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College of Medicine & Health
Sciences
Pharmacology for Health
Sciences
1
Compiled by: Birhanu G.(B.Pharm)
July, 2015General Pharmacology Compiled by: Birhanu Geta
Birhanu G. ( B.Pharm)
Objectives
@ the end of this session students will be able to:
Define what Pharmacology is?
Define what meant by drugs?
Identify source of drugs.
Differentiate Pharmacokinetics and
Pharmacodynamics.
Explain principles of Pharmacokinetics and
Pharmacodynamics.
3General Pharmacology Compiled by: Birhanu Geta
4General Pharmacology Compiled by: Birhanu Geta
Derivation
Pharmacology =>
Pharmakon = Active Principle/Active
Ingredient or equivalent to drug, medicine or
poison &
Logia = study.
PHARMACOLOGY
means:
“THE SCIENCE OF DRUGS”
5General Pharmacology Compiled by: Birhanu Geta
DEFINITION
Pharmacology:
 Is the study of substances that interact with
living systems through chemical process,
especially by binding to regulatory molecules &
activating or inhibiting normal body process.
 Includes, history, source, properties,
compounding, biochemical and physiological
effects, PK and PD, therapeutic and other uses,
precautions, adverse effects, interactions and
contra-indications of drugs.
6General Pharmacology Compiled by: Birhanu Geta
 A French word ‘Drogue’ which means dry herb.
 Any substance that brings about a change in biologic
function through its chemical action.
 Alters state in the body:
=>can’t create new function but alter existing
function.
 Are poisons if they used irrationally.
 Poisons are drugs that have almost exclusively harmful
effects. However, Paracelsus famously stated that
"the dose makes the poison,"
 “Poisons in small doses are the best medicines; and
useful medicines in too large doses are poisonous.
“Every drug is a medicine but every medicine is not a drug!!!”
7General Pharmacology Compiled by: Birhanu Geta
Receptors
 Specialized target macromolecules present on
the cell surface or intracellularly.
 The biological molecule plays a regulatory role.
 Drugs bind with receptors & initiate events
leading to alterations in biochemical activity of a
cell, and consequently, the function of an organ.
 Some times, the drug may act through non-
specific physicochemical mechanisms.
– Osmotic properties (bulk laxatives, saline
purgatives, mannitol)
– Adsorbents (kaolin, charcoal)
8General Pharmacology Compiled by: Birhanu Geta
Basic Areas of Pharmacology
 Pharmacokinetics (Biodisposition of drugs)
 Pharmacodynamics
 Pharmacokinetics: deals with absorption, distribution,
biotransformation & excretion of drugs.
 Pharmacodynamics: study of biochemical &
physiological effects of drugs & their MOA.
 Pharmacotherapeutics: use of drugs in prevention &
treatment of disease.
 Chemotherapy: effect of drugs upon microorganisms,
parasites and neoplastic cells living & multiplying in living
organism.
 Toxicology: branch of pharmacology which deals with
the undesirable effects of chemicals on living systems.
 Pharmacogenomics: relationship of individual’s genetic
makeup to his/her response to specific drugs.
9General Pharmacology Compiled by: Birhanu Geta
History of Pharmacology
 Prehistoric people recognized beneficial & toxic
effects of many plant & animal materials.
 Preceding the modern era, there were attempts
to introduce rational methods into medicine.
 But none were successful owing to the
dominance of systems of thought [without
experimentation & observation].
 Around end of 17th century, reliance on
observation & experimentation began.
 About 60yrs ago, controlled clinical trial
reintroduced; expansion of research efforts;
 Drug action & receptor.
 Now, the molecular mechanism of action of many
drugs is known.
10General Pharmacology Compiled by: Birhanu Geta
Application of pharmacology
 To control speed of onset, intensity of the drug's
effect, and duration of action. Hence decide on
route of administration, the amount and frequency
of each dose, and the dosing intervals.
 To identify the possible side effect, and
withdrawal symptoms of drugs and take measures
to manage.
 To avoid adverse effects from drug interaction
and contraindicated drugs.
 To avoid adverse effects in special populations
like geriatrics, paediatrics, pregnant and lactating
mothers.
 To avoid treatment failure due to tolerance &
resistance.
 To control misuse of drugs by the patient & health
professionals.
11General Pharmacology Compiled by: Birhanu Geta
Drugs
 Drugs mostly interact with a specific molecule in
a biologic system that plays a regulatory role
[receptor].
 Clinically, drugs used for:
–Diagnosis: Barium salts,
–Prevention: Vaccines, chemoprophylaxis
–Treatment: ART
–Cure: Antibiotics
–Alteration of physiological processes:
Hormones & their derivatives (insulin, GH,
contraceptives….)
–Global effect: General anesthetics
12General Pharmacology Compiled by: Birhanu Geta
To interact chemically with its receptor, a
drug molecule must have the appropriate:
 Size (MW100-1000Dalton),
 For specificity of action, the ability to move
within the body (e.g., from the site of
administration to the site of action).
 Electrical charge (bonding), exception Xe.
 Shape (complementary to that of the receptor
site in the same way that a key is complementary
to a lock).
– Most of drugs are chiral molecules.
 Atomic composition.
13General Pharmacology Compiled by: Birhanu Geta
 A number of useful or dangerous drugs are
inorganic elements, e.g. lithium, iron, & heavy
metals.
 Many organic drugs are weak acids or bases.
– This fact has important implications for the
way they are handled by the body, because pH
differences in the various compartments of
the body may alter the degree of ionization of
such drugs.
14General Pharmacology Compiled by: Birhanu Geta
Source of Drugs
 Drugs are obtained from various sources.
 Drugs may be synthesized within the body
(hormones) or not. i.e. xenobiotics (from the
Greek xenos, meaning "stranger").
15General Pharmacology Compiled by: Birhanu Geta
 According to sources they are:-
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 pork/beef
. Cod liver oil from Cod fish liver.
C. Minerals: Iron, Iodine, Potassium salts.
D. Micro – organisms: Penicillin from penicillium
notatum, Chloramphenicol from Streptomyces
venezuelae (Actinomycetes).
General Pharmacology Compiled by: Birhanu Geta 16
2. Synthetic drugs: prepared by chemical
synthesis in pharmaceutical laboratories.
E.g. Sulphonamides, quinolones, barbiturates.
3. Semi-synthetic 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 (humulin), human GH.
17General Pharmacology Compiled by: Birhanu Geta
Drug Nomenclature
• Existence of many names for each drug causes
lamentable & confusing situation.
• A drug has at least three types of names;
 Chemical name (IUPAC) or scientific name,
 Based on molecular structure of the drug
 Very long, too complex to use in common practice.
 International Nonproprietary/generic name,
- Given by FDA/WHO while approved, the short hand
version of chemical name.
- Recommended in RX.
 Proprietary/trademark/Brand name,
- Given by the pharmaceutical company.
- Costly.
18General Pharmacology Compiled by: Birhanu Geta
Examples:
 2-acetoxybenzoic acid
 Aspirin
 Jusprin®
 Ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]
cyclohepta[1,2-b] pyridin-11-ylidene)-1-piperidine
carboxylate.
 Loratadine
 Claritin®
19General Pharmacology Compiled by: Birhanu Geta
DOSAGE FORMS (PREPARATIONS)
Dosage forms (DFs) are the means by which drug
molecules are delivered to sites of action within
the body.
The need for dosage forms:
1. Accurate dose.
2. Protection e.g. coated tablets, sealed ampules.
3. Protection from gastric juice.
4. Masking taste and odour.
5. Placement of drugs within body tissues.
6. Sustained release medication.
7. Controlled release medication.
8. Optimal drug action.
9. Insertion of drugs into body cavities (rectal,
vaginal)
10.Use of desired vehicle for insoluble drugs.
20General Pharmacology Compiled by: Birhanu Geta
Types of Dosage forms
According to route of administration:
Oral
Rectal
Vaginal
Parenteral
Inhaled
Topical
Ophthalmic
Otic
21General Pharmacology Compiled by: Birhanu Geta
Types of Dosage forms…
According to physical form of a drug;
1. Solid
a. Tablets – Conventional
- Chewable
- Sublingual
- Extended release
b. Capsules – Hard gelatin & Soft gelatin
c. Powders – Effervesent granules
- Insufflations
- Dentrifices
- Powder for injections
d. Suppositories
General Pharmacology Compiled by: Birhanu Geta 22
2. Liquid – Solutions, Suspensions, Emulsions
3. Semisolids – Ointments
- Creams
- Pastes
- Jellies
- Pessaries
4. Gases (pressurized) - aerosols
23General Pharmacology Compiled by: Birhanu Geta
 Orally (swallowed)
 Through Mucus Membranes
– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)
 Topical/Transdermal
(through skin)
 Rectally (suppository)
According to on set of action
Slow Absorption
General Pharmacology Compiled by: Birhanu Geta 24
Faster Absorption
 Parenterally (injection)
– Intravenous (IV)
– Intramuscular (IM)
– Subcutaneous (SC)
– Intradermal(ID)-15⁰
– Intraperitoneal (IP)
 Inhaled (through lungs)
90⁰ 45⁰
General Pharmacology Compiled by: Birhanu Geta 25
Medication Administration
– Right Medication
– Right Dosage
– Right Time
– Right Route
– Right Patient
– Right Documentation
26General Pharmacology Compiled by: Birhanu Geta
Routes of Drug administration
Is the path by which a drug, fluid, poison
or other substance is brought into contact
with the body.
27
General Pharmacology Compiled by: Birhanu Geta
Commonly Used Routes of Drug Administration
General Pharmacology Compiled by: BirhanuGeta 28
IV = intravenous;
IM = intramuscular;
SC = subcutaneous.
Factors governing choice of Route
General Pharmacology Compiled by: BirhanuGeta
29
 Drug characteristics
 Ease of administration
 Site of action
 Onset of action
 Duration of action
 Quantity of drug administered
 Liver and kidney diseases
General Pharmacology Compiled by: BirhanuGeta 30
Enteral Routes
 Enteral - drug placed directly in the GI tract:
–sublingual - placed under the tongue
–Oral - swallowing (p.o., per os)
–Rectal - absorption through the rectum
Oral Route
General Pharmacology Compiled by: BirhanuGeta 31
ADVANTAGES
 Safe
 Convenient
 Economical
 Usually good absorption
 Can be self
administered
DISADVANTAGES
 Slow absorption slow
action
 Irritable and unpalatable
drugs
 Un co-operative &
unconscious pts.
 Some drugs destroyed
 First-pass effect
Sublingual Route
General Pharmacology Compiled by: Birhanu Geta 32
ADVANTAGES
 Economical
 Quick termination
 First-pass avoided
 Drug absorption is quick
 Can be self administered
DISADVANTAGES
 Unpalatable & bitter drugs
 Irritation of oral mucosa
 Large quantities not given
 Few drugs are absorbed
Rectal Route
General Pharmacology Compiled by: BirhanuGeta 33
ADVANTAGES
Used in children
Little or no first pass effect
Used in vomiting/unconsciuos
Higher concentrations rapidly
achieved
DISADVANTAGES
Inconvenient
Absorption is slow and erratic
Irritation or inflammation of
rectal mucosa can occur
Vaginal Routes
 Drug may be administered locally in the vagina in
the form of pessaries.
E.g. Antifungal vaginal pessaries
General Pharmacology Compiled by: BirhanuGeta 34
First-pass Effect
 The first-pass effect is the term used for the
hepatic metabolism of a pharmacological agent
when it is absorbed from the gut and delivered to
the liver via the portal circulation.
 The greater the first-pass effect, the less the
agent will reach the systemic circulation when the
agent is administered orally.
General Pharmacology Compiled by: BirhanuGeta 35
First-pass Effect cont’d…
Magnitude of first pass hepatic effect:
 Extraction ratio (ER)
ER = CL liver/Q
 Where, Q is hepatic blood flow (usually about 90 L per
hour for 70 kg adult).
 Systemic drug bioavailability (F) may be
determined from the extent of absorption (f) &
the extraction ratio (ER),
F = f x (1-ER)
First-pass Effect cont’d…
General Pharmacology Compiled by: BirhanuGeta 36
Systemic Routes
General Pharmacology Compiled by: BirhanuGeta 37
Parenteral
First-pass
metabolism
can occur
with orally
administered
drugs.
Administration of drugs by the Parenteral
Route
General Pharmacology Compiled by: BirhanuGeta 38
Needle insertion for
parenteral drug:
A. Intradermal
injection @15⁰.
B. Subcutaneous
injection @45⁰.
C. Intramuscular
injection @90⁰.
D. Intravenous
injection
Intravascular (IV)
General Pharmacology Compiled by: BirhanuGeta 39
1. Absorption phase is bypassed (100% BA)
2. Precise, accurate and almost immediate onset of
action.
3. Large quantities can be given, fairly pain free
4. Greater risk of adverse effects
a. High concentration attained rapidly
b. Risk of embolism and cannot be recalled by
strategies such as emesis or by binding to
activated charcoal
5. IV is the most common parenteral route for
drugs that are not absorbed orally.
Intramuscular Route(IM)
General Pharmacology Compiled by: BirhanuGeta 40
Advantages
 Absorption reasonably
uniform
 Rapid onset of action for
drugs in aqueous solution.
 Mild irritants can be given
 Repository and slow release
preparations
 First pass avoided
 Gastric factors can be
avoided
Disadvantages
 Only up to 10ml drug given
 Local pain and abscess
 Expensive
 Infection
 Nerve damage
General Pharmacology Compiled by: BirhanuGeta 41
Subcutaneous route(SC)
1. Slow and constant absorption
2. Absorption is limited by blood flow, affected if
circulatory problems exist
3. Concurrent administration of vasoconstrictor will
slow absorption
Inhalation
1. Aerosols (gaseous & volatile agents)-lungs
2. Rapid onset of action due to rapid access to
circulation
A. Large surface area
B. Thin membranes separates alveoli from
circulation
C. High blood flow
General Pharmacology Compiled by: BirhanuGeta 42
General Pharmacology Compiled by: BirhanuGeta 43
Inhalation cont’d
Respiratory system. Except for IN, risk hypoxia.
 Intranasal (snorting) Snuff, cocaine may be partly oral via
post-nasal dripping. Fairly fast to brain, local damage to
septum. Some of the volatile gases also appear to cross
nasal membranes.
 Smoke (Solids in air suspension, vapors) absorbed across
lung alveoli: Nicotine, opium, THC, freebase and crack
cocaine, crystal meth.Particles or vapors dissolve in lung
fluids, then diffuse. Longer action than volatile gases.
Tissue damage from particles, tars, CO.
 Volatile gases: Some anaesthetics (nitrous oxide, ether).
 Lung-based transfer may get drug to brain in as little as
five seconds.
General Pharmacology Compiled by: BirhanuGeta 44
Topical
 Mucosal membranes (eye drops, nasal drops,
antiseptic, sunscreen, callous removal etc.)
 Skin
A. Dermal - rubbing in of oil or ointment (local
action)
B. Transdermal - absorption of drug through
skin (systemic action)
i. Stable blood levels
ii. No first pass metabolism
iii. Drug must be potent or patch
becomes to large
General Pharmacology Compiled by: BirhanuGeta 45
Routes of administration
Time of onset
 Intravenous 30-60 seconds
 Intraosseous 30-60 seconds
 Endotracheal 2-3 minutes
 Inhalation 2-3 minutes
 Sublingual 3-5 minutes
 Intramuscular 10-20 minutes
 Subcutaneous 15-30 minutes
 Rectal 5-30 minutes
 Ingestion 30-90 minutes
 Transdermal (topical) variable (minutes to hours)
General Pharmacology Compiled by: BirhanuGeta 46
Time-release preparations
 Oral - controlled-release, timed-release,
sustained-release
 Designed to produce slow, uniform
absorption for 8 hours or longer.
 Better compliance, maintain effect over
night, eliminate extreme peaks and troughs.
General Pharmacology Compiled by: BirhanuGeta 47
Time-release preparations
 Depot or reservoir preparations
Parental administration (except IV), may be
prolonged by using insoluble salts or
suspensions in non-aqueous vehicles.
Example: Implantable contraceptives.
The ROA is determined by:
 Physical characteristics of the drug,
 Speed which the drug is absorbed and/or released,
 The need to bypass hepatic metabolism and achieve
high conc. at particular sites
Important
Info
General Pharmacology Compiled by: BirhanuGeta 48
No single method of drug administration is ideal for all
drugs in all circumstances !!!!!!!!!!!!!!!
General Pharmacology Compiled by: BirhanuGeta 49
Pharmacokinetics (The life cycle of a Drug)
 Pharmacokinetics:
– Pharmakon: drug
– Kinesis: motion
 Action of body on drug/ how body handles drugs
 Pharmacokinetics: ADME
 Four pharmacokinetic properties determine the
onset, intensity & duration of drug action.
 Using knowledge of pharmacokinetic parameters;
clinicians can design optimal drug regimens;
including the route of administration, dose,
frequency & duration of treatment.
50General Pharmacology Compiled by: Birhanu Geta
Absorption
 Absorption is the process by which a drug enters
the bloodstream without being chemically altered
or
 The movement of a drug from its site of
application into the blood or lymphatic system
How drugs transfer form site of administration?
1. Filtration [aqueous diffusion]-passage of drugs
through aqueous pores.
Size should be less than size of pore
 Has to be water soluble.
E.g. Na+, glucose, caffeine.
51General Pharmacology Compiled by: Birhanu Geta
2. Diffusion: drugs supposed to pass membrane.
Drugs must be lipid soluble.
High partition coefficient  high absorption.
3. Carrier mediated absorption
a. Facilitated diffusion
- Passive but facilitated.
E.g. levodopa & amino acid into brain.
b. Active transport
- Use ATP & carrier proteins.
- Against the concentration gradient.
E.g. levodopa & methyldopa from the gut.
52General Pharmacology Compiled by: Birhanu Geta
4. Phagocytosis & pinocytosis
- Process by which large molecules are engulfed by
the cell membrane forming a vesicle & releases
them intracellularly.
E.g. protein, toxin
53General Pharmacology Compiled by: Birhanu Geta
Summary of transport across a membrane
54General Pharmacology Compiled by: Birhanu Geta
Drug absorption
• Transfer of a drug from its site of
administration to the bloodstream.
• The rate and efficiency of absorption depend on
the route of administration.
– For IV delivery, absorption is complete; that
is, the total dose of drug reaches the systemic
circulation.
– Drug delivery by other routes may result in
only partial absorption and, thus, lower
bioavailability.
55General Pharmacology Compiled by: Birhanu Geta
Factors affecting GI absorption
PH of media & pKa of the drug
Area of absorbing surface
Particle size of the drug
Formulation
Gut motility
GIT blood flow
Gastric secretion
Drug interaction
56General Pharmacology Compiled by: Birhanu Geta
 A drug must be in solution to be absorbed, since
most drugs are either weak acids or weak bases,
pH affects their solubility and hence absorption.
 Weak bases are absorbed more rapidly from the
intestine than stomach.
 Small intestine is the major absorption site
because:
–It has large surface area (microvilli
200M2)
–There is good blood supply (1L blood/min
compared to 150mL/min stomach)
–Permeability to drugs is greater
57General Pharmacology Compiled by: Birhanu Geta
Bioavailability (F)
• Fraction of administered drug that reaches the
systemic circulation in a chemically unchanged
form.
– Amount of drug available in the circulation/site
of action
– It is expressed in percentage
– It is 100% for drugs given IV.
• For example, if 100 mg of a drug is administered
orally and 70 mg of this drug are absorbed
unchanged, the bioavailability is 0.7 or 70%.
Factors affecting bioavailability
– Extent of absorption
– First pass effect
58General Pharmacology Compiled by: Birhanu Geta
59
Oral Dose
PlasmaConcentration
Time
Bioavailability (F)
General Pharmacology Compiled by: Birhanu Geta
Drug distribution
 Reversible movement of drug from bloodstream
to interstitium (extracellular fluid) and/or cells.
Factors affecting drug distribution
1. Plasma protein binding
– Albumin [acidic & hydrophobic drugs]
– -glycoprotein [basic drugs]
2. Tissue uptake of drugs/tissue binding
-Adipose tissue [DDT]
-Bone [TTC]
-Liver [chloroquine]
-Thyroid gland [iodine]
60General Pharmacology Compiled by: Birhanu Geta
3. Barriers –capillary permeability
 Blood brain barrier (BBB)
 Placental blood barrier (PBB)
 Cell membrane
4. Rate of blood flow
 Brain,
 Kidney, highly perfused
 Liver &
 Lung
5. Plasma concentration
61General Pharmacology Compiled by: Birhanu Geta
Drug metabolism
 Enzymatically mediated alteration in drug
structure.
 Transforms lipophilic drugs into more polar
readily excretable products.
 Liver - major site for drug metabolism, but
specific drugs may undergo biotransformation in
other tissues, such as the kidney and the
intestines.
 Note: Some agents are initially administered as
inactive compounds (pro-drugs) and must be
metabolized to their active forms.
62General Pharmacology Compiled by: Birhanu Geta
Inducers
 The cytochrome P450 enzymes are an important
target for pharmacokinetic drug interactions.
 Certain drugs, most notably phenobarbital,
rifampin, and carbamazepine, are capable of
increasing the synthesis of one or more CYP
isozymes.
 This results in increased biotransformations of
drugs.
1. Decreased plasma drug concentrations.
2. Decreased drug activity if metabolite is
inactive.
3. Increased drug activity if metabolite is
active.
4. Decreased therapeutic drug effect. 63General Pharmacology Compiled by: Birhanu Geta
Inhibitors
 Inhibition of CYP isozyme activity is also an
important source of drug interactions that leads to
serious adverse effects.
 The most common form of inhibition is through
competition for the same isozyme.
 For example, omeprazole is a potent inhibitor of
three of the CYP isozymes responsible for
warfarin metabolism.
 If the two drugs are taken together, plasma
concentrations of warfarin increase, which leads to
greater inhibition of coagulation and risk of
hemorrhage and other serious bleeding reactions.
 CYP inhibitors are erythromycin, cimetidine,
ketoconazole, and ritonavir, because they each
inhibit several CYP isozymes. 64General Pharmacology Compiled by: Birhanu Geta
Inhibition of drug metabolism may lead to;
- Increased plasma levels over time with long-term
medications.
- Prolonged pharmacological drug effect.
- Increased drug-induced toxicities.
Microsomal enzyme inducers
Phenobarbitone
Phenytoin
Rifampicin
Carbamazepine
Sulphonamides
St. John’s Wort
Cigarette smoking
Microsomal enzyme inhibitors
 Isoniazid
 Disulfiram
 Cimetidine
 Allopurinol
 Chloramphenicol
 Erythromycin
 Metronidazole
 Grape fruit juice
65General Pharmacology Compiled by: Birhanu Geta
First-Pass Effect: significant metabolic
inactivation of some drugs by the liver following
oral administration.
- Drugs absorbed from the GI tract enter the
portal circulation and are carried to the liver
before entering the systemic circulation.
66General Pharmacology Compiled by: Birhanu Geta
Drug excretion
 Removal of a drug from the body occurs via a
number of routes.
 The major routes of excretion include renal
excretion, hepatobiliary excretion & pulmonary
excretion.
 The minor routes of excretion are saliva, sweat,
tears, breast milk, vaginal fluid & hair.
 The rate of excretion influences the duration of
action of drugs.
 If the drug is excreted slowly, the concentration
of drug in the body is maintained and the effects
of the drug will continue for longer period.
67General Pharmacology Compiled by: Birhanu Geta
Routes of drug excretion
a. Renal excretion
 For water soluble and non volatile drugs.
 The three principal processes that determine the
urinary excretion of a drug.
– Glomerular filtration
– Active tubular secretion
– Passive tubular reabsorption
 The function of glumerular filtration and active
tubular secretion is to remove drug out of the
body, while tubular reabsorption retain the drug.
68General Pharmacology Compiled by: Birhanu Geta
b. Hepatobiliary Excretion
 The conjugated drugs are excreted by
hepatocytes in the liver.
 After excretion of drugs through bile to the
intestine; certain amount of drug is reabsorbed
in to the portal vein leading to an entrohepatic
cycling which can prolong the action of drug.
 E.g. Chloramphenicol, estrogen.
69General Pharmacology Compiled by: Birhanu Geta
c. Gastro intestinal excretion
 When a drug is administered orally, part of the
drug is not absorbed and excreted in the faeces.
 The drug which do not undergo enterohepatic
cycling after excretion in to the bile are
subsequently passed with stool.
 E.g. Aluminum hydroxide changes the stool
color in to white, Ferrous sulphate darkens it
and Rifampicine gives orange red colour to the
stool.
70General Pharmacology Compiled by: Birhanu Geta
d. Pulmonary excretion
 Many inhalation anesthetics and alcohol are
excreted through the lungs.
e. Sweat
 E.g. Rifampcine, metalloids like arsenic are
excreted in to the sweat.
71General Pharmacology Compiled by: Birhanu Geta
f. Mammary excretion
 Many drugs are excreted in to breast milk.
 Lactating mothers should be cautious about the
intake of these drugs because they may enter in
to baby through milk and produce harmful
effects in the baby.
 E.g. Ampicillin, Aspirin, Chlorodizepoxide,
Streptomycin.
72General Pharmacology Compiled by: Birhanu Geta
Pharmacodynamics
Pharmacodynamics include:
 Mechanism of actions of the drug.
How does a drug act in the body?
 Effects of the drug: both beneficial &
harmful effects.
What does a drug do in the body
73General Pharmacology Compiled by: Birhanu Geta
Pharmacodynamics…
Mechanisms of drug action
 It is of two types:
A. Receptor mediated mechanism
Receptors- targets of drug action.
May present either on the cell surface or
inside the cell.
D + R → DR → Biological effect
Where; D=Drug, R=Receptor, DR=Drug Receptor Complex
B. Non-receptor mechanisms
 Simple physical or chemical reaction.
 E.g. Antacids: neutralization reaction.
74General Pharmacology Compiled by: Birhanu Geta
Types of Receptors
 Regulatory proteins
 For endogenous regulatory ligands – particularly
hormones, growth factors, and neurotransmitters.
 E.g. Insulin receptors-insulin
 Enzymes
 Receptors that are inhibited by binding with a drug.
 E.g. Cyclooxygenase – Aspirin
 Transport proteins: Na+/K+ ATPase- Digoxin
 Structural proteins: Tubulin- colchicine
 Genetic materials: Rifampcin- RNA polymerase
 Ion channels: Na, Ca, K, channel blockers.
75General Pharmacology Compiled by: Birhanu Geta
Models of D-R interaction…
 Lock & key
 Drug acts as key, receptor as lock, combination
yields response.
 Induced-fit models
 Dynamic & flexible interaction.
76General Pharmacology Compiled by: Birhanu Geta
Implications of drug-receptor interaction
 Drugs can potentially alter rate of any function
in the body.
 Drugs cannot impart entirely new functions to
cells.
 Drugs do not create effects, only modify
ongoing ones.
 Drugs can allow for effects outside of normal
physiological range.
77General Pharmacology Compiled by: Birhanu Geta
Three aspects of drug receptor function
1. Receptors determine the quantitative
relation between drug concentration and
response.
 This is based on receptor’s affinity to bind
and it’s abundance in target cells.
2. Receptors (as complex molecules) function
as regulatory proteins and components of
chemical signaling mechanisms that
provide targets for important drugs.
3. Receptors determine the therapeutic and
toxic effects of drugs in patients.
78General Pharmacology Compiled by: Birhanu Geta
Dose response relationship
 Dose: amount of a drug required to produce
desired response in an individual.
 Dosage: the amount, frequency and duration
of therapy.
 Potency: measure of how much a drug is
required to elicit a given response. The lower
the dose, the more potent is the drug.
 Efficacy: the intrinsic ability of the drug to
produce an effect at the receptor.
 Maximal efficacy: largest effect that a drug
can produce. 79General Pharmacology Compiled by: Birhanu Geta
Dose response relationship...
Drug response depends on:
 Affinity of drug for receptor.
 Intrinsic activity (degree to which a drug is
able to induce intrinsic effects).
80General Pharmacology Compiled by: Birhanu Geta
Agonism and Antagonism
 Agonists facilitate
receptor response.
 Antagonists inhibit
receptor response.
81
(Direct Ant/agonists)
General Pharmacology Compiled by: Birhanu Geta
Types of drug-receptor interactions
 Agonist drugs: bind to and activate the receptor
which directly or indirectly brings about the
effect.
 Some agonists inhibit their binding molecules
to terminate the action of endogenous
agonists.
 E.g. slowing the destruction of endogenous
acetylcholine by using acetyl cholinesterase
inhibitors.
 Antagonist drugs: bind to a receptor to prevent
binding of other molecules, but lack intrinsic
activity.
 E.g. Atropine decrease acetylcholine effects.82General Pharmacology Compiled by: Birhanu Geta
Types of drug-receptor interactions…
 Partial agonist drugs: acts as agonist or
antagonist depending on the circumstance, have
affinity but have lowered maximal efficacy.
 E.g. Pindolol can act as an antagonist if a “full
agonist” like Isoproterenol is present.
 Inverse agonist: is a ligand which produces an
effect opposite to that of the agonist by
occupying the same receptor.
 E.g. metoprolol in some tissues.
83General Pharmacology Compiled by: Birhanu Geta
 Full agonist- A drug with high positive efficacy & produce the
system maximal response.
 Partial agonist- maximal response to the ligand is below the system
maximal response.
 Antagonists- no efficacy or such a low level of efficacy with no
visible response.
 Inverse agonist- A ligand with negative efficacy can reduce the
basal response. 84General Pharmacology Compiled by: Birhanu Geta
Graded dose–response relations
 As the concentration of a drug increases, its
pharmacologic effect also gradually increases
until all the receptors are occupied (the
maximum effect).
 It is used to determine affinity, potency,
efficacy and characteristics of antagonists.
General Pharmacology Compiled by: Birhanu Geta 85
Potency
 Is relative strength of response for a given dose.
 Effective concentration (EC50) is the concentration of an
agonist needed to elicit half of the maximum biological
response of the agonist.
 The potency of an agonist is inversely related to
its EC50 value.
 D-R curve shifts left with greater potency.
86General Pharmacology Compiled by: Birhanu Geta
Efficacy
 Maximum possible effect
relative to other agents.
 Indicated by peak of D-R
curve.
 Full agonist = 100%
 Partial agonist = 50%
 Antagonist = 0%
 Inverse agonist = -100%
87General Pharmacology Compiled by: Birhanu Geta
Quantal(cumulative) dose response r/ship:
 Is between the dose of the drug and the
proportion of a population that responds to it.
 For any individual, the effect either occurs or it
does not (‘all’ or ‘none’).
 Are useful for determining doses to which most
of the population responds; ED50%, TD50%,
LD50%, TI(r/ship b/n dose & toxicity) & inter
subject variability in drug responses.
 They do not predict idiosyncratic reactions and
hypersensitivity.
General Pharmacology Compiled by: Birhanu Geta 88
Therapeutic index
 Median Lethal Dose (LD50): dose which would
be expected to kill one half of a study
population.
 Median Effective Dose (ED50): dose which
produces a desired response in 50% of the
test population.
 Therapeutic Index: gives a rough idea about the
potential effectiveness and safety of the drug in humans.
Therapeutic Index (TI) = LD50/ED50
The smaller the TI, the less safer the drug is.
 Margin of safety=LD1/ED99.
89General Pharmacology Compiled by: Birhanu Geta
Therapeutic Index…
ED50 LD50
90General Pharmacology Compiled by: Birhanu Geta
Factors modifying the dosage & action of drugs
1. Age
2. Sex
3. Body weight
4. Genetics
5. Drug tolerance
6. Drug intolerance
7. Disease states
91General Pharmacology Compiled by: Birhanu Geta
Drug- Drug interactions
Consequences of Drug- Drug Interactions
1. Intensification of effects: increased therapeutic
or adverse effects.
Additive Drug Effects (Summation): 1 + 1 = 2.
 Most frequently seen when two drugs possess similar intrinsic
activity.
E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol,
benzodiazepines (diazepam, etc.) administered in combination
will produce additive effects resulting in over-sedation.
Synergism - the effect of two drugs in combination is greater
than the sum of the drugs administered alone (1 + 1 > 2).
E.g. Aminoglycosides with penicillins.
Potentiation – one substance alone does not have effect
but when added to another chemical, it becomes
effective. (1 + 0 > 1).
92General Pharmacology Compiled by: Birhanu Geta
2. Reduction of effects – inhibit drug effects;
Either beneficial or detrimental.
Antagonism: it occurs when the effect of one drug
is diminished by another drug.(1+1<1).
Types of antagonism;
 Chemical antagonism or inactivation
 Physiological (functional) antagonism
 Pharmacologic or Receptor antagonism
 Pharmacokinetic/Dispositional antagonism
93General Pharmacology Compiled by: Birhanu Geta
Basic mechanisms of Drug- Drug interactions
 Direct chemical or physical interaction - can occur
with drugs mixed together.
 Pharmacokinetic interaction – can alter all four
processes.
 Absorption – increase or decrease (e.g., PH, laxative,
changes in blood flow).
 Distribution – competition for protein binding or changes in
extra cellular PH.
 Metabolism - induction of drug metabolizing enzymes,
inhibition of metabolizing, and competition of metabolism.
 Excretion - altered renal excretion (e.g. filtration,
reabsorption, and secretion).
 Pharmacodynamic interaction
 Interactions at same receptor – almost always
inhibitory.
 Interactions resulting from actions at separate sites
(if drugs influence same physiologic process).
94General Pharmacology Compiled by: Birhanu Geta
Drug- Food interactions
 Impact of Food on Drug Absorption
– Decreasing rate and/or extent of absorption
– Some foods can increase extent of drug
absorption.
 Impact of Food on Drug metabolism
– The grapefruit juice effect (can inhibit
metabolism of certain drugs  increased drug
levels).
 Impact of Food on Drug Toxicity
– MAOIs with tyramine
– Caffeine with theophylline
 Impact of Food on Drug Action
– Vitamin K with warfarin. 95General Pharmacology Compiled by: Birhanu Geta
Adverse drug reactions (ADRs)
 Any undesired response to a drug.
 Can range in intensity from annoying to life
threatening.
Types of adverse drug reactions
 Side Effects: unavoidable secondary drug effect
produced at therapeutic drugs doses.
E.g. 1. Drowsiness that often accompanies the use of
antihistamines
2. Gastric bleeding that can be produced by low
therapeutic doses of aspirin.
 Toxicities: an adverse drug reaction caused by
excessive levels of drug.
E.g. Coma caused by overdose with morphine.
 Allergic reactions:
– Prior sensitization of the immune system.
– Re- exposure to that drug can bring on an allergic response.
E.g. Penicillin allergy
96General Pharmacology Compiled by: Birhanu Geta
ADRs...
 Idiosyncratic effects: an unusual drug response
resulting from a genetic predisposition.
 Physical dependence: a state in which the body
has adapted to prolonged drug exposure in such a way
that if drug use is discontinued abstinence syndrome
will result.
 Develop during long-term use of certain drugs (e.g. Opoids,
barbiturates etc)
 Carcinogenic effects: ability of certain
mediations /chemicals to cause cancer.
Although a number of carcinogenic compounds have
been identified, very few of these are employed
therapeutically.
 Teratogenic Effects: drug- induced birth defect.
97General Pharmacology Compiled by: Birhanu Geta
Any???
10Q!!!
98General Pharmacology Compiled by: Birhanu Geta

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Chapter 1 general pharmacology

  • 1. College of Medicine & Health Sciences Pharmacology for Health Sciences 1 Compiled by: Birhanu G.(B.Pharm) July, 2015General Pharmacology Compiled by: Birhanu Geta
  • 2. Birhanu G. ( B.Pharm)
  • 3. Objectives @ the end of this session students will be able to: Define what Pharmacology is? Define what meant by drugs? Identify source of drugs. Differentiate Pharmacokinetics and Pharmacodynamics. Explain principles of Pharmacokinetics and Pharmacodynamics. 3General Pharmacology Compiled by: Birhanu Geta
  • 5. Derivation Pharmacology => Pharmakon = Active Principle/Active Ingredient or equivalent to drug, medicine or poison & Logia = study. PHARMACOLOGY means: “THE SCIENCE OF DRUGS” 5General Pharmacology Compiled by: Birhanu Geta
  • 6. DEFINITION Pharmacology:  Is the study of substances that interact with living systems through chemical process, especially by binding to regulatory molecules & activating or inhibiting normal body process.  Includes, history, source, properties, compounding, biochemical and physiological effects, PK and PD, therapeutic and other uses, precautions, adverse effects, interactions and contra-indications of drugs. 6General Pharmacology Compiled by: Birhanu Geta
  • 7.  A French word ‘Drogue’ which means dry herb.  Any substance that brings about a change in biologic function through its chemical action.  Alters state in the body: =>can’t create new function but alter existing function.  Are poisons if they used irrationally.  Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus famously stated that "the dose makes the poison,"  “Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous. “Every drug is a medicine but every medicine is not a drug!!!” 7General Pharmacology Compiled by: Birhanu Geta
  • 8. Receptors  Specialized target macromolecules present on the cell surface or intracellularly.  The biological molecule plays a regulatory role.  Drugs bind with receptors & initiate events leading to alterations in biochemical activity of a cell, and consequently, the function of an organ.  Some times, the drug may act through non- specific physicochemical mechanisms. – Osmotic properties (bulk laxatives, saline purgatives, mannitol) – Adsorbents (kaolin, charcoal) 8General Pharmacology Compiled by: Birhanu Geta
  • 9. Basic Areas of Pharmacology  Pharmacokinetics (Biodisposition of drugs)  Pharmacodynamics  Pharmacokinetics: deals with absorption, distribution, biotransformation & excretion of drugs.  Pharmacodynamics: study of biochemical & physiological effects of drugs & their MOA.  Pharmacotherapeutics: use of drugs in prevention & treatment of disease.  Chemotherapy: effect of drugs upon microorganisms, parasites and neoplastic cells living & multiplying in living organism.  Toxicology: branch of pharmacology which deals with the undesirable effects of chemicals on living systems.  Pharmacogenomics: relationship of individual’s genetic makeup to his/her response to specific drugs. 9General Pharmacology Compiled by: Birhanu Geta
  • 10. History of Pharmacology  Prehistoric people recognized beneficial & toxic effects of many plant & animal materials.  Preceding the modern era, there were attempts to introduce rational methods into medicine.  But none were successful owing to the dominance of systems of thought [without experimentation & observation].  Around end of 17th century, reliance on observation & experimentation began.  About 60yrs ago, controlled clinical trial reintroduced; expansion of research efforts;  Drug action & receptor.  Now, the molecular mechanism of action of many drugs is known. 10General Pharmacology Compiled by: Birhanu Geta
  • 11. Application of pharmacology  To control speed of onset, intensity of the drug's effect, and duration of action. Hence decide on route of administration, the amount and frequency of each dose, and the dosing intervals.  To identify the possible side effect, and withdrawal symptoms of drugs and take measures to manage.  To avoid adverse effects from drug interaction and contraindicated drugs.  To avoid adverse effects in special populations like geriatrics, paediatrics, pregnant and lactating mothers.  To avoid treatment failure due to tolerance & resistance.  To control misuse of drugs by the patient & health professionals. 11General Pharmacology Compiled by: Birhanu Geta
  • 12. Drugs  Drugs mostly interact with a specific molecule in a biologic system that plays a regulatory role [receptor].  Clinically, drugs used for: –Diagnosis: Barium salts, –Prevention: Vaccines, chemoprophylaxis –Treatment: ART –Cure: Antibiotics –Alteration of physiological processes: Hormones & their derivatives (insulin, GH, contraceptives….) –Global effect: General anesthetics 12General Pharmacology Compiled by: Birhanu Geta
  • 13. To interact chemically with its receptor, a drug molecule must have the appropriate:  Size (MW100-1000Dalton),  For specificity of action, the ability to move within the body (e.g., from the site of administration to the site of action).  Electrical charge (bonding), exception Xe.  Shape (complementary to that of the receptor site in the same way that a key is complementary to a lock). – Most of drugs are chiral molecules.  Atomic composition. 13General Pharmacology Compiled by: Birhanu Geta
  • 14.  A number of useful or dangerous drugs are inorganic elements, e.g. lithium, iron, & heavy metals.  Many organic drugs are weak acids or bases. – This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs. 14General Pharmacology Compiled by: Birhanu Geta
  • 15. Source of Drugs  Drugs are obtained from various sources.  Drugs may be synthesized within the body (hormones) or not. i.e. xenobiotics (from the Greek xenos, meaning "stranger"). 15General Pharmacology Compiled by: Birhanu Geta
  • 16.  According to sources they are:- 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 pork/beef . Cod liver oil from Cod fish liver. C. Minerals: Iron, Iodine, Potassium salts. D. Micro – organisms: Penicillin from penicillium notatum, Chloramphenicol from Streptomyces venezuelae (Actinomycetes). General Pharmacology Compiled by: Birhanu Geta 16
  • 17. 2. Synthetic drugs: prepared by chemical synthesis in pharmaceutical laboratories. E.g. Sulphonamides, quinolones, barbiturates. 3. Semi-synthetic 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 (humulin), human GH. 17General Pharmacology Compiled by: Birhanu Geta
  • 18. Drug Nomenclature • Existence of many names for each drug causes lamentable & confusing situation. • A drug has at least three types of names;  Chemical name (IUPAC) or scientific name,  Based on molecular structure of the drug  Very long, too complex to use in common practice.  International Nonproprietary/generic name, - Given by FDA/WHO while approved, the short hand version of chemical name. - Recommended in RX.  Proprietary/trademark/Brand name, - Given by the pharmaceutical company. - Costly. 18General Pharmacology Compiled by: Birhanu Geta
  • 19. Examples:  2-acetoxybenzoic acid  Aspirin  Jusprin®  Ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6] cyclohepta[1,2-b] pyridin-11-ylidene)-1-piperidine carboxylate.  Loratadine  Claritin® 19General Pharmacology Compiled by: Birhanu Geta
  • 20. DOSAGE FORMS (PREPARATIONS) Dosage forms (DFs) are the means by which drug molecules are delivered to sites of action within the body. The need for dosage forms: 1. Accurate dose. 2. Protection e.g. coated tablets, sealed ampules. 3. Protection from gastric juice. 4. Masking taste and odour. 5. Placement of drugs within body tissues. 6. Sustained release medication. 7. Controlled release medication. 8. Optimal drug action. 9. Insertion of drugs into body cavities (rectal, vaginal) 10.Use of desired vehicle for insoluble drugs. 20General Pharmacology Compiled by: Birhanu Geta
  • 21. Types of Dosage forms According to route of administration: Oral Rectal Vaginal Parenteral Inhaled Topical Ophthalmic Otic 21General Pharmacology Compiled by: Birhanu Geta
  • 22. Types of Dosage forms… According to physical form of a drug; 1. Solid a. Tablets – Conventional - Chewable - Sublingual - Extended release b. Capsules – Hard gelatin & Soft gelatin c. Powders – Effervesent granules - Insufflations - Dentrifices - Powder for injections d. Suppositories General Pharmacology Compiled by: Birhanu Geta 22
  • 23. 2. Liquid – Solutions, Suspensions, Emulsions 3. Semisolids – Ointments - Creams - Pastes - Jellies - Pessaries 4. Gases (pressurized) - aerosols 23General Pharmacology Compiled by: Birhanu Geta
  • 24.  Orally (swallowed)  Through Mucus Membranes – Oral Mucosa (e.g. sublingual) – Nasal Mucosa (e.g. insufflated)  Topical/Transdermal (through skin)  Rectally (suppository) According to on set of action Slow Absorption General Pharmacology Compiled by: Birhanu Geta 24
  • 25. Faster Absorption  Parenterally (injection) – Intravenous (IV) – Intramuscular (IM) – Subcutaneous (SC) – Intradermal(ID)-15⁰ – Intraperitoneal (IP)  Inhaled (through lungs) 90⁰ 45⁰ General Pharmacology Compiled by: Birhanu Geta 25
  • 26. Medication Administration – Right Medication – Right Dosage – Right Time – Right Route – Right Patient – Right Documentation 26General Pharmacology Compiled by: Birhanu Geta
  • 27. Routes of Drug administration Is the path by which a drug, fluid, poison or other substance is brought into contact with the body. 27 General Pharmacology Compiled by: Birhanu Geta
  • 28. Commonly Used Routes of Drug Administration General Pharmacology Compiled by: BirhanuGeta 28 IV = intravenous; IM = intramuscular; SC = subcutaneous.
  • 29. Factors governing choice of Route General Pharmacology Compiled by: BirhanuGeta 29  Drug characteristics  Ease of administration  Site of action  Onset of action  Duration of action  Quantity of drug administered  Liver and kidney diseases
  • 30. General Pharmacology Compiled by: BirhanuGeta 30 Enteral Routes  Enteral - drug placed directly in the GI tract: –sublingual - placed under the tongue –Oral - swallowing (p.o., per os) –Rectal - absorption through the rectum
  • 31. Oral Route General Pharmacology Compiled by: BirhanuGeta 31 ADVANTAGES  Safe  Convenient  Economical  Usually good absorption  Can be self administered DISADVANTAGES  Slow absorption slow action  Irritable and unpalatable drugs  Un co-operative & unconscious pts.  Some drugs destroyed  First-pass effect
  • 32. Sublingual Route General Pharmacology Compiled by: Birhanu Geta 32 ADVANTAGES  Economical  Quick termination  First-pass avoided  Drug absorption is quick  Can be self administered DISADVANTAGES  Unpalatable & bitter drugs  Irritation of oral mucosa  Large quantities not given  Few drugs are absorbed
  • 33. Rectal Route General Pharmacology Compiled by: BirhanuGeta 33 ADVANTAGES Used in children Little or no first pass effect Used in vomiting/unconsciuos Higher concentrations rapidly achieved DISADVANTAGES Inconvenient Absorption is slow and erratic Irritation or inflammation of rectal mucosa can occur Vaginal Routes  Drug may be administered locally in the vagina in the form of pessaries. E.g. Antifungal vaginal pessaries
  • 34. General Pharmacology Compiled by: BirhanuGeta 34 First-pass Effect  The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation.  The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally.
  • 35. General Pharmacology Compiled by: BirhanuGeta 35 First-pass Effect cont’d… Magnitude of first pass hepatic effect:  Extraction ratio (ER) ER = CL liver/Q  Where, Q is hepatic blood flow (usually about 90 L per hour for 70 kg adult).  Systemic drug bioavailability (F) may be determined from the extent of absorption (f) & the extraction ratio (ER), F = f x (1-ER)
  • 36. First-pass Effect cont’d… General Pharmacology Compiled by: BirhanuGeta 36
  • 37. Systemic Routes General Pharmacology Compiled by: BirhanuGeta 37 Parenteral First-pass metabolism can occur with orally administered drugs.
  • 38. Administration of drugs by the Parenteral Route General Pharmacology Compiled by: BirhanuGeta 38 Needle insertion for parenteral drug: A. Intradermal injection @15⁰. B. Subcutaneous injection @45⁰. C. Intramuscular injection @90⁰. D. Intravenous injection
  • 39. Intravascular (IV) General Pharmacology Compiled by: BirhanuGeta 39 1. Absorption phase is bypassed (100% BA) 2. Precise, accurate and almost immediate onset of action. 3. Large quantities can be given, fairly pain free 4. Greater risk of adverse effects a. High concentration attained rapidly b. Risk of embolism and cannot be recalled by strategies such as emesis or by binding to activated charcoal 5. IV is the most common parenteral route for drugs that are not absorbed orally.
  • 40. Intramuscular Route(IM) General Pharmacology Compiled by: BirhanuGeta 40 Advantages  Absorption reasonably uniform  Rapid onset of action for drugs in aqueous solution.  Mild irritants can be given  Repository and slow release preparations  First pass avoided  Gastric factors can be avoided Disadvantages  Only up to 10ml drug given  Local pain and abscess  Expensive  Infection  Nerve damage
  • 41. General Pharmacology Compiled by: BirhanuGeta 41 Subcutaneous route(SC) 1. Slow and constant absorption 2. Absorption is limited by blood flow, affected if circulatory problems exist 3. Concurrent administration of vasoconstrictor will slow absorption
  • 42. Inhalation 1. Aerosols (gaseous & volatile agents)-lungs 2. Rapid onset of action due to rapid access to circulation A. Large surface area B. Thin membranes separates alveoli from circulation C. High blood flow General Pharmacology Compiled by: BirhanuGeta 42
  • 43. General Pharmacology Compiled by: BirhanuGeta 43 Inhalation cont’d Respiratory system. Except for IN, risk hypoxia.  Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes.  Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO.  Volatile gases: Some anaesthetics (nitrous oxide, ether).  Lung-based transfer may get drug to brain in as little as five seconds.
  • 44. General Pharmacology Compiled by: BirhanuGeta 44 Topical  Mucosal membranes (eye drops, nasal drops, antiseptic, sunscreen, callous removal etc.)  Skin A. Dermal - rubbing in of oil or ointment (local action) B. Transdermal - absorption of drug through skin (systemic action) i. Stable blood levels ii. No first pass metabolism iii. Drug must be potent or patch becomes to large
  • 45. General Pharmacology Compiled by: BirhanuGeta 45 Routes of administration Time of onset  Intravenous 30-60 seconds  Intraosseous 30-60 seconds  Endotracheal 2-3 minutes  Inhalation 2-3 minutes  Sublingual 3-5 minutes  Intramuscular 10-20 minutes  Subcutaneous 15-30 minutes  Rectal 5-30 minutes  Ingestion 30-90 minutes  Transdermal (topical) variable (minutes to hours)
  • 46. General Pharmacology Compiled by: BirhanuGeta 46 Time-release preparations  Oral - controlled-release, timed-release, sustained-release  Designed to produce slow, uniform absorption for 8 hours or longer.  Better compliance, maintain effect over night, eliminate extreme peaks and troughs.
  • 47. General Pharmacology Compiled by: BirhanuGeta 47 Time-release preparations  Depot or reservoir preparations Parental administration (except IV), may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles. Example: Implantable contraceptives.
  • 48. The ROA is determined by:  Physical characteristics of the drug,  Speed which the drug is absorbed and/or released,  The need to bypass hepatic metabolism and achieve high conc. at particular sites Important Info General Pharmacology Compiled by: BirhanuGeta 48
  • 49. No single method of drug administration is ideal for all drugs in all circumstances !!!!!!!!!!!!!!! General Pharmacology Compiled by: BirhanuGeta 49
  • 50. Pharmacokinetics (The life cycle of a Drug)  Pharmacokinetics: – Pharmakon: drug – Kinesis: motion  Action of body on drug/ how body handles drugs  Pharmacokinetics: ADME  Four pharmacokinetic properties determine the onset, intensity & duration of drug action.  Using knowledge of pharmacokinetic parameters; clinicians can design optimal drug regimens; including the route of administration, dose, frequency & duration of treatment. 50General Pharmacology Compiled by: Birhanu Geta
  • 51. Absorption  Absorption is the process by which a drug enters the bloodstream without being chemically altered or  The movement of a drug from its site of application into the blood or lymphatic system How drugs transfer form site of administration? 1. Filtration [aqueous diffusion]-passage of drugs through aqueous pores. Size should be less than size of pore  Has to be water soluble. E.g. Na+, glucose, caffeine. 51General Pharmacology Compiled by: Birhanu Geta
  • 52. 2. Diffusion: drugs supposed to pass membrane. Drugs must be lipid soluble. High partition coefficient  high absorption. 3. Carrier mediated absorption a. Facilitated diffusion - Passive but facilitated. E.g. levodopa & amino acid into brain. b. Active transport - Use ATP & carrier proteins. - Against the concentration gradient. E.g. levodopa & methyldopa from the gut. 52General Pharmacology Compiled by: Birhanu Geta
  • 53. 4. Phagocytosis & pinocytosis - Process by which large molecules are engulfed by the cell membrane forming a vesicle & releases them intracellularly. E.g. protein, toxin 53General Pharmacology Compiled by: Birhanu Geta
  • 54. Summary of transport across a membrane 54General Pharmacology Compiled by: Birhanu Geta
  • 55. Drug absorption • Transfer of a drug from its site of administration to the bloodstream. • The rate and efficiency of absorption depend on the route of administration. – For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. – Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. 55General Pharmacology Compiled by: Birhanu Geta
  • 56. Factors affecting GI absorption PH of media & pKa of the drug Area of absorbing surface Particle size of the drug Formulation Gut motility GIT blood flow Gastric secretion Drug interaction 56General Pharmacology Compiled by: Birhanu Geta
  • 57.  A drug must be in solution to be absorbed, since most drugs are either weak acids or weak bases, pH affects their solubility and hence absorption.  Weak bases are absorbed more rapidly from the intestine than stomach.  Small intestine is the major absorption site because: –It has large surface area (microvilli 200M2) –There is good blood supply (1L blood/min compared to 150mL/min stomach) –Permeability to drugs is greater 57General Pharmacology Compiled by: Birhanu Geta
  • 58. Bioavailability (F) • Fraction of administered drug that reaches the systemic circulation in a chemically unchanged form. – Amount of drug available in the circulation/site of action – It is expressed in percentage – It is 100% for drugs given IV. • For example, if 100 mg of a drug is administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%. Factors affecting bioavailability – Extent of absorption – First pass effect 58General Pharmacology Compiled by: Birhanu Geta
  • 60. Drug distribution  Reversible movement of drug from bloodstream to interstitium (extracellular fluid) and/or cells. Factors affecting drug distribution 1. Plasma protein binding – Albumin [acidic & hydrophobic drugs] – -glycoprotein [basic drugs] 2. Tissue uptake of drugs/tissue binding -Adipose tissue [DDT] -Bone [TTC] -Liver [chloroquine] -Thyroid gland [iodine] 60General Pharmacology Compiled by: Birhanu Geta
  • 61. 3. Barriers –capillary permeability  Blood brain barrier (BBB)  Placental blood barrier (PBB)  Cell membrane 4. Rate of blood flow  Brain,  Kidney, highly perfused  Liver &  Lung 5. Plasma concentration 61General Pharmacology Compiled by: Birhanu Geta
  • 62. Drug metabolism  Enzymatically mediated alteration in drug structure.  Transforms lipophilic drugs into more polar readily excretable products.  Liver - major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines.  Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms. 62General Pharmacology Compiled by: Birhanu Geta
  • 63. Inducers  The cytochrome P450 enzymes are an important target for pharmacokinetic drug interactions.  Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes.  This results in increased biotransformations of drugs. 1. Decreased plasma drug concentrations. 2. Decreased drug activity if metabolite is inactive. 3. Increased drug activity if metabolite is active. 4. Decreased therapeutic drug effect. 63General Pharmacology Compiled by: Birhanu Geta
  • 64. Inhibitors  Inhibition of CYP isozyme activity is also an important source of drug interactions that leads to serious adverse effects.  The most common form of inhibition is through competition for the same isozyme.  For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism.  If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.  CYP inhibitors are erythromycin, cimetidine, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes. 64General Pharmacology Compiled by: Birhanu Geta
  • 65. Inhibition of drug metabolism may lead to; - Increased plasma levels over time with long-term medications. - Prolonged pharmacological drug effect. - Increased drug-induced toxicities. Microsomal enzyme inducers Phenobarbitone Phenytoin Rifampicin Carbamazepine Sulphonamides St. John’s Wort Cigarette smoking Microsomal enzyme inhibitors  Isoniazid  Disulfiram  Cimetidine  Allopurinol  Chloramphenicol  Erythromycin  Metronidazole  Grape fruit juice 65General Pharmacology Compiled by: Birhanu Geta
  • 66. First-Pass Effect: significant metabolic inactivation of some drugs by the liver following oral administration. - Drugs absorbed from the GI tract enter the portal circulation and are carried to the liver before entering the systemic circulation. 66General Pharmacology Compiled by: Birhanu Geta
  • 67. Drug excretion  Removal of a drug from the body occurs via a number of routes.  The major routes of excretion include renal excretion, hepatobiliary excretion & pulmonary excretion.  The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid & hair.  The rate of excretion influences the duration of action of drugs.  If the drug is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period. 67General Pharmacology Compiled by: Birhanu Geta
  • 68. Routes of drug excretion a. Renal excretion  For water soluble and non volatile drugs.  The three principal processes that determine the urinary excretion of a drug. – Glomerular filtration – Active tubular secretion – Passive tubular reabsorption  The function of glumerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption retain the drug. 68General Pharmacology Compiled by: Birhanu Geta
  • 69. b. Hepatobiliary Excretion  The conjugated drugs are excreted by hepatocytes in the liver.  After excretion of drugs through bile to the intestine; certain amount of drug is reabsorbed in to the portal vein leading to an entrohepatic cycling which can prolong the action of drug.  E.g. Chloramphenicol, estrogen. 69General Pharmacology Compiled by: Birhanu Geta
  • 70. c. Gastro intestinal excretion  When a drug is administered orally, part of the drug is not absorbed and excreted in the faeces.  The drug which do not undergo enterohepatic cycling after excretion in to the bile are subsequently passed with stool.  E.g. Aluminum hydroxide changes the stool color in to white, Ferrous sulphate darkens it and Rifampicine gives orange red colour to the stool. 70General Pharmacology Compiled by: Birhanu Geta
  • 71. d. Pulmonary excretion  Many inhalation anesthetics and alcohol are excreted through the lungs. e. Sweat  E.g. Rifampcine, metalloids like arsenic are excreted in to the sweat. 71General Pharmacology Compiled by: Birhanu Geta
  • 72. f. Mammary excretion  Many drugs are excreted in to breast milk.  Lactating mothers should be cautious about the intake of these drugs because they may enter in to baby through milk and produce harmful effects in the baby.  E.g. Ampicillin, Aspirin, Chlorodizepoxide, Streptomycin. 72General Pharmacology Compiled by: Birhanu Geta
  • 73. Pharmacodynamics Pharmacodynamics include:  Mechanism of actions of the drug. How does a drug act in the body?  Effects of the drug: both beneficial & harmful effects. What does a drug do in the body 73General Pharmacology Compiled by: Birhanu Geta
  • 74. Pharmacodynamics… Mechanisms of drug action  It is of two types: A. Receptor mediated mechanism Receptors- targets of drug action. May present either on the cell surface or inside the cell. D + R → DR → Biological effect Where; D=Drug, R=Receptor, DR=Drug Receptor Complex B. Non-receptor mechanisms  Simple physical or chemical reaction.  E.g. Antacids: neutralization reaction. 74General Pharmacology Compiled by: Birhanu Geta
  • 75. Types of Receptors  Regulatory proteins  For endogenous regulatory ligands – particularly hormones, growth factors, and neurotransmitters.  E.g. Insulin receptors-insulin  Enzymes  Receptors that are inhibited by binding with a drug.  E.g. Cyclooxygenase – Aspirin  Transport proteins: Na+/K+ ATPase- Digoxin  Structural proteins: Tubulin- colchicine  Genetic materials: Rifampcin- RNA polymerase  Ion channels: Na, Ca, K, channel blockers. 75General Pharmacology Compiled by: Birhanu Geta
  • 76. Models of D-R interaction…  Lock & key  Drug acts as key, receptor as lock, combination yields response.  Induced-fit models  Dynamic & flexible interaction. 76General Pharmacology Compiled by: Birhanu Geta
  • 77. Implications of drug-receptor interaction  Drugs can potentially alter rate of any function in the body.  Drugs cannot impart entirely new functions to cells.  Drugs do not create effects, only modify ongoing ones.  Drugs can allow for effects outside of normal physiological range. 77General Pharmacology Compiled by: Birhanu Geta
  • 78. Three aspects of drug receptor function 1. Receptors determine the quantitative relation between drug concentration and response.  This is based on receptor’s affinity to bind and it’s abundance in target cells. 2. Receptors (as complex molecules) function as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs. 3. Receptors determine the therapeutic and toxic effects of drugs in patients. 78General Pharmacology Compiled by: Birhanu Geta
  • 79. Dose response relationship  Dose: amount of a drug required to produce desired response in an individual.  Dosage: the amount, frequency and duration of therapy.  Potency: measure of how much a drug is required to elicit a given response. The lower the dose, the more potent is the drug.  Efficacy: the intrinsic ability of the drug to produce an effect at the receptor.  Maximal efficacy: largest effect that a drug can produce. 79General Pharmacology Compiled by: Birhanu Geta
  • 80. Dose response relationship... Drug response depends on:  Affinity of drug for receptor.  Intrinsic activity (degree to which a drug is able to induce intrinsic effects). 80General Pharmacology Compiled by: Birhanu Geta
  • 81. Agonism and Antagonism  Agonists facilitate receptor response.  Antagonists inhibit receptor response. 81 (Direct Ant/agonists) General Pharmacology Compiled by: Birhanu Geta
  • 82. Types of drug-receptor interactions  Agonist drugs: bind to and activate the receptor which directly or indirectly brings about the effect.  Some agonists inhibit their binding molecules to terminate the action of endogenous agonists.  E.g. slowing the destruction of endogenous acetylcholine by using acetyl cholinesterase inhibitors.  Antagonist drugs: bind to a receptor to prevent binding of other molecules, but lack intrinsic activity.  E.g. Atropine decrease acetylcholine effects.82General Pharmacology Compiled by: Birhanu Geta
  • 83. Types of drug-receptor interactions…  Partial agonist drugs: acts as agonist or antagonist depending on the circumstance, have affinity but have lowered maximal efficacy.  E.g. Pindolol can act as an antagonist if a “full agonist” like Isoproterenol is present.  Inverse agonist: is a ligand which produces an effect opposite to that of the agonist by occupying the same receptor.  E.g. metoprolol in some tissues. 83General Pharmacology Compiled by: Birhanu Geta
  • 84.  Full agonist- A drug with high positive efficacy & produce the system maximal response.  Partial agonist- maximal response to the ligand is below the system maximal response.  Antagonists- no efficacy or such a low level of efficacy with no visible response.  Inverse agonist- A ligand with negative efficacy can reduce the basal response. 84General Pharmacology Compiled by: Birhanu Geta
  • 85. Graded dose–response relations  As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).  It is used to determine affinity, potency, efficacy and characteristics of antagonists. General Pharmacology Compiled by: Birhanu Geta 85
  • 86. Potency  Is relative strength of response for a given dose.  Effective concentration (EC50) is the concentration of an agonist needed to elicit half of the maximum biological response of the agonist.  The potency of an agonist is inversely related to its EC50 value.  D-R curve shifts left with greater potency. 86General Pharmacology Compiled by: Birhanu Geta
  • 87. Efficacy  Maximum possible effect relative to other agents.  Indicated by peak of D-R curve.  Full agonist = 100%  Partial agonist = 50%  Antagonist = 0%  Inverse agonist = -100% 87General Pharmacology Compiled by: Birhanu Geta
  • 88. Quantal(cumulative) dose response r/ship:  Is between the dose of the drug and the proportion of a population that responds to it.  For any individual, the effect either occurs or it does not (‘all’ or ‘none’).  Are useful for determining doses to which most of the population responds; ED50%, TD50%, LD50%, TI(r/ship b/n dose & toxicity) & inter subject variability in drug responses.  They do not predict idiosyncratic reactions and hypersensitivity. General Pharmacology Compiled by: Birhanu Geta 88
  • 89. Therapeutic index  Median Lethal Dose (LD50): dose which would be expected to kill one half of a study population.  Median Effective Dose (ED50): dose which produces a desired response in 50% of the test population.  Therapeutic Index: gives a rough idea about the potential effectiveness and safety of the drug in humans. Therapeutic Index (TI) = LD50/ED50 The smaller the TI, the less safer the drug is.  Margin of safety=LD1/ED99. 89General Pharmacology Compiled by: Birhanu Geta
  • 90. Therapeutic Index… ED50 LD50 90General Pharmacology Compiled by: Birhanu Geta
  • 91. Factors modifying the dosage & action of drugs 1. Age 2. Sex 3. Body weight 4. Genetics 5. Drug tolerance 6. Drug intolerance 7. Disease states 91General Pharmacology Compiled by: Birhanu Geta
  • 92. Drug- Drug interactions Consequences of Drug- Drug Interactions 1. Intensification of effects: increased therapeutic or adverse effects. Additive Drug Effects (Summation): 1 + 1 = 2.  Most frequently seen when two drugs possess similar intrinsic activity. E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol, benzodiazepines (diazepam, etc.) administered in combination will produce additive effects resulting in over-sedation. Synergism - the effect of two drugs in combination is greater than the sum of the drugs administered alone (1 + 1 > 2). E.g. Aminoglycosides with penicillins. Potentiation – one substance alone does not have effect but when added to another chemical, it becomes effective. (1 + 0 > 1). 92General Pharmacology Compiled by: Birhanu Geta
  • 93. 2. Reduction of effects – inhibit drug effects; Either beneficial or detrimental. Antagonism: it occurs when the effect of one drug is diminished by another drug.(1+1<1). Types of antagonism;  Chemical antagonism or inactivation  Physiological (functional) antagonism  Pharmacologic or Receptor antagonism  Pharmacokinetic/Dispositional antagonism 93General Pharmacology Compiled by: Birhanu Geta
  • 94. Basic mechanisms of Drug- Drug interactions  Direct chemical or physical interaction - can occur with drugs mixed together.  Pharmacokinetic interaction – can alter all four processes.  Absorption – increase or decrease (e.g., PH, laxative, changes in blood flow).  Distribution – competition for protein binding or changes in extra cellular PH.  Metabolism - induction of drug metabolizing enzymes, inhibition of metabolizing, and competition of metabolism.  Excretion - altered renal excretion (e.g. filtration, reabsorption, and secretion).  Pharmacodynamic interaction  Interactions at same receptor – almost always inhibitory.  Interactions resulting from actions at separate sites (if drugs influence same physiologic process). 94General Pharmacology Compiled by: Birhanu Geta
  • 95. Drug- Food interactions  Impact of Food on Drug Absorption – Decreasing rate and/or extent of absorption – Some foods can increase extent of drug absorption.  Impact of Food on Drug metabolism – The grapefruit juice effect (can inhibit metabolism of certain drugs  increased drug levels).  Impact of Food on Drug Toxicity – MAOIs with tyramine – Caffeine with theophylline  Impact of Food on Drug Action – Vitamin K with warfarin. 95General Pharmacology Compiled by: Birhanu Geta
  • 96. Adverse drug reactions (ADRs)  Any undesired response to a drug.  Can range in intensity from annoying to life threatening. Types of adverse drug reactions  Side Effects: unavoidable secondary drug effect produced at therapeutic drugs doses. E.g. 1. Drowsiness that often accompanies the use of antihistamines 2. Gastric bleeding that can be produced by low therapeutic doses of aspirin.  Toxicities: an adverse drug reaction caused by excessive levels of drug. E.g. Coma caused by overdose with morphine.  Allergic reactions: – Prior sensitization of the immune system. – Re- exposure to that drug can bring on an allergic response. E.g. Penicillin allergy 96General Pharmacology Compiled by: Birhanu Geta
  • 97. ADRs...  Idiosyncratic effects: an unusual drug response resulting from a genetic predisposition.  Physical dependence: a state in which the body has adapted to prolonged drug exposure in such a way that if drug use is discontinued abstinence syndrome will result.  Develop during long-term use of certain drugs (e.g. Opoids, barbiturates etc)  Carcinogenic effects: ability of certain mediations /chemicals to cause cancer. Although a number of carcinogenic compounds have been identified, very few of these are employed therapeutically.  Teratogenic Effects: drug- induced birth defect. 97General Pharmacology Compiled by: Birhanu Geta