Pharmacokinetics (ADME1)

Fundamentals of Medicine
Dr Maryam Malekigorji
m.malekigorji@qmul.ac.uk
Resources

1. Medical Pharmacology at a Glance (9th edition)

by Michael J. Neal (Chapter 3,4)

2. Rang & Dales Pharmacology (10th edition) by

James Ritter, Rod Flower et al

3. The Top 100 Drugs (3rd edition) by Andrew

Hitchings, Dagan Lonsdale et al

4. Lippincott Illustrated Reviews : Pharmacology

(8th edition) by Karen Whalen (Chapter 1)
(£66.71 paperback, £32.99 Kindle – Amazon UK)

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 Learning Outcomes
1. Give an overview of ADME, the process of drug delivery, function and
elimination from tissues.
2. Identify the main routes of drug administration.
3. Describe the determinants necessary for the most suitable route of drug
administration.
4. Explain what is meant by first pass metabolism.
5. Describe the chemical properties and physiological variables which determine
the rate and efficiency of drug action.
6. Understand what is meant by drug bioavailability and how this property is
determined.
7. Describe the determinants of drug distribution.
8. Calculate apparent volume of distribution of a drug.

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Learning Objectives 1-3

1. Identify the main routes of drug administration.

2. Describe the determinants necessary for the most suitable route of
drug administration.
3. Explain what is meant by first pass metabolism.

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Principles of drug administration

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Oral Route (PO)
• The most common route of
drug administration
• Pass through the gut wall and
liver which contains several
inactivating enzymes. This
process is called “first-pass”
metabolism.
• Onset > 30 min
• Dosage forms:
- Solids: tablets, capsules
- Liquid: syrups, elixirs,
solutions, suspensions
emulsions

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Sublingual Route

• Placed under the tongue

• Rapidly absorbed by mucosa
• Goes to the systemic circulation
• Onset = few minutes
• Preferred in emergency

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Buccal Route
• Placed between the gum and the inner lining of
the cheek
• Absorbed by buccal mucosa
• Less permeable than sublingual
• Onset = 5-10 min
• Advantages:
- Relatively rapid absorption
- Bypass first-pass metabolism
• Disadvantages:
- Drug dose limit
- Effect is lost if swallowed (local treatment)
- Inconvenient

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Rectal Route
• Effective for many medications
• Rectal mucosa allows for rapid and effective
absorption
• Systemic and local administration
• Onset = 5-30 min

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Vaginal Route
• Commonly used for the topical delivery of the drugs into the vagina
• Systemic drug delivery and uterine targeting is also possible
Advantages
Accessible, non-invasive and non-parenteral route
- Highly perfused tissue with a well-developed blood supply
- High permeability for penetrates which certain physiochemical characteristics
Disadvantages
Cultural and hygiene issues
Messiness associated with certain semi solid systems
Poor retention of the drug
Poor user compliance
- Tissue permeability is strongly influenced by oestrogen concentration thereby affecting
pharmacokinetics of drugs designed for systemic action

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 Parenteral Route
• Parenteral means “outside of the GI tract”
• Commonly refers to injections
• Various options are available for the injection of
a drug
Advantages:
- Limitations seen with oral drug
administration are avoided
- Rapid onset of action
Disadvantages:
- Requires aseptic techniques
- Invasive and painful
- Can cause irritation or infection
- Assistance of another person is often
required

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Pulmonary Route
A common route, both for local and for systemic
actions
• Aerosolised agents target the lung topically
(local effect) such as in asthma and COPD
- Salbutamol: local bronchodilator
• Drugs diffuses across the alveolar membrane
(systemic effect)
- Insulin inhaler (Afrezza®) - does not
currently have a marketing authorisation in
the UK
- Nitrous oxide: general anaesthetic agents
• New medical devices have further strengthened
the delivery of pulmonary drugs

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Nasal Route
• Rapid onset ~ 5 min
• Can be use for local administrations such
as decongestants
• Can be used for systemic administration
• Nasal cavity is covered by a thin mucosa
which is well vascularised
- Bypass first-past metabolism
• Nasal-brain drug delivery – bypass BBB

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Topical Route
• Advantages:
• Local therapeutic effect
- Lower risk of side effects
• Disadvantages:
- Some drugs cannot be absorbed
through the skin or mucosa
• Examples
- Antibiotics
- Antiseptics
- Local anaesthetics
- NSAIDs

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Transdermal Route
• An increasing number of drugs are being formulated for application to the skin
• Drug is absorbed percutaneously (systemic)
• Comparable to injections
• Long term continuous delivery of drugs
• Examples:
- Nitroglycerine
- Contraceptives
- Nicotine

• Advantages:
- First pass metabolism is avoided
- Stable drug levels in the plasma are achieved

• Disadvantages:
• Drugs must be potent
- Skin irritation

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 Other routes of parenteral injections
• Intrathecal: an injection into the spinal canal, or into
the subarachnoid space
• Epidural: Outside of spinal dura
• Intraosseous: Into the marrow of the bone
• Intra-arterial: into the artery (tumours) - diagnostic
applications
• Intravitreal: used by ophthalmic surgeons to treat Intrathecal Contrast Administration through Lumbar Puncture

conditions like age-related macular degeneration

• Intra-articular: into the joint such as corticosteroids

Epidural injection 16
 Route of administration and time to effect
• Intravenous
 30-60 seconds

• Inhalation
 2-3 minutes

• Sublingual
 3-5 minutes

• Rectal
 5-30 minutes

• Intramuscular / subcutaneous
 10-20 minutes

• Oral
 30-90 minutes

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Route of administration selection
Physiochemical properties of the drug

Pharmacokinetics of the drug- onset and duration of action

Effect of the GI tract fluids and first-pass metabolism on the drug

Site of desired action local or systemic

Mode of drug effect - immediate or prolonged

• Convenience - condition of the patients

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Learning
Objective 4
Give an overview of ADME, the
process of drug delivery,
function and elimination from
tissues.

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ADME

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 Pharmacokinetics (PK)
• Describes the passage of drugs through the body

• A distinctive set of parameters are used to describe:

 rate and extent of drug absorption
 rate and extent of drug movement out of the blood
into tissues
 rate of drug removal from the body

• These parameters can then be used to predict the

blood concentration of drug that will arise with a given
regime

• Important for both clinical practice (initial and

maintenance dose, dose adjustment) and drug
development (the best route, optimum dosage forms) Therapeutic window

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Learning Objective 5
Describe the chemical properties and
physiological variables which determine the
rate and efficiency of drug action.

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 Drug absorption
• Drugs must diffuse through a variety
of biological membranes after
administration to the body
• The ability of a drug to diffuse
through membranes is a function of
its molecular size and its
lipophilicity
• The undissociated form is lipid
soluble (uncharged, pronated)
• The dissociated form is water soluble
(charged, proton has been lost)

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 Drug absorption
• The rate and efficiency of absorption is mainly and
significantly dependent on the route of administration.
• Most drugs are given orally and as such must pass
through the wall of the GI tract to enter the bloodstream.
• It is the chemical properties of a drug and the site of
absorption that determines its ability to be absorbed.

• In general, most drugs presently used:

 are small organic molecules

 have molecular weights under 1000
 exist as either weak acids or bases
 diffuse through biological membranes in their uncharged form

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Other physical factors influencing drug absorption
1. Blood flow to the absorption site: since blood flow to the intestine is
greater than that to the stomach, the intestine is the favoured site of
absorption

2. Surface area available: the intestine has a surface rich in microvilli

making its total surface area 1000 times greater than that of the stomach
thus increasing its efficiency of absorption

3. Contact time at absorption surface: any condition that delays rate of

passage of drug from the stomach to the GI tract (e.g., presence of food)
or increases its rate of passage through the GI (e.g., severe diarrhoea)
reduces efficiency of absorption

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Learning
Objective 6
Understand what is meant by drug
bioavailability and how this property is
determined.

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Bioavailability

• The proportion of administered dose

that is absorbed chemically
unchanged into the systemic blood
circulation.
• Also called “fractional availability”,
hence presented in PK calculations
as F
• Bioavailability of IV administration is
100%
• For other routes, F is less than 100% ×100
in most cases

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Bioavailability Example
A new immunosuppressant, Noreject, is being studied in the
renal transplantation clinic where you work.

Based on previous studies, the following area under the serum

concentration-time curves (AUC) were measured after single
doses of 10 mg in renal transplant recipients: intravenous
bolus AUC = 1530 mg . h/L, oral capsule AUC = 1220 mg .
h/L, oral liquid AUC = 1420 mg . h/L.

What is the bioavailability of the oral capsule and oral

liquid?

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 Factors that affect bioavailability
1. First pass hepatic metabolism: If the drug is rapidly metabolised by the liver, the amount of
unchanged drug that can enter the systemic circulation will significantly decrease.

2. Solubility of drug: very hydrophilic drugs are poorly absorbed (due to inability to cross lipid
membrane) as are very hydrophobic drugs (insoluble in body fluids and cannot gain access
to the surface of cells). Ideal drugs are largely hydrophobic with some solubility in aqueous
solutions.

3. Chemical instability: drugs can be susceptible to break down in the acidic environment of
the stomach (e.g., penicillin G) whilst others can be degraded by enzymes in the GI tract
(e.g., insulin).

4. Type of drug formulation: particle size, salt form, crystal polymorphism, binders and
dispersing agents can influence ease of dissolution and rate of absorption.

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Learning
Objective
7&8
• Describe the determinants of drug
distribution.
• Calculate apparent volume of distribution of
a drug.
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 Apparent Volume of Distribution (VD)
• The body comprises several fluid compartments. Unbound
drug can move between compartments and accumulate in
them. VD is a hypothetical volume of fluid into which a drug can
be disseminated.
• Determined by:
 partitioning across various membranes
 Size of the organ
 Capillary structure – e.g., blood-brain barrier, sealed with
tight junctions
 binding to tissue components (presence of non-active binding sites)
 binding to blood components (RBC, plasma protein)
 Physiochemical properties of the drug – e.g., drug solubility,
hydrophobic drugs
 blood flow through the tissue physiological volumes

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Why VD is a very important parameter?
• VD allows you to know the concentration and location of the drug in the body
• Drugs with a large VD are distributed to the tissues (such as the fat or brain) – e.g., quinacrine has a
VD = 50000 litres in a 70 kg individual
• Drugs with a very small VD (<10 L) are mainly confined to the blood. Either:
- The molecule is too large to leave
- The molecule binds preferably to plasma proteins (e.g., to albumin) and much less to tissue
proteins.
• You can also work backwards:
Total amount of drug in the bod
V D=
- the VD for drugs is a known constant Drug blood plasma concentration
- the concentration in plasma is measurable
- Therefore, you know how much drug is left in the body
• It can also be useful for titrating doses
- smaller people need to take less of a drug to have the same effect

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Plasma Binding Proteins
• This alters the amount of drug that is available to
bind to the target
• Act as drug reservoir
• Equilibrium between bound and free forms
• There are lots of proteins in the blood
• Bound drug is
 Albumin (most important)  non-diffusible
 Alpha 1-acid glycoproteins  not metabolised
 Lipoproteins  not excreted
 Beta globulin
• Competition between drugs for protein
binding

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Protein binding can have important medical
implications
Stopping or starting a drug that binds to protein changes the level of other protein bound
drugs
• Example: Warfarin (anticoagulant) and phenytoin (anti-seizure)

• Normally both warfarin and phenytoin bind to albumin (relatively low V D)

• Patient goes for surgery: Warfarin stopped

• More sites for phenytoin to bind to albumin

• Sub-therapeutic levels of free phenytoin

• Epilepsy?

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To sum up!

• We now appreciate the most common routes of administration

• We understood main factors effecting drug plasma level after
administration
• We should have a better understanding about how a drug moves
throughout and is processed by the body
• We understood drug elimination general procedures

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 Thank you!
m.malekigorji@qmul.ac.uk