WEEK 2: BASIC PRINCIPLES OF

PHARMACOKINETICS AND 401182 - Pharm for Pods

Steven Walmsley

PHARMACODYNAMICS
PHARMACODYNAMICS + PHARMACOKINETICS
Pharmacodynamics:
Physiological and biochemical effects of
drugs + their mechanism of action at organ
system/subcellular/macromolecular levels

Pharmacokinetics:
Movement of the drug in and alteration of
the drug by the body. Often expressed as
ADME…
Absorbtion
Distribution
Metabolism ADME
Excretion
 PHARMACOKINETICS – PHARMK
How does a drug go from
this? PET images of human subjects following administration of
radioactive trovafloxacin (Fischman et al, 1998)

The amount of drug in

target tissue/organ is
only a small amount of
the total amount of drug
present in the body

To this?
 DRUG DISPOSITION: ABSORPTION
Movement of a drug from site of admin into the circulation.
 Unless injected intravenously, a drug will have to cross several cell
membranes to reach the blood and reach its target.
 There are 3 main ways by which drugs can cross cell membranes:

 What do you think they are?

 Which do you think is the common

mode of transport across cell membranes?

BOTH FRACTION ABSORBED + RATE OF ABSORPTION

ARE IMPORTANT
DRUG DISPOSITION: ABSORPTION
• There are several factors per se that impact on absorption:

1. Aqueous and lipid solubility

2. Concentration There is an absorption process for every
administered drug, with the exception of those
3. Area of absorbing surface
that are IV.
4. Vascularity of absorbing surface
5. Contact time at absorbing surface
6. Route of adminstration
AN IMPORTANT CONCEPT FOR ADME
• The lipid solubility of a drug depends on its state of ionisation.
• Drugs that are unionised are usually lipid soluble, but ionized drugs are not.
• The extent to which a drug is ionised depends on the pH of the local environment
(different compartments in the body) + the pKa of the drug.
• Chemically most drugs are either weak acids or weak bases

- - Acidic drug

- Basic drug
KEY RULES TO REMEMBER
• pKa = pH where a drug exists in 50% ionised and 50% unionised form

•An ACIDIC DRUG IN AN ACIDIC ENVIRONMENT WILL NOT IONIZE

• AN ACIDIC DRUG IN A BASIC SOLUTION WILL IONIZE
• A BASIC DRUG IN A BASIC SOLUTION WILL NOT IONIZE
•A BASIC DRUG IN AN ACIDIC SOLUTION WILL IONIZE
QUESTIONS
Which drugs do you think will have a preference for being absorbed from the
stomach?

Which drugs do you think will have a preference for being absorbed from the small
intestine?
 Unionised Ionised

WEAK ACID – PKA = 8.5

More of drug in unionised form!

About 93% unionised

form of drug
SO predominates

It is mainly
UNIONISED and
pH – pKa = -1.1 (7.4% ionised) LIPOPHILIC
 Ionised Unionised

BASIC DRUG – PKA = 9.1 BH+ B

More of drug in ionised

form

SO About 98% ionised

form of drug and 2%
pH (7.4) – pKa (9.1) = -1.7 unionised form of
drug
CONSEQUENCES OF PH FOR ACIDIC + BASIC
DRUGS

MAJOR CONSEQUENCES FOR

ABSORPTION, DISTRIBUTION AND
EXCRETION
SOME MORE ACIDIC DRUG EXAMPLES (AT PH7.4)
Unionised Ionised
• Paracetamol pKa = 9.5
• Morphine pKa = 9.9
• Levothyroxine pKa = 10 For Acidic Drugs:
When the pH is smaller than pKA,
uncharged acid drug predominates

•Let’s work out % ionisation: pH (7.4) – pKa

•Paracetamol: 7.4 – 9.5 = -2.1
• Morphine: 7.4 – 9.9 = -2.3 Ionised to <
1% in blood
•Levothyroxine: 7.4 – 10 = -2.6
BASIC DRUGS @PH 7.4 Ionised Unionised

BH+ B
• Lidocaine pKa 7.9
• Ketamine pKa 7.5
For Basic Drugs:
• Cocaine pKa 8.6 When the pH is larger than pKA,
uncharged basic drug predominates

• Let’s work out % ionisation:

• Lidocaine = 7.4 – 7.9 = - 0.4 = 76% ionised
• Ketamine = 7.4 – 7.5 = -0.1 = 55.7% ionised
• Cocaine = 94.1% ionised = - 1.2 = 94.1 % ionised
 EXAMPLES OF ACIDIC AND BASIC DRUGS
BASIC

ACIDIC
 DRUG DISPOSITION: ABSORPTION – ROUTE OF
ADMIN
Local Routes Systemic Routes
Topical, Deeper Oral, sublingual (or
tissues (LA injection), buccal), rectal,
arterial supply (e.g. cutaneous (highly
contrast media in lipid soluble drugs),
angiography, inhalation, nasal,
anticancer drugs in parenteral
femoral/brachial (subcutaneous,
artery for localised intramuscular,
tx of limb intravenous,
malignancies) intradermal)
DRUG DISPOSITION: ABSORPTION – ORAL
ADMIN
What factors do you think may affect drug absorption here?
 DRUG DISPOSITION: FACTORS AFFECTING
ABSORPTION FROM GI TRACT
Factors
pH of GI contents
Surface area
Gastric emptying and intestinal transit time (an e.g. of contact time
at absorbing surface)
Blood flow
Plasma protein binding
Active transport mechanisms
Formulation
Note: Once absorbed by the GI tract, a drug passes directly to the
liver via the hepatic portal circulation and may be subjected to
metabolism before further distribution…
 HEPATIC FIRST PASS EFFECT/FIRST PASS
METABOLISM
• First pass metabolism (FPM) can result in
considerable loss of activity for some drugs.
• Reduced BIOAVAILABILITY

• The proportion of drug administered reaching

the systemic circulation in tact.
• Varies from patient to patient and with
different drugs.
The bioavailability of oral terbinafine HCl as a result of FPM is From Gahane and Yadav (2012)

40%
The bioavailability of oral diclofenac as a result of FPM is appx See:
55% http://dailymed.nlm.nih.gov/dailymed/about.cfm
CONSEQUENCES OF 1 ST PASS METABOLISM
TO DO: Access and read the below article

Hernandez (2007)
ENTEROHEPATIC SHUNTING
• A considerable number of drugs are excreted from liver into bile and from bile into
small intestines.
• From here some drugs are reabsorbed by hepatic portal circulation to liver and then
back into circulation.
 DRUG DISPOSITION: BIOAVAILABILITY
• The rate and extent of absorption of drugs reaching the blood stream by
any route.
• Many factors can affect bioavailability of a drug (not just FPM):
• Physiology of the patient
• Foods, other drugs and disease states
• Drug formulation

Effect of particle size on

drug absorption
DRUG DISPOSITION: BIOAVAILABILITY

Effects of meals on absorption(From Fleisher et al, 1999)

Cirrhosis of the liver and
bioavailability of drugs (From
Bervee, 2008)
DRUG DISPOSITION: DISTRIBUTION
• Only free drug (unbound) at its site of action can produce a pharmacological effect.
• The body can be considered to be made up of 2 compartments: aqueous + lipid.

Lipid compartment Aqueous compartment

Cell membranes and adipose Tissue fluid, cellular fluid, blood
tissue plasma, fluid in CNS,
lymphatics, joints, GI tract
The drug moves from blood to other tissues
that have no drug i.e. high to low (or no)
concentration
Distribution of a drug depends on many
factors…such as?
DRUG DISPOSITION: DISTRIBUTION
• Factors that affect drug distribution include:
1. Aqueous solubility
2. Blood flow
3. Plasma protein binding
4. Lipid solubility
5. Tissue sequestration
6. Metabolism and excretion
 DRUG DISPOSITION – RATE OF DISTRIBUTION
• Capillary permeability and blood perfusion

• Determines how fast a drug can move from circulation to organs/tissues

capillaries
Renal + hepatic
Brain capillaries

Lots of slit junctions

No slit junctions
Varying degrees of capillary permeability throughout the body
DRUG DISPOSITION – RATE OF DISTRIBUTION
• Drug structure – permeability vs. perfusion limited transport
Thiopental
Penicillin

• pKa = 7.5
• pKa = 2.8
• Highly lipid soluble
• Not very lipid soluble
• Perfusion limits transport
• Permeability limits transport
• E.g. transfer – brain>muscle
• E.g. transfer – muscle>brain
DRUG DISPOSITION – EXTENT OF DISTRIBUTION
• Dictated by factors such as:
1. Drug structure
2. Compartment pH Mediate the extent of
distribution of a drug
3. Protein binding into specific organs
and tissues
4. Intracellular binding
DRUG DISPOSITION – EXTENT OF DISTRIBUTION
• Drug Structure and pH of compartments
• Drug pKa and compartment pH control the amount of drug (i.e. extent) that
distribute into an organ or tissue
 DRUG DISPOSITION – EXTENT OF DISTRIBUTION
Plasma protein binding
• Drugs binding to plasma proteins can restrict them to the blood compartment (if it is
high)
• Acidic drugs (e.g. warfarin) commonly bind to albumin
• Basic drugs (chloropropamide) bind to glycoproteins and
lipoproteins

Albumin comprises 50% of plasma proteins

and is the most common binding protein
DRUG DISPOSITION – EXTENT OF DISTRIBUTION
Intracellular drug binding
• May involve binding to: nucleic acids, tissue proteins, dissolving in lipid
 4 OVERALL TYPES OF DRUG DISTRIBUTION?
Patterns Example drugs

4. Various organs – 1) Highly bound to Warfarin

kidneys, liver, muscle plasma proteins
2) Low weight, Ethanol, some
2. Total body
hydrophilic drugs – sulphonamides
water
distribute throughout
3. Specific organ or tissues: body water
site of action, target and 3) Drugs that Tetracyclines, thyroxine
1.Blood
non-target tissues concentrate in tissues
which are/are not site
of action
4) Drugs show a Most drugs
Vd can give combination of
insight into previous patterns
distribution
pattern
DRUG DISPOSITION: DISTRIBUTION (VOLUME OF
DISTRIBUTION)
• Describes body compartments into which a drug might be distributed.
• A lower volume of distribution (< 5L) implies that a drug is retained within
vasculature.
 Certain acidic drugs tend to bind to plasma albumin, so remain in the blood stream and have a small
volume of distribution.

• A higher volume of distribution (> 15L) suggests that a drug is more lipid soluble
and distributed to many parts of the body or concentrated in certain tissues.
 Basic drugs tend to bind to tissue proteins, which causes them to have a large volume of distribution.
 DRUG DISPOSITION: DISTRIBUTION (VOLUME OF
DISTRIBUTION) – TOTAL BODY WATER
Total Body Water in a 70kg man ≈ 42 L Where are these
COMPARTM VOLUME (L) drugs distributing
ENT to?...
Plasma 3–4 Drug Vd (L/70 Kg)
Interstitial 10 – 13 Tolbutamide 7
fluids Enalapril 40 Consider the
Extracellular 13 – 16 Fluoxetine 2500 relevance of
fluids protein binding
Chloroquine Up to 17,500
Intracellular 25-28 vs. tissue
fluids
components
Total Body 40-46
Water
Is this an important consideration for dosing?
DRUG DISPOSITION: METABOLISM
• Drugs are treated by the body as if they are toxic substances, which need to be
detoxified (if a mechanism exists) and eliminated as soon as possible.
• Most drugs are subjected to some kind of metabolism + then excreted.
• Mainly involves the liver, but significant metabolism of drugs can occur in intestinal
mucosa, lungs + plasma.

Metabolism involves enzymes changing the molecular

structure of drug. Two important effects:
1) Drug is made more water soluble, so easier to excrete
2) Metabolites are usually less pharmacologically active (not
always)
DRUG DISPOSITION: OUTCOMES OF METABOLISM
Active Drug Active metabolite

Active Drug Inactive metabolite

Pro-drug Active drug

Active drug Toxic metabolite

DRUG DISPOSITION: METABOLISM [PRO-DRUGS]
• There are some drugs that have been designed to remain inactive until they are
metabolised by the body – Pro-drugs
• Useful for drugs that are difficult to administer in active form, where active drug is
not absorbed/distributed to intended site of action easily.
DRUG DISPOSITION - METABOLISM
The liver is involved in two general types of reaction. • Can you think of any
examples of Phase 1 and
phase 2 reactions?
 DRUG DISPOSITION – PHASE 1 METABOLISM
• Involve the biotransformation of a drug to a more polar metabolite by unmasking (or
introducing) a functional group (-OH, -NH2, -SH)

• The metabolites are more water soluble, so more likely to be excreted by

kidneys or move onto phase 2.

Phase 1 Reactions
Oxidation – most important + common
Reduction
Hydrolysis
ADME – PHASE 1 METABOLISM CYP450 ENZYMES
• Most clinically significant oxidation enzymes include cytochrome P450 family

Major Hepatic Relative • About 6 P450 isozymes account for most

CYP 450 enzymes abundance (%) drug metabolism. CYP3A4 metabolises more
3A4 >35 than 50% of drugs.
2D6 <5
2C9 >15
2E1 Appx. 15
1A2 >10
2A6 Appx. 10
2C19 <5
2C8 Appx. 5
2B6 <5

Adapted from Rosenbaum (2012)

 DRUG DISPOSITION – PHASE 2 METABOLISM
•Usually occur in the liver.
•Essentially make drugs or Phase 1 metabolites more hydrophilic, less toxic substances
via conjugation with endogenous compounds in the liver. Also encourages renal
excretion.
•There are different types of conjugates: sulphate, acetyl, methyl + glycine groups

What enzymes are

significantly
involved in
Phase 1 and Phase 2 Metabolism of Aspirin. From Greenstein (2008) biotransformation?
DRUG DISPOSITION – ENZYMES INVOLVED IN
METABOLISM
Microsomal enzymes (monooxygenases, cytochrome P450, glucuronyl transferase)
located in smooth endoplasmic reticulum catalyse: oxidation, reduction, hydrolysis +
glucronide conjugation.

Cytochrome p450 isozymes – many, exist with different but frequently overlapping
substrate specificities.

About 6 p450 isozymes account for most drug metabolism. CYP3A4 metabolises
more than 50% of drugs.

What factors may affect the metabolism of drugs?

DRUG DISPOSITION – FACTORS AFFECTING
METABOLISM OF DRUGS
Enzyme induction – e.g. carbamazepine, phenytoin + alcohol are inducers of
cytochrome p450 enzymes.

Enzyme inhibition – e.g. erythromycin increases the activity if theophylline, warfarin

+ digoxin

Genetic polymorphisms - variations accord to a Gaussian distribution. E.g. 8% of

general population poor hydroxylators of propranolol.

Note: Genetic polymorphism of

Age – Elderly have reduced hepatic enzyme function. CYP2D6 is results in a wide variation
in dose requirements for Warfarin!
(Rosenbaum, 2011)
TO DO
Drug metabolism: What is meant by Zero Order Kinetics and First Order Kinetics?

Identify examples of drugs that

display zero order kinetics and
first order kinetics.
DRUG DISPOSITION - EXCRETION
Main route of excretion of drugs + drug metabolites is the kidneys, but other
pathways account for elimination of some drugs.
 E.g. faeces, expiration, sweat + breast milk

Elimination rate varies between individuals and depends on:

1. Rate of metabolism of drug
2. Rate of production of urine
3. pH of urine
DRUG DISPOSITION - EXCRETION
Glomerular filtration – Most drugs small enough to be filtered . If
drug is lipid soluble will be reabsorbed from other parts of the
kidney tubule (proximal convoluted tubule). Drugs extensively
protein bound pass through glomerulus slowly.

Tubular secretion – Active transport mechanisms normally used

for removal of waste products can secrete some acidic and basic
drugs. Can overcome plasma protein binding.

Examples: Penicillins, NSAIDs, Metformin,

Ranitidine
DRUG DISPOSITION – ELIMINATION
• Clearance – the volume of blood cleared of drug per unit of time. Efficiency of
irreversible drug elimination, including:
1. Excretion of unchanged drug in sweat, expired air, faeces…
2. Biotransformation into a different chemical
AUC = dose of
drug
Elimination rate = CL x Cplasma
(mg/h) (L/h) (mg/L)

Clearance is needed to work out the maintenance dose

for maintaining drug plasma concentration at a steady
state
HALF LIFE AND ELIMINATION
• What is meant by the half life of a drug?

• Why do you think half life is important?

• What factors do you think might influence

the half life of a drug?

Drug Example Vd CL T1/2

Chloroquinine 13,000 45 214
Lithium 55 1.5 22
Acyclovir 48 19.8 2.4
Erythromycin 55 38.4 1.6
 DRUG CONCENTRATION IN PLASMA – STEADY
STATE (CPSS)

For drug plasma concentration

to remain constant, try to
achieve:

Elimination rate =
maintenance dose
 PHARMK PARAMETERS FOR ANTIFUNGALS
Drug Onset Peak Duration Protein Bioavailability Half life Elimination
Binding

Fluconazole Slow 1-2 hours 24 hours 11-12% >90% 30 hours >80% unchanged in
urine; 11% as
metabolites in urine
Itraconazole Rapid 1.5-5 hours 12-24 hours 99% 55% 21 hours 40% in urine as
inactive metabolites; 3-
18% in faeces
Ketoconazole Rapid 1-4 hours 24 hours 99% 75% 8 hours 85-90% in bile +
faeces; 10-15% in
urine
Terbinafine Slow 2 hours UA >99% 40% 11-17 80% in urine as
hours metabolites; 20% in
faeces

Adapted from: Kester et al (2012)

PHARMK CONSIDERATIONS WHEN SELECTING
DRUG DOSAGES
• Dose
• Bioavailability
• Route of administration
• Drug interactions
• Time interval between dosages
• Desired steady state plasma concentration
• Volume of distribution
•Clearance
•Half life
PHARMACODYNAMICS
The effect of a drug on the body: action-effect sequence + dose effect relationship.
Also includes how one drug may modify the actions of another.
There are 5 basic types of drug action:
1. Stimulation – e.g. adrenaline stimulates the heart.
2. Depression – e.g. quinidine depresses the heart
3. Irritation – non-selective, noxious effects
4. Replacement – Metabolites, hormones used in deficiency states – e.g. Levodopa
+ Parkinson’s
5. Cytotoxic action – Selective for invading parasites or cancer cells
DRUGS AND SIGNAL TRANSDUCTION PATHWAYS

For
e.g…

http://www.uninet.edu/cin2001-old/conf/bala/fig2.jpg

Schwertz et al (1997)
PHARMACODYNAMICS – MECHANISMS OF
ACTION
• A small number of drugs work directly as a result of their physical or chemical
properties – non-specific drug action
• Other drugs act as fake substrates or inhibitors for transport systems or enzymes.
• Most drugs act by binding to receptors - acting on specific protein molecules that
are typically located in cell membranes.
PHARMACODYNAMICS – DRUG RECEPTOR
INTERACTION
• Receptor – A macromolecule (or binding site) that is located on the surface or inside
an effector cell. It recognises signal molecule or drug and initiates the response to it.
• There are 4 main types of receptors:

Type 1 Type 2 Type 3 Type 4

Receptors that Receptors Directly linked Located in
are coupled coupled to to tyrosine nucleus or
directly to ion effector kinase. Have cytoplasm of a
channels systems by G- an extra and cell
proteins intracellular
domain
PHARMACODYNAMICS – TYPE 2 RECEPTORS IN
ACTION

Cardiac glycosides
PHARMACODYNAMICS – RECEPTOR
INTERACTIONS
What is an agonist?

What is an inverse agonist?

What is an antagonist? Competitive? Non-competitive?

What is a partial agonist? Full agonist?

 PHARMACODYNAMICS –
RECEPTOR INTERACTIONS

Partial agonist? Full agonist? Inverse agonist?

PHARMACODYNAMICS – THE THERAPEUTIC INDEX
 ADME IS NOT THE CLEAREST CLINICAL PICTURE
OF PHARMK + PHARMD: ABCD
• Administration – drug and
adherence

• Bioavailability – movement of
From drug
prescription to active drug around systemic
patient health circulation
(taken from
Doogue and
Polasck, 2013) • Clearance – active drug
leaving systemic circulation

• Distribution – site(s) of action

WHAT WILL YOU NEED TO TAKE AWAY FROM
THESE LECTURES?
Aspirin
• Taken orally (GI tract), absorbed rapidly in small intestine
• 50-80% plasma protein bound, free drug distributed via systemic circulation, acting
on COX 1 and COX 2 enzymes
• Non-selective, COX inhibitor. Irreversible inhibition of COX results in decreased
prostaglandin and thromboxane production.
• Metabolised in the liver and excreted via the kidneys.

AEs: GI irritation, bleeding

CIs: Hepatic/renal disease, children under 16,
YOU WILL NEED TO APPLY THIS KNOWLEDGE ON
CLINIC
What therapeutic drug group does a patients’ drug belong?

What are the indications ?

What is the mechanism of action?

What are the AEs and CIs?

YOU WILL NEED TO CONSIDER HOW THE TAKING OF
PARTICULAR DRUG(S) MAY AFFECT YOUR MANAGEMENT
STRATEGY
NSAIDs – renal damage, asthma attacks
Anti-rheumatics + steroids – immunosuppression
Local anaesthetics – toxic reactions/anaphylaxis
Warfarin/aspirin – impaired haemostasis
Beta-blockers – cold extremities
Topical steroids – skin atrophy, aggravation of fungal infections
Statins – myalgia, interaction with grapefruit juice
A basic understanding of pharmacology and
its application is a critical facet of podiatric
care.