Download Basic concepts in clinical pharmacology

Basic concepts in clinical pharmacology
Tony Fox
_________________________________
Anthony W Fox MSc MBBS MD(Lond) FRCP FFPM DipPharmMed MCSFS DipFHI CBiol
Visiting Professor, Institute of Pharmaceutical Sciences
School of Biomedical Sciences, King’s College London.
[email protected]
Types of drug
Pharmacodynamics vs. pharmacokinetics
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG
What is ADME ?
Lipid membranes
Molecular weight, pH, pK, and LogP
Liver and kidney
Clinical example: The treatment of aspirin overdose
PHARMACODYNAMICS: WHAT THE DRUG DOES TO THE BODY
Types of drug target
Receptors, enzymes, ion channels, and ‘second messengers’
Receptor occupancy – response relationships and theories
Agonists, partial agonists
Competitive antagonists, uncompetitive antagonists
Quantitation of drug effect / antagonism
Power, potency and selectivity
Unwanted drug effects: concentration-dependent and –independent
PK – PD RELATIONSHIPS
The classic single-dose time-> concentration curve
Chronopharmacology and ‘hysteresis’
Clinical examples : Heroin, morphine, buprenorphine, and codeine
: ’Beta blockers’
TYPES OF DRUG
Types of drug: or how, basically, do drugs work ?
Extension of nutrition: Oxygen, vitamin C, etc.
Non-specific Membrane effects: Alcohol, inhaled anaesthetics
Enzyme inhibition: ACE inhibitors, physostigmine, sulfonamides
Cell surface receptors: Beta blockers, opioids, monoclonals, many others
Nuclear receptors and nucleic acids: Steroids, antisense drugs, chemotherapy
Ion channel interference: Local anaesthetics, anti-epileptic drugs
‘Chelation’ of endogenous ions / molecules: heparins, tetracyclines
PHARMACOKINETICS: BASIC CONCEPTS
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG:
VARIOUS ROUTES OF ADMINISTRATION AND FORMULATIONS
A
Absorption
D
Distribution
M
E
Metabolism
Elimination
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG:
Getting from the site of absorption to sites of action,
metabolism and elimination
A
Absorption
D
Distribution
M
E
Metabolism
Elimination
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG:
S+E+R
A
D
M
E
Metabolism
↔
SE + R
P + R’ + E
Absorption
Circulation
Distribution
Tissue(s)
Elimination
TYPICAL “Two-compartment”
PHARMACOKINETIC MODEL
A Typical Time-> Plasma concentration curve
Venous plasma sumatriptan concentration (ng/mL)
(oral sumatriptan; normal volunteer)
Cmax (= 50 ng/mL)
50
40
Absorption ,
distribution and
elimination
phase
What is the
half-time of
elimination ?
Elimination phase
30
Decay curve
‘1st order
elimination’
20
15
10
7.5
3.75
0
1
Dose (50 mg)
2
3
4
Tmax(= 2 h)
5
6
7
8
9
Time post-dose (hours)
10
11
12
NOTE:- There are exceptions.
Some drugs don’t exhibit 1st order elimination
(usually at relatively high doses)
WHY ?
Drug Metabolism:
Usually pathways that are used by liver to defend the body
against ingested xenobiotics
Aim is typically to increase polarity of drug molecule so as
to increase urinary and biliary excretion
Cytochrome P450 (CYP; ‘sip’) enzymes are especially
important, supporting drug metabolism, usually with
NADPH, NADH, or flavoprotein coenzymes:
Examples
De-alkylation: Codeine, diazepam, imipramine
Hydroxylation: Phenytoin, ibuprofen, ciclosporine
N-oxidation:
chlorpheniramine, pethidine, dapsone
Sulfation:
Paracetamol (acetaminophen), steroids
Glucuronidation: morphine, lorazepam
Deamination: diazepam, amphetamine
Acetylation:
isoniazid, sulfonamides
Methylation:
L-dopa, captopril
(Mixed function oxidases)
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG:
A
D
M
E ELIMINATION
OUTSIDE
INSIDE
How can
drugs get
inside that ?
A. They don’t: stimulate receptors on the surface
B. Actively transported in by a trans-membrane protein
C. Passively get in if sufficiently lipophilic
LIPOPHILICITY:
1. Electro-negative or –positive substituents can alter the
lipophilicity markedly among a series of congeners
practolol
2. Non-ionized drugs cross lipid membranes more
easily than ionized ones.
DRUG CHEMISTRY: GET THE UNITS RIGHT
0.
1 mol = 6.022 x 1023 molecules of a pure substance
Avagadro’s constant (L) ~ 6.022 x 1023 mol-1
A molar (1 M) solution has a concentration of 1 mol / L
1. pH: the negative logarithm of the ambient hydrogen ion
concentration:
H3O+ + OH- <-> 2H2O
For pure water [H3O+] is about 0.1 μM => pH = 7
= a chemical definition of acid/base neutrality
(physiological neutrality 7.36 – 7.44)
The pK is the pH at which half the drug is ionized
Two Options for drug solutions
Drug+ + OHpH > 7.0
Basic drug
pK > 7.0
OR
Drug-
+
pH < 7.0
H+
Acidic drug
pK < 7.0
MEASURING LIPOPHILICITY: the Partition Coefficient
Drug + cap and shake x 12 h
[Drug] in octanol
Log P = Log
[Drug] in aqueous
(Usually octanol)
+ phosphate buffer pH=7.4
(Or HPLC using a non-polar column and compare unknown to set of knowns validated by
the equilibrium shaking method)
CLINICAL EXAMPLE: TREATING ASPIRIN OVERDOSE
LESS THAN 4 HOURS PRIOR
OBJECTIVES:
1. Reduce drug absorption – stomach washout
2. Hasten aspirin excretion
Acetylsalicylate m.w. 138, Log P 2.26, pKa 2.97
(Therefore easily filtered by the glomerulus).
To encourage urine flow: administer IV fluids
Should bicarbonate or ammonium chloride also be
given ?
Pharmacodynamics: Basic Concepts
PHARMACODYNAMICS: WHAT THE DRUG DOES TO THE BODY
Types of drug target
Receptors, enzymes, ion channels, and ‘second messengers’
Receptor occupancy – response relationships and theories
Agonists, partial agonists
Competitive antagonists, uncompetitive antagonists
Quantitation of drug effect / antagonism
Power, potency and selectivity
Unwanted drug effects: concentration-dependent and –independent
PK – PD RELATIONSHIPS
The classic single-dose time-> concentration curve
Chronopharmacology and ‘hysteresis’
Clinical examples : Heroin, morphine, buprenorphine, and codeine
: ’Beta blockers’
Types of drug target I
Enzymes:
Useful targets if circulating or form cell surface
glycoproteins, e.g., angiotensin converting enzyme
(ACE)
’
Ion channels:
Usually represent cell surface targets, e.g. sodium
channels and local anaesthetics.
Types of drug target II:
Classical ‘receptors’ (7-transmembrane, G-protein coupled
receptors) where conformational change can lead to intracellular
‘second messenger’ formation
Examples:
Adrenergic receptors:
Alpha-1 (vasoconstriction) : antagonists, antihypertensives
prazosin, labetalol
Beta-1 (cardiac): antagonists protect against angina,
long QT syndrome TdP, antihypertensive
propranolol et al
Beta-2 (bronchodilation): agonists for asthma, salbutamol etc
Serotonin receptors: 5HT-1B: agonists triptans, ergots, acute migraine
-1F : antagonists, ondansetron, CT emesis
Enkephalin receptors: agonists:
opioids, analgesia, respiratory depression, g/i stasis,
euphoria, dysphoria
antagonists: opioid reversal, opioid blockade, naloxone etc
Acetylcholine receptors: muscarinic, vagal tone, g/I motility
antagonists: oropharyngeal drying (premeds)
: sedatives : chlorpheniramine etc
The Indirect Relationship between receptor occupancy
and drug effect
Drugs are conceived as having two properties:
i) RECEPTOR AFFINITY:
Ability to bind to the receptor (measured as
the KD or Kd, i.e., the concentration (mM or μM)
needed to achieve 50% receptor occupancy)
And ii) RECEPTOR EFFICACY:
The ability, once actually bound, to stimulate
second messenger generation (Stephenson’s
dimensionless constant e).
Confusingly, e is also dependent upon available receptor
density (see below).
Graphs of mass action become semi-log plots
For a drug with Kd = 1 μM
Kd is a constant, defined
as measured in the
absence of any other
interfering drug /
hormone
Kd = 1 μ M
-7
-6
-6
Log([Radioligand] (M))
-5
Agonism and Antagonism: The difference between binding to a
receptor and activating it. EQUILIBRIAL / REVERSIBLE DRUGS
[DR] = 1.0 x k(Effect size)
[D] + [R]
% Maximum (effect or bound)
100
80
BINDING
‘FULL AGONIST’
(e.g. adrenaline,
beta-1 adrenoceptor,
heart contractility)
EFFECT
60
e=1
40
Kd = EC50 = 1 μM
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
Agonism and Antagonism: The difference between binding to a
receptor and activating it. EQUILIBRIAL / REVERSIBLE DRUGS
[DR] = 0.6 x k(Effect size)
[D] + [R]
100
% Maximum (effect or bound)
80
‘PARTIAL AGONIST’
(e.g. clonidine,
alpha-1 adrenoceptor,
blood pressure elevation)
BINDING
EFFECT
60
e = 0.6
40
Kd = EC50 = 1 μM
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
Agonism and Antagonism: The difference between binding to a
receptor and activating it. EQUILIBRIAL / REVERSIBLE DRUGS
[CA-R] = 0.0 x k(Effect size)
[CA] + [R]
100
% Maximum (effect or bound)
80
‘COMPETITIVE AGONIST’
(e.g. propranolol,
beta-1 adrenoceptor,
Heart rate)
BINDING
60
e = 0.0
40
Kd = 1 μM, no EC50
20
EFFECT
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
Agonism and Antagonism: The difference between binding to a
receptor and activating it. EQUILIBRIAL / REVERSIBLE DRUGS
[DR] + [CA-R] = 1.0 x k (Effect) + 0.0 x k (Effect)
[D] + [CA] + [R]
% Maximum (effect or bound)
100
80
No Antagonist
‘FULL AGONIST’
With and without
COMPETITIVE
AGONIST
With Antagonist
60
e=1
40
Kd = EC50 = 1 μM
Apparent
EC50 > Kd
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
Agonism and Antagonism: The difference between binding to a
receptor and activating it. IRREVERSIBLE ANTAGONISM
% Maximum (effect or bound)
100
80
60
40
20
IRREVERSIBLE INACTIVATION OF RECEPTOR:
Classically: phenoxybenzamine, alpha-1
adrenoceptors, anti-hypertension
Others:
Monoclonals at various
lymphocyte receptors
Carbon monoxide
Various other poisons
No antagonist
BINDING
EFFECT
With
antagonist
e = 0.6
Kd = EC50 = 1 μM
0
-9
-8
-7
-6
-5
-4
Log [Adrenaline (M)] + phenoxybenzamine Rx
Agonism and Antagonism: The difference between binding to a
receptor and activating it. EQUILIBRIAL / REVERSIBLE DRUGS
[DR] = 10.0 x k(Effect size)
% Maximum (effect or bound)
[D] + [R]
100 ‘SUPER AGONIST’
Or
‘AGONIST WITH
80
RECEPTOR RESERVE’
(e.g. noradrenaline,
60 beta-1 adrenoceptor,
heart rate)
EFFECT
BINDING
40
20
e>1
EC50 < Kd
Kd = 1 μM (> EC50)
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
PK – PD RELATIONSHIPS
A Typical Time-> Plasma concentration curve
Venous plasma sumatriptan concentration (ng/mL)
(oral sumatriptan; normal volunteer)
Cmax (= 50 ng/mL)
50
40
Absorption ,
distribution and
elimination
phase
What is the
half-time of
elimination ?
Elimination phase
30
Decay curve
‘1st order
elimination’
20
15
10
7.5
3.75
0
1
Dose (50 mg)
2
3
4
Tmax(= 2 h)
5
6
7
8
9
Time post-dose (hours)
10
11
12
WHEN DRUG EFFECT IS DIRECTLY RELATED TO DRUG CONCENTRATION
(e.g., many antibiotics, isoflurane, remifentanil)
Venous plasma drug concentration (ng/mL)
Cmax (= 50 ng/mL)
50
PEAK EFFECT
40
30
20
LAG
THRESHOLD CONCENTRATION
Duration of effect
10
Time of onset of effect
No effect
0
1
Dose (50 mg)
2
3
4
Tmax(= 2 h)
5
6
7
8
9
Time post-dose (hours)
10
11
12
THE DYNAMIC SITUATION:
% Maximum effect or concentration
100
80
60
40
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
BUT MANY EXCEPTIONS TO THIS SIMPLE SITUATION:
- Big distribution phases
- Drug sequestration in tissues (especially lipophilic drugs)
- Drug interactions
- Slow off-phases of drug-receptor equilibria
- Tachyphylaxis / sensitization
CLINICAL EXAMPLE: Buprenorphine
- administer 0.3 mg IV
- no detectable drug in circulation after 10 minutes
- analgesia onset at about 15 – 30 minutes
- duration of effect 6 – 12 hours
THE DYNAMIC SITUATION:
‘PHASE PLANE’ or ‘HYSTERESIS LOOP’
100
% Maximum effect
80
‘Persistent effect’ or
‘Hangover effect’ or
‘Washout effect’
60
40
20
Lag
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
THE DYNAMIC SITUATION: BUPRENORPHINE
‘PHASE PLANE’ or ‘HYSTERESIS LOOP’
100
‘Persistent effect’ or
‘Hangover effect’ or
‘Washout effect’
% Maximum effect
80
60
40
20
Lag
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
ADVERSE DRUG EFFECTS CAN HAVE THEIR OWN DOSE-RESPONSE
CURVES: (“Type A adverse events”)
e.g., paracetamol analgesia and hepatotoxicity
100
Wanted Drug
Effect
% Maximum effect
80
Unwanted drug
effect
60
‘Therapeutic
Window’
40
Compromise
Concentration
(or dose)
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
CHECK QUESTIONS
1. What does ADME stand for ? (Four words)
2. NAME STRUCTURES
marked 3, (5 + 6)
3. Which of ADME does
this organ participate in
(in general) ?
4. What might be
typical units for
Km ?
5. Provide the three missing words:
Km is the _______________ of ________________
where the reaction rate is half of the ______________
reaction rate.
6. Whose equation is this
? (Two names)
7. If at T1, [S] is vastly
greater than Km,
Then what is V1 ?
8. If at T1, [S] is vastly
greater than Km, then
are V1 and V2 (at T2,
few minutes later)
likely to be the same
or different ?
9. Is sodium acetylsalicylate (aspirin) the salt
of an acidic or basic drug ?
10. Is the pK of aspirin greater than or less
than 7.0 ?
11. Is amphetamine hydrochloride the salt of
a basic or acidic drug ?
12. Is the pK of amphetamine hydrochloride
greater than or less than 7.0 ?
Venous plasma sumatriptan concentration
(ng/mL)
13. After a single oral dose of drug, during the time period when the
plasma concentration time curve exhibits first-order elimination
(Elimination phase), does the half-time of elimination change ?
Absorption ,
distribution and
elimination
phase
Cmax (= 50 ng/mL)
50
40
Elimination phase
30
2
0
10
0
Dose (50
mg)
1
2
3
4
Tmax(= 2 h)
5
6
7
8
9
Time post-dose (hours)
10
11
12
14. For equilibrial drugs, compared with 4, which is A. Non-competitive
antagonism, B. Competitive antagonism, C. Partial Agonism, D. Super agonism
15. What is the arrow pointing at ?
% Maximum (effect or bound)
100
3
80
BINDING
4
2
60
EFFECT
1
40
20
0
-9
-8
-7
-6
Log [Drug (M)]
-5
-4
16. QUESTION- CLINICAL EXAMPLE:
1. You are the OOH drug information scientist / pharmacist / GP /
on-call officer for the pharmaceutical company / nurse / etc.
2. The (male) patient has a longstanding history of kidney stones.
They are usually small, they usually pass within 48 h, and the
patient has been responsibly using 10 mg morphine (full
agonist) tablets PRN for a long time.
3. The patient’s partner phones. Usual problem, renal colic, took
morphine tablets 6 h and 2 h ago, still in great pain. Some
within-date dihydrocodeine (partial agonist) tablets are in the
bathroom cabinet, which she was given to use PRN after an
out-patient gynaecological procedure 3 weeks ago. Can her
partner take additional dose(s) of dihydrocodeine ?
Reading
Buxton ILO. Pharmacokinetics and pharmacodynamics: The dynamics of drug
absorption, distribution, metabolism, and excretion. In: Brunton LL, Lazo JS, Parker
KL(Eds) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New
York: McGraw Hill, 2008; 11th edition ISBN 0-07-142280-3, pp.1-39
Reading
Buxton ILO. Pharmacokinetics and pharmacodynamics: The dynamics of drug
absorption, distribution, metabolism, and excretion. In: Brunton LL, Lazo JS, Parker
KL(Eds) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New
York: McGraw Hill, 2008; 11th edition ISBN 0-07-142280-3, pp.1-39