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Seminar on routes of drug administratin and biotranformation
1. SEMINAR ON
Routes of Drug Administration and
Biotransformation of drug
Presented by:
Dr. Md. Naseem Ashraf
Pg 1st year
2. Content
Introduction
Definition
Classification
Factors Consider for Route of Administration
First pass Metabolism
Transdermal therapeutic system
Biotransformation
Function of biotransformation
Prodrugs
3. Drug metabolizing organs
Drug Metabolizing enzyme
Phases of biotransformation
Factors affecting metabolism of drugs
Conclusion
References
4. Introduction
We usually divide routes of drug administration that produce systemic
effect in Enteral or Parenteral. From Greek Enteros = Intestine and Para =
Beside. Thus either it passes through the intestinal tract or it avoids it.
This is extremely important as some drugs are poorly absorbed in the
intestines, others are well absorbed however are metabolized almost
completely by first-pass effect.
Oral route of drug administration is usually the most acceptable way of
self- medication due to enhanced patient convenience and compliance. It
has limitations because of the way a drug typically moves through the
digestive tract. After oral administration of drug, absorption may begin
in the mouth and stomach.
Biotransformation is the process by which an organism or its enzyme bring
out chemical changes on compounds that are not part of their metabolism
and they result in the formation of novel or useful products that are often
difficult or impossible to obtain by conventional chemical means. The
total chemical transformation of one steroid to another not only requires
many stages but an expensive process although provide only low yield.
5. Route of drug administration :
Definition:
A route of administration is the path by which a drug,
fluid, poison or other substance is brought into contact
with the body.
OR is the path by which a drug is taken into the body.
7. Factors Consider for Route of Administration
Site of action of
the drug (local or
systemic)
Characteristics
of the drug
Condition of the
patient (unconscious,
vomiting, diarrhea).
Factors
Effect of gastric pH,
digestive enzymes and
firstpass metabolism
Emergency/routine use
Age of patient
8. ORAL ROUTE
The most common route of drug administration.
Drug is given through oral cavity.
Dosage forms are tablet, capsule, syrup, mixture, etc., e.g.,
paracetamol tablet for fever, omeprazole capsule for peptic ulcer are
given orally.
9. ADVANTAGES
It is very Safe route
Convenient- self- administered, pain free, noninvasive
and easy to take
Economical- compared to other parentral routes
Usually good absorption- takes place along the whole
length of the GI tract
No need for sterilization
ORAL ROUTE……
10. DISADVANTAGES
Not suitable for emergency as onset of action of orally administered
drugs is slow.
Irritable and unpalatable drugs- nausea and vomiting
Cannot be used Uncooperative, vomiting and unconscious patients
Some drugs destroyed by digestive juices (e.g. insulin)
Sometimes inefficient drug absorbed, some drugs are not absorbed like
streptomycin (e.g. aminoglycosides)
First-pass effect-Due to Biotransformation.Drugs with extensive first-
pass metabolism (e.g. lignocaine)
Food–Drug interactions and Drug-Drug interactions
ORAL ROUTE…..
11. First pass Metabolism
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.
so the amount reaching systemic circulation is less than
the amount absorbed.
The greater the first-pass effect, the less the agent will
reach the systemic circulation when the agent is
administered orally.
First pass metabolism occurs primarily in liver and gut.
12.
13. SUBLINGUAL/BUCCAL ROUTE
Tab or pellet containing the drug is placed under tongue or crushed in mouth and
spread over the buccal mucosa. The drug is absorbed through the buccal mucous
membrane and enters the systemic circulation directly, e.g. nitroglycerin for
acute anginal attack and buprenorphine for myocardial infarction.
Advantages
• Quick onset of action.
• Action can be
terminated by spitting
out the tablet.
• Bypasses first-pass
metabolism
• Self-administration is
possible.
• Economical
Disadvantages
• It is not suitable for:
Irritant and lipid-insoluble
drugs.
• Drugs with bad smell and
taste.
• Large quantities not given
• Few drugs are absorbed
14. Rectal Route
Drugs can be given in the form of solid or liquid
a. Suppository: It can be used for local (topical) effect as well as
systemic effect, e.g. indomethacin for rheumatoid arthritis.
b. Enema: Retention enema can be used for local effect as well as
systemic effect. The drug is absorbed through rectal mucous
membrane and produces systemic effect, e.g. diazepam for status
epilepticus in children.
15. Rectal Route….
Advantages
Used in children
Little or no first pass effect .
Useful in the patient is having recurrent
vomiting or unconscious stage.
Potential of long term drug absorption with
various intrauterine devices (IUDs).
Some irritant and unpleasant drugs can be
introduced into rectum as suppositories.
Higher concentrations rapidly achieved.
16. Disadvantages
This is rather inconvenient and embarrassing.
Absorption is slower, irregular and
unpredictable.
Bleeding problems such as discomfort to real
pathologies.
Irritation or inflammation of rectal mucosa
can occur.
Rectal Route….
17. PARENTERAL ROUTES
Direct delivery of drug in to systemic circulation without intestinal mucosa
Intradermal (I.D.) (into skin)
Subcutaneous (S.C.) (into subcutaneous tissue)
Intramuscular (I.M.) (into skeletal muscle)
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)
18.
19. Advantages
Onset of action of
drugs is faster; hence
it is suitable for
emergency.
Useful in:
Unconscious,
Uncooperative and
unreliable patients.
It is suitable for:
Irritant drugs, Drugs
with high first-pass
metabolism, Drugs not
absorbed orally, Drugs
destroyed by digestive
juices.
Disadvantages
Preparations should
be sterile and is
expensive.
Requires invasive
techniques that are
painful.
Cannot be usually
self-administered.
Can cause local tissue
injury to nerves,
vessels etc.
Require aseptic
conditions.
Expensive
20. INTRAVENOUS ROUTE
Injection into a peripheral vein over 1 to 2 minutes (bolus)
or longer as an infusion.
Drugs are injected directly into the blood stream through
a vein. Drugs are administered as:
1. Bolus: Single, relatively large dose of a drug injected
rapidly or slowly as a single unit into a vein. For example,
i.v. ranitidine in bleeding peptic ulcer.
2. Intravenous infusion: For example, dopamine infusion
in cardiogenic shock; mannitol infusion in cerebral
oedema;
fluids infused intravenously in dehydration.
3. Slow intravenous injection: For example, i.v.
morphine in myocardial infarction.
21. Advantages
• Bioavailability is 100%.
• Quick onset of action; therefore, it is
the route of choice in emergency.
• Large volume of fluid can be
administered, e.g. intravenous fluids in
patients with severe dehydration.
• Highly irritant drugs, e.g. anticancer
drugs can be given because they get
diluted in blood.
• Hypertonic solution can be infused by
intravenous route, e.g. 20% mannitol in
cerebral oedema.
Disadvantages
• Local irritation may cause phlebitis.
• Self-medication is not possible.
• Once the drug is injected, its action cannot be
halted.
• Strict aseptic conditions are needed.
• Extravasation of some drugs can cause injury,
necrosis and sloughing of tissues.
22. INTRAMUSULAR ROUTE
Drugs are injected into large muscles such as deltoid, gluteus maximus and vastus lateralis, e.g.
paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time
Advantages
Absorption is more rapid
as compared to oral
route.
Mild irritants, depot
injections, soluble
substances and
suspensions can be given
by this route.
Rapid onset of action.
First pass avoided
Gastric factors can be
avoided
Disadvantages
Aseptic conditions are
needed.
Intramuscular injections
are painful and may cause
abscess.
Self-administration is not
possible.
There may be injury to
the nerves.
Only upto10ml drug given
23. SUBCUTANEOUS ROUTE
The drug is injected into the subcutaneous tissues of the thigh,
abdomen and arm, e.g. adrenaline, insulin, etc. Only small amount can
be injected S.C
self injection is possible because deep penetration in not needed
Advantages
• Self-administration is possible
(e.g. insulin).
• Depot preparations can be
inserted into the subcutaneous
tissue, e.g. norplant for
contraception.
Disadvantages
• It is suitable only for nonirritant drugs.
• Drug absorption is slow; hence it is not
suitable for emergency
24. Advancement in Subcutaneous Route
Dermojet • A high velocity jet of drug solution is projected from a microfine
orifice using a gun like implement.
• The solution passes through the superficial layers and gets deposited in the
subcutaneous tissue.
Pellet implantation • The drug in the form of a solid pellet is introduced
with a trochar and cannula.
• This provides sustained release of the drug over weeks and months e.g.
deoxycorticosterone ( DOCA), testosterone.
Sialistic (nonbiodegradable) and biodegradable implants
• Crystalline drug is packed in tubes or capsules made of suitable materials and
implanted under the skin.
• Slow and uniform leaching of the drug occurs over months providing constant
blood levels.
• The nonbiodegradable implant has to be removed later on but not the
biodegradable one. • Examples - for hormones and contraceptives (e.g.
NoRPLANT).
25. Intradermal Route
The drug is injected into the layers of the skin, e.g. Bacillus Calmette–Guerin (BCG)
vaccination and drug sensitivity tests. It is painful and only a small amount of the drug can
be administered.
Intradermal injection also known as the mantoux method.
Purpose : Injects medication below the epidermis drugs are absorbed slowly. Typically used
for diagnosis of tuberculosis and allergens.
26. Intrathecal/intraventricular
It is sometimes necessary to
introduce drugs directly into the
cerebrospinal fluid.
For example, amphotericin B is used
in treating Cryptococcal meningitis.
27. Transdermal
The drug is administered in the form of a patch or ointment that delivers the drug into the
circulation for systemic effect .
For example, scopolamine patch for sialorrhoea and motion sickness, nitroglycerin
patch/ointment for angina, oestrogen patch for hormone replacement therapy (HRT).
The rate of absorption can vary markedly, depending on the physical characteristics of the
drug (lipid soluble) and skin at the site of application. Slow effect (prolonged drug action)
Site – Upper arm, chest, abdomen, mastoid region
First pass effect avoided
Absorption- increase by oily base, occlusive dressing, rubbing preparation
28. Transdermal therapeutic system
Drug in solution or bound to a polymer is held in reservoir between occlusive backing film
and rate controlling micropore membrane under surface of which is smeared with an
adhesive impregnated with priming dose of drug.
Adhesive layer protected with film which is peeled off just before application
To provide smooth plasma concentration without fluctuations
More convenient, patient compliance is better
29. Topical Application
Produce local effect to
Oral Cavity
Suspension (Nystatin),
Troche (Clotrimazole - for oral candidiasis) ,
Cream (Acyclovir - for herpes labialis)
Ointment and Jelly (5% Lignocaine hydrochloride - for
topical anaesthesia) ,
Spray (10% Lignocaine hydrochloride - for topical
anaesthesia)
30. Skin( percutaneous) e.g. allergy testing, topical local
anesthesia,
Ointment, cream, lotion or powder, e.g. clotrimazole
(antifungal) for cutaneous candidiasis.
Mucous membrane of respiratory tract (Inhalation) e.g.
salbutamol, ipratropium bromide, etc. (for bronchial
asthma and chronic obstructive pulmonary disease).
Eye drops e.g. conjunctivitis Drops, ointments and sprays
(for infection, allergic conditions, etc.) e.g. gentamicin
eye/ear drops
Ear drops e.g. otitis externa
Intranasal, e.g. decongestant nasal spray
31. Inhalation
Inhalation provides the rapid delivery of a drug across the large surface
area of the mucous membranes of the respiratory tract and pulmonary
epithelium, producing an effect almost as rapidly as with IV injection.
Drugs which are gaseous (e.g., nitrous oxide) or readily vaporized (e.g.,
isoflurane) may be inhaled.
Solid drugs may also be given by inhalation route in the form of aerosols
or suspended powder (e.g., salbutamol and beclomethasone). The
inhalation route may be used for producing both local (e.g.,
bronchodilatation in asthma) as well as systemic effects (anesthesia).
32. Advantages
Quick onset of action.
Dose required is very less, so
systemic toxicity is minimized.
Amount of drug administered can
be regulated.
Low bioavailability, less side effects.
No first pass effect
Inhalation….
Disadvantages
Local irritation may cause
increased respiratory
secretions and
bronchospasm.
Only few drugs can be used
33. Intranasal
This route involves administration of drugs directly into
the nose.
Agents include nasal decongestants such as the
antiinflammatory corticosteroid.
Desmopressin is administered intranasally in the
treatment of diabetes insipidus; salmon calcitonin, a
peptide hormone used in the treatment of osteoporosis, is
also available as a nasal spray.
The abused drug, cocaine, is generally taken by
intranasal sniffing.
34. Note: No single method of drug
administration is ideal for all drugs in all
circumstances.
35. BIOTRANSFORMATION
Chemical alterations of a compound that occur within the
body, as in drug metabolism. The term is used
synonymously with METABOLISM.
Chemical alteration of the drug in body that converts
nonpolar or lipid soluble compounds to polar or lipid
insoluble compounds.
36. Function of biotransformation
Active Inactive
Phenytoin P-Hydroxy phenytoin
Amphetamine Phenyl acetone
1) Pharmacological inactivation
2) Toxicological activation/ Bio activation
Activation Reactive intermediates
Isoniazid Tissue acylating
intermediate
Paracetamol Imidoquinone of N-
hydroxylated metabolite
37. Inactive(Pro drug) Active
Aspirin Salicylic acid
Phenacetin Paracetamol
3)Pharmacological activation
4) No change in pharmacological activity
Active Active
Digitoxin Digoxin
Diazepam Temazepam
39. Prodrugs: Inactive drug is converted to active metabolite
• Coined by Albert in 1958
Advantages:
• Increased absorption
• Elimination of an unpleasant taste
• Decreased toxicity
• Decreased metabolic inactivation
• Increased chemical stability
• Prolonged or shortened action
40. Drug metabolizing organs
The liver is adapted to clear toxins from
the body and is the major site for drug
metabolism, but specific drugs may
undergo biotransformation in other
tissues.
Decreasing order of drug metabolising
ability of various organs is
Liver>Lungs>Kidney>Intestine>Placenta>
Adrenals>Skin
Brain, Testes, muscles, spleen etc. also
metabolise drugs but to a small extent.
41. Drug Metabolizing enzyme
In the first type of reaction drugs are made more polar through
oxidation-reduction reactions
or hydrolysis.
These reactions use metabolic enzymes, most often those of the
cytochrome P450 enzyme system, to catalyze the
biotransformation.
The enzymes are broadly divided into two categories:
1) Microsomal enzyme 2) Non-microsomal enzyme
42. Microsomal enzyme:
A group of enzymes associated with a certain
particulate fraction of liver homogenate.
These are a mixed function oxidase system or
monooygenases.
These requires NADPH ( Nicotinamide adenine
dinucleotide phosphate hydrogen) and oxygen.
The 2 most impotent microsomal enzyme.
a) NADPH cyctochrome P450 Reductase,
b) CYT.P450
43. Non Microsomal enzyme:
These are present in the cytoplasm and mitochondria of
hepatic cells as well as in other tissues including
plasma.
Enzymes occurring in organelles/ sites other than
endoplasmic reticulum are called Non-microsomal
enzymes.
45. Phase I / Non Synthetic Reactions
Functionalization reactions . Converts the parent drug
to a more polar metabolite by introducing or unmasking
a functional group (-OH, -NH2, -SH).
1) Oxidative reaction
2) Reductive reaction
3) Hydrolytic reaction
46. Phase II / Synthetic reactions
Conjugation reactions
- Subsequent reaction in which a covalent linkage is
formed between a functional group on the parent
compound or Phase I metabolite and an endogenous
substrate such as glucuronic acid, sulfate, acetate, or
an amino acid
1) Sulfate conjugation 2) Glucuronide conjugation
3) Glutathione conjugation
4) Amino acid conjugation
47. Phase I / Non Synthetic Reactions
Oxidation
• Addition of oxygen/ negatively charged radical or
removal of hydrogen/ positvely charged radical.
• Reactions are carried out by group of monooxygenases
in the liver.
• Fianl step: Involves cytochrome P-450 haemoprotein,
NADPH, cytochrome P-450 reductase and O2
49. Reduction reactions
Addition of hydrogen or removal of oxygen from a drug molecule.
Drugs primarily reduced are chloralhydrate, chloramphenicol, halothane.
Nitro Reduction:
Chloramphenicol arylamine
Keto Reduction:
Cortisone hydrocortisone
50. Hydrolysis
Process where a drug molecule is split by the addition of a molecule of water.
Both microsomal and non microsomal enzymes maybe involved.
Sites: Liver, intestines, plasma and other tissues
Examples: Choline esters, Procaine, Isoniazid, pethidine, oxytocin.
Acetylcholine+H2O Choline+ acetic acid
51. Phase II/ Synthetic reactions
Conjugation of the drug or its phase I metabolite with an endogenous substrate to
form a polar highly ionized organic acid.
Glucuronide Conjugation
Conjugation to α-d-glucuronic acid
• Quantitatively the most important phase II pathway for drugs
and endogenous compounds
• Products are often excreted in the bile
• Requires enzyme UDP-glucuronosyltransferase (UGT)
52. Glucuronide Conjugation Continued..
• Compounds with a hydroxyl or carboxylic acid group are
easily conjugated with glucuronic acid which is derived from
glucose
Enterohepatic recycling may occur due to gut glucuronidases
• Drug glucuronides excreted in bile can be hydrolysed by
bacteria in gut and reabsorbed and undergoes same fate.
• This recycling of the drug prolongs its action
e.g.Phenolpthalein, Oral contraceptives
• Examples: Chloramphenicol, aspirin, phenacetin, morphine,
metronidazole
53.
54. Acetylation
Common reaction for aromatic amines and sulfonamides
• Requires co-factor acetyl-CoA
• Responsible enzyme is N-acetyltransferase
• Important in sulfonamide metabolism because acetyl-
sulfonamides are less soluble than the parent compound and may
cause renal toxicity due to precipitation in the kidney
• E.g. Sulfonamides, isoniazid, Hydralazine.
55. Sulfate Conjugation
Major pathway for phenols but also occurs for alcohols, amines
and thiols
• Sulfate conjugates can be hydrolyzed back to the parent
compound by various sulfatases
• Sulfoconjugation plays an important role in the hepatotoxicity
and carcinogenecity of
N-hydroxyarylamides
• Infants and young children have predominating O-sulfate
conjugation
• Examples include: a-methyldopa, albuterol, terbutaline,
acetaminophen, phenacetin.
56.
57. Glutathione conjugation
Glutathione is a protective factor
for removal of potentially toxic
compounds
Conjugated compounds can
subsequently be attacked by g-
glutamyltranspeptidase and a
peptidase to yield the cysteine
conjugate => product can be further
acetylated to N-acetylcysteine
conjugate .
E.g. Paracetamol
58. Amino acid conjugation
ATP-dependent acid: CoA ligase forms active CoA amino acid conjugates which then
react with drugs by N-Acetylation: –
Usual amino acids involved are: Glycine. Glutamine, Ornithine, Arginine
59. Hofmann elimination
Inactivation of the drug in the body fluids by
spontaneous molecular re arrangement without the
agency of any enzyme
e.g. Atracurium.
60. Factors affecting metabolism of drugs
• Physiochemical properties
of the drug
• Biological factor
Molecular size
pKạ acid/base
characteristics
Lipophilicity
Steric characteristics
Chemical factor
Enzyme induction
Enzyme inhibition
Species difference
Genetic differences
Sex differences
Age differences
Diet
61. conclusion
The oral route of drug delivery is typically considered the most
favorable and preferred route of drug administration in case of
conscious and co-operating patients because of convenience,
possibility of self administration and enhanced compliance. More
than 60% of drugs are marketed in the form of oral products.
Biotransformation is of primary importance to xenobiotics because
the biological activity of xenobiotics is enhanced or decreased by
this process.
Characterization of the mechanisms of inhibition
of biotransformation provides the basis for therapeutic
intervention. Understanding the relationship of
chemical biotransformation to adverse biological effects is
oftentimes central to understanding mechanisms of xenobiotics
