape fruit juice ( inhibit CYP3A4)
 Age: in infants UGT less developed
 Sex: e.g. Alcohol Vs alcoholic dehydrogenase
 Disease state: e.g., Liver damage
 Concomitant drug use: (Drug-drug interaction)
 Enzyme inducers (e.g. phenobarbitone, phenytoin, etc.)

 Enzyme inhibitors (e.g. Cimetidine, ketoconazole etc.)

D. Excretion
 What?
 Is the elimination (passage out) of a systemically
absorbed drug from the body in the form of metabolites

or unchanged drug.
 Where?
 The kidneys are the main organ of excretion for most
drugs especially for water soluble and non-volatile

drugs and their metabolites.

D. Excretion
 Other routes of drug elimination:
 Lungs: for volatile substances
 Sweat: for volatile oils
 Bile and colon (for conjugated large molecular weight
drug or metabolite)
 Saliva, Tears, Milk

Excretion…
Renal drug excretion
 Involves glomerular filtration, tubular reabsorption and
tubular secretion
 The amount of drug excreted is the sum of the amounts
filtrated and secreted minus the amount reabsorbed

 If renal function is impaired (disease or old age) then
there is decrease in the elimination rate of drugs that

usually undergo renal excretion , e.g. streptomycin,
gentamicin.

Excretion…
Glomerular filtration:
 More common route of renal elimination
 Free drug is cleared by filtration but macromolecules like
heparin and drugs bound to plasma proteins can’t cross

the glomerulus
 Only 20% of the drugs delivered to the kidney are filtered
via the glomerulus

 Depends on:
 Molecular size
 Plasma protein binding
 Rate of blood flow

Excretion…
Glomerular filtration…
 Glomerular capillaries allow drug molecules of molecular
weight below about 20,000 D to diffuse into the

glomerular filtrate
 Most drugs cross the barrier freely
 However reabsorption occurs for some drugs/metabolites.

Excretion…
Passive tubular reabsorption/diffusion
 Only the non-ionized lipid soluble drugs are reabsorbed,
ionized drugs are excreted in urine.

 The rate /amount of passive diffusion depend on PH of
urine (since drug are weak base/acid).

 Reabsorption primarily occur in distal tubules and
collecting ducts where most of acidification take place, so

at urinary PH:
 Weak acidic drug ----↑reabsorption -----↓ elimination
 Weak basic drug ----↓reabsorption -----↑ elimination

Excretion…
 Effect of PH on urinary drug elimination have important
medical application.
 Toxicity management by facilitating excretion
 For weak acid drug toxication --- alkalinizing the
urine--bicarbonate administration.
 For weak base drug toxication---acidification of the
urine --- ammonium administration.

 Generally reabsorption of drug mainly take place by
passive diffusion, however there is active reabsorption
also.

Excretion…
Active tubular secretion
 By transport system located in the proximal tubular cell
 Important in drug excretion b/c charged and cations are
often strongly bound to plasma protein

 However since protein binding reversible, they excreted
by active secretory system.

Excretion…
Biliary excretion
 Many drugs are excreted in bile as the parent compound
or a drug metabolite.
 Biliary excretion favors compounds with Mol. Wt. > 300.
 A drug excreted in bile may be reabsorbed from the
gastrointestinal tract
 After the bile empties into the intestines, a fraction of
drug may be reabsorbed into the circulation & eventually

return into the liver.
 This phenomenon is called enterohepatic cycle

Excretion…
Enterohepatic recirculation
 The recirculation of highly conjugated drugs between the
liver-bile-and the GI
 Involves the release of free drug by the GI microflora and
free drug is reabsorbed back to the liver

 Produce long half-life
 Drugs undergoing EHR
 Morphine
 CAF
 Digoxin
 Rifampin

Excretion…
Enterohepatic recirculation…

Excretion…
Pulmonary excretion
 Any volatile material has the potential for pulmonary
excretion
 Volatile general anesthetics are excreted unchanged
through lungs
 Alcohol is partially excreted by lungs and impart its odor
to breath.

Excretion…
Sweat and Saliva excretion
 Excretion into sweat may be responsible for the skin
reactions caused by some therapeutic agents

 Excretion of drugs into saliva accounts for the drug taste
of certain compounds given by IV.

 Iodide and metallic salts are excreted into saliva.

Excretion…
Breast milk
 Is a quantitatively relatively minor route of drug excretion
 Nearly all the drugs taken by the mother are likely to be
founded in milk though not necessarily in the

concentration that can effect the infant.
 The baby will ingest drugs excreted in the breast milk.
 A number of drugs can reach clinically significant
concentrations in the breast milk and thereby affect

nursing babies

Excretion…
Skin drug excretion
 Arsenic and mercury are excreted in small quantities
through the skin.

Intestine drug excretion
 Purgatives which act mainly on the large bowl are
particularly excreted into that area from the blood stream

after their absorption from the small intestine.
 Heavy metals are also excreted through intestines and can
also produce intestinal ulceration.

Kinetics of Elimination
Clearance (Cl)
 Plasma clearance is the plasma volume which is totally
cleared of drug per unit of time

 Example: Cl = 2 L/min
 Plasma clearance measuring the overall ability of the
living organism to eliminate a drug.

 It is a volume of plasma cleared off the drug by
metabolism (liver) and excretion (renal) and other organs.

 Sum of all organs clearance
 Plasma Cl = Hepatic Cl + Renal Cl + other organs Cl

Kinetics of Elimination…
Plasma half-life
 Defined as time taken for the plasma concentration of a
drug to be reduced to half of its original value

or
 The time it takes for one half of the original amount of a
drug in the body to be removed

 Example: 4 mg of a drug is administered. Blood
concentration become 2mg (50%) after 10 minutes. So,

plasma half-life =10 minutes

 1st half life = 50%
 2nd half life = 75%
 3rd half life = 87.5
 4th half life = 93.75
 5th half life = 96.875… eliminated over five t½

Plasma half-life importance:
 Half life gives idea about the duration of action of a drug.
 It can guide the dosage schedules.
 Short Half life → Frequent administration
 Long half life→ Should be given once or twice daily

 The half-life of a drug is increased by:
 Diminished renal plasma flow or hepatic blood flow
for example heart failure or hemorrhage

 Decreased metabolism
 Example, when another drug inhibits its
biotransformation or in hepatic insufficiency, as with

cirrhosis.

 The half-life of a drug may decrease by:
 Increased hepatic blood flow.
 Decreased protein binding.
 Increased metabolism.

 Loading dose (LD)
 Is one or series of doses that may be given at the onset
of therapy with the aim of achieving the target

concentration rapidly.
 The drugs having long half life
 Chloroquine in Malaria – 600 mg Stat, 300mg after
8 hours, 300 mg after 2 days

 Maintenance dose (MD)
 Loading dose normally followed by maintenance dose.
 Needed to maintain the steady state plasma
concentration attained after giving the LD

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General Pharmacology

By Biruk S. (Bpharm., MSc. in Pharmacology)

drugs, Routes of drug administration

 Dosage and dosage regimen

 Factors modifying drug effects

 Adverse drug reactions

General Pharmacology By: Biruk S. 2

 Is the study of interaction of drugs with living

General Pharmacology By: Biruk S. 3

in biology and chemistry; then, physiology and

General Pharmacology By: Biruk S. 4

 Is any substance or product that is used or intended to be

used to modify or explore physiological system or

General Pharmacology By: Biruk S. 5

 Prevention: Vaccine, Contraceptives

 Suppression/Control: Insulin for DM, Anti-

edema, analgesic for pain

General Pharmacology By: Biruk S. 6

 All drugs are poisons

 “All substances are poisons; there is none that is not a

poison. The right dose differentiates a poison and a

General Pharmacology By: Biruk S. 7

 Chemically formulated form of a drug(s)

 May contain more than one drug

 Medicine = Drug(s) + Additives (excipients)

 Medicine = a compound with therapeutic value

 Drugs are formulated into medicines

General Pharmacology By: Biruk S. 8

General Pharmacology By: Biruk S. 9

patient care and outcomes

events are manifested in a measurable behavioral form

General Pharmacology By: Biruk S. 11

gives rise to differing response to drugs

any chemical substance in excess (including those

General Pharmacology By: Biruk S. 12

General Pharmacology By: Biruk S. 13

 E.g. Erythromycin has the following brand names (not

 Brand named drugs are usually more expensive

 Are confusing for use … are not promoted for prescription

General Pharmacology By: Biruk S. 14

 Designated by the WHO

 The difference b/n generic product and brand product

is only the additives but not active ingredient

General Pharmacology By: Biruk S. 15

 Digoxin from Digitalis lanta (Foxglove)

 Atropine from Atropa belladona (Nightshade)

 Insulin from sheep pancreas

 Anticoagulants from snake venom

 Gonadotropins from a woman’s urine (Menotropin)

 Iron sulfate, magnesium trisilicate

General Pharmacology By: Biruk S. 16

 Cephalosporins from cephalosporium

 Synthetic and semi-synthetic drugs

 Products of DNA recombination

General Pharmacology By: Biruk S. 17

 User appeal / Organoleptic effect

 Ease for packaging, labeling, transporting and storage

General Pharmacology By: Biruk S. 18

 Based on physical property

 Solid dosage forms: Tablets, capsules (powder filled),

powders, pessaries (vaginal tabs)

General Pharmacology By: Biruk S. 19

solutions, suspensions, inhalations, syrups