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Pharmacology
GENERAL PHARMACOLOGY
PHARMACOKINETICS
Anna Lorenc-Duda
[email protected]
Synonyms for drug
medicinal drug
medication
medicine
agent
pharmacologic tool
substance of abuse
gr. pharmacon- drug;
logos- word, science
Drug
any substance, other than food, used in
the prevention, diagnosis, alleviation,
treatment, or cure of disease
John Jacob Abel
(1859 – 1938)
Drugs' names
chemical name
international name (nonproprietary,
generic name)
brand name (trade name)
Groups of drugs
analgesics
antihistamine
diuretics
tranquillizers
antipyretics
anticoagulants
laxatives
antibiotics
1
Drug doses
threshold (subtherapeuthic, minute) dose
therapeutic dose
initial loading dose
toxic dose
lethal dose
Drug formulation - solid
Suppositories : suppositories for
application into the rectum, urethra, and
vagina.
Drug ingredients
active ingredient(s)
auxiliary substances:
– disintegrants
– binders
– solvents etc.
Drug formulation
Drug formulation - solid
Tablets : uncoated tablets,
coated tablets,
effervescent tablets,
enteric (gastroresistant)
tablets.
Capsules : hard capsules,
soft capsules,
gastroresistant capsules.
Drug formulation
Parenteral preparations : injections,
intravenous infusion.
Ointments : lipophilic, water-emulsifying, or
hydrophylic ointments, dermatological
ointments, pastes, tooth pastes, creams, gels,
(glicerol ointments).
Medicinal solutions : aqueous solutions,
alcoholic solutions, glycole solutions,
paraffine solutions.
Aerosols : aerosols for topical use, ophtalmic
aerosols, aerosols for administration into the
body cavities (rectum,vagina), aerosols for
inhalations
(administration via the respiratory system or
nasal passages).
Ophtalmic preparations : ophtalmic
solutions, ophtalmic ointments.
Transdermal systems
2
Compliance/non-compliance
Rate of compliance
Controlled-release preparations
Extended-release, sustained-release, prolongedaction preparations
Most appropriate for drugs with short half-lives
Advantages:
„Drugs don’t work if you don’t take them”
↓ the number of required dosing
occasions will improve adherence to a
prescribed dosage regiments
– reduction in the frequency of administration of the drug
– maintenance of a therapeutic effect overnight,
– a decreased incidence and/or intensity of undesired effects
Drawbacks:
– interpatient variability
– „dose-dumping”
Principles of appropriate antibiotic use
Michael S. Niederman*
International Journal of Antimicrobial Agents 26 Suppl. 3 (2005)‫‏‬
Pharmacokinetics vs.
pharmacodynamics
Pharmacokinetics what the body does
to the drug
Pharmacodynamics what the drug
does to the body
Pharmacokinetics - overview
• How drugs are absorbed, distributed,
and eliminated
Site of administration
Urine, feces, bile
Absorption
Elimination
Plasma
Distribution
Tissues
Drug action
Metabolism
Absorption
DEF: transfer of drug from site of
administration to blood stream
Determining factors:
– lipid diffusion
– blood flow to the absorption site (eg. intestine vs.
stomach, epinephrine)
– surface area (large in duodenum – microvilli, lungs –
pulmonary alveoli)
– contact time at the absorption surface (eg.
diarrhea, constipation atropine)
3
is crucial for the absorption, distribution and excretion of a drug
Bioavailability
120
100
80
Ionization state – key factor
Passive diffusion
Carrier-mediated processes
– % of drug which reaches systemic circulation
– for IV injection 100%
C (mg/l)
Drug diffusion across a lipid
membrane
Passage across membranes
Absorption
Bioavailability=AUCoral/AUCiv
60
40
20
– uncharged – lipid soluble (lipophilic)
– (+) or (-) – lipid insoluble (hydrophilic)
– facilitated diffusion
– active transport
Henderson-Hasselbach equation
– log([XH]/[X]) = pKa - pH
Through pores or ion channels
By pinocitosis
• XH – protonated form of the drug
• X – unprotonated form of the drug
• pKa – acid dissociation constant of the drug
0
0
2
4
6
8
10
time (h)‫‏‬
– Important factors: first-pass effect, solubility, stability,
formulation
Drug diffusion across a lipid
membrane
The effect of pH on drug ionisation
Henderson-Hasselbach equation
– log([XH]/[X]) = pKa – pH
Acid -
Drug
Protonated form
Unprotonated form
Acid
HA H+ + A-
Uncharged
(lipophilic)‫‏‬
(-) (hydrophilic)‫‏‬
(+) (hydrophilic)‫‏‬
Uncharged
(lipophilic)‫‏‬
Base
BH+ B+H+
– Conclusion – for weak acids the lower the pH,
the higher the lipid solubility (inversely for
weak bases)
Routes of drug administration
Low pH
(e.g. –COO- )‫‏‬
(e.g. –COO- )‫‏‬
Acid-H
High pH
(e.g. –COOH)‫‏‬
High pH
Base-H +
(e.g. –NH3+ )‫‏‬
Ionised
water-soluble form
Base
Low pH
(e.g. –NH2 )‫‏‬
Enteral
Parenteral
Other
–
–
–
–
–
inhalation
intranasal
intrathecal/intraventricular
topical
transdermal
Unionised
lipid-soluble form
4
Enteral administration
First-pass effect
(metabolism)
LIVER
Oral
– absorption: intestine (duodenum), stomach
General circulation
(much less)
– high variability
•
•
•
•
Metabolism
degradation in the GI tract
uneven absorption (food...)
formulation, e.g. sustained-release preparations
Portal circulation
metabolism of a drug
Metabolic barriers for drugs
after oral administration
Intestinal lumen
Intestinal wall
Liver
Lung
Drug administered
intravenously (iv)
enters directly into the
systemic circulation
and has direct access to
the rest of the body.
REST OF BODY
Drugs administered orally are
first exposed to liver and may
be extensively metabolised
before reaching the rest of the
body.
Factors affecting oral absorption
Drug structure
Formulation
Gastric emptying
Blood flow to the absorption site
Examples of drugs undergoing
substantial first-pass metabolism
Glyceryl trinitrate
Levodopa
Lidocaine
Morphine
Propranolol
Salbutamol
Verapamil
Enteral administration
Sublingual
– under the tongue
– absorption through capillary network
– lower variability
• no first-pass effect
• no degradation in the GI tract
5
Enteral administration
Rectal
– drug placed in the rectum
– absorption through capillary network
– lower variability
• 50% of the drug bypasses portal circulation
• no degradation in the GI tract
– used for drugs which provoke vomiting, or
for patients already vomiting
– irregular and incomplete absorption
– may be irritant
Parenteral administration
Intramuscular (IM)
• requires absorption
• Administration of larger volumes than s.c.; drug can be released
slowly into the circulation, while some of it being stored in the
muscle
• Antibiotics usually given this way
• often used as depot preparations (slow diffusion from lipid
medium – e.g. haloperidol decanoate)
Subcutaneous (SC)
•
•
•
•
•
requires absorption
Advantage – injection not too deep and painful
Disadvantage – only a small volume can be injected (max 2 ml)
sometimes used with epinephrine to limit area of action
used with solids (contraceptive capsules, insulin pumps)
Intradermal
Parenteral administration
Avoids the GI tract
Used for:
– drugs poorly absorbed or unstable in the GI tract
– unconscious patients
– drugs requiring quick onset of action
Advantages:
– control over dose administered
– no first-pass effect
– quick onset of action
Disadvantages:
– disliked by many patients (painful)
– usually requires qualified staff to administer
– high cost
Intradermal vs. subcutaneous injection
Parenteral administration
Types of parenteral administration:
– Intravascular: Intravenous (IV) or intraarterial (IA; rarely)
• Advantage - most control over dose
administered (no absorption phase, no first-pass
effect – bioavailability 100%)
• Disadvantage – invasive, uncomfortable, risk of
introducing bacteria, induction of hemolysis and
other adverse effects
Other administration routes
Inhalation
– Advantages:
• rapid delivery – very large surface
• quick onset of action (e.g. anesthetics)
– used for patients with respiratory
disorders
Intranasal
– absorbed through dense capillary network
– used for desmopressin, calcitonin, and
locally acting decongesting drugs, also for
addictive drugs (cocaine, amphetamine)
6
Other administration routes
Intrathecal/intraventricular
– introduction of drugs directly into the
cerebrospinal fluid (CSF)
– e.g. methotrexate in acute lymphocytic leukemia
– Advantages: no need to cross the BBB
Topical
– Mucous membranes, skin, eye
– local effect (e.g. clotrimazole – antifungal)
Transdermal (percutaneous)
– systemic effect – application on the skin (patch)
(e.g. nitroglycerin, nicotine for addicts)
Distribution
Volume of distribution (Vd)
DEF: transfer of drug from blood stream to the tissues
Steps:
– dilution in blood
– movement into extracellular fluid surrounding cells
– uptake into cells
Important factors:
–
–
–
–
binding to proteins
blood flow
ability of the drug to cross cell membranes
capillary permeability
– D – total dose of drug administered
– C – concentration of drug in the plasma
• capillary structure (blood-brain barrier tight junctions vs.
liver slit junctions)
• drug structure
– pH differences across membrane barriers
The blood-brain barrier
Junctions between endothelial cells in
capillaries:
– slit junctions large spaces, even proteins
pass (liver, spleen)
– tight junctions CNS cells virtually
glued together BBB
• additional barrier glial cells (astrocytes)
surrounding capillaries
• only lipophilic compounds pass (e.g., levodopa)
Def: the volume of plasma that would
contain the total body content of the
drug at a concentration equal to that in
plasma
Vd=D/C
Can be used to calculate the dose
required to obtain desired plasma
concentration
The blood-brain barrier
Typical
Capillary
Brain
Capillary
The blood-brain barrier
Weaker:
–
–
–
–
–
–
in fetuses and young children (<2 years of age)
stress
infection
hypertension
trauma
aging
Chemical trigger zone
– area postrema toxic substances pass and trigger
vomiting (dopaminergic system)
7
The placental „barrier”
Drugs may cause congenital anomalies
All drugs cross the placenta and enter
breast milk!!!
Binding to proteins
Predominantly albumin
– high affinity for weak acids and lipophilic
drugs
α1-acid glycoprotein (basic drugs)
Metabolism
Most frequently two phases
– Phase I introduction of hydrophilic polar
group (-OH, -NH2)
– Phase II conjugation (glucuronidation,
acetylation, sulfonylation, conjugation with
amino acids)
active/inactive
D
Phase I metabolism
Most reactions depend on the Cytochrome P450 (CYP 450) system (microsomal mixed
function oxidase)
– important for metabolism of exogenous and
endogenous compounds
– many isozymes grouped into families
• overlapping functions
• induction/inhibition of CYP isozymes interactions
Some reactions CYP-independent
– amine oxidation (histamine), alcohol
dehydrogenation (ethanol), hydrolysis
(procainamide),…
Contribution of the CYP isoforms
in the metabolism of drugs
CYP3A4, CYP3A5 – 50% of drugs
CYP2C
CYP2D6
active/inactive
Ph I
D -OH
inactive
Ph II
D -O- C
Phase II metabolism
Conjugation
– some drugs do not undergo this phase
– some drugs enter Phase II directly
– for some drugs Phase II and Phase I are
reversed (isoniazid acetylation then
hydrolysis)
– neonates deficient in glucuronidation
system increased toxicity of
chloramphenicol
8
Factors affecting drug
metabolism
Genetic variation
Environmental determinants
Disease factors
Age and sex
Drug metabolism
INHIBITORS
cimetidine
erythromycin
grapefruit juice
ketoconazole
quinidine
Routes of drug elimination
kidney
biliary system
lungs
external secretions
– sweat
– milk
INDUCERS
ethanol
omeprazole
phenobarbital
rifampi(ci)n
smoking
Elimination
Clearance
– volume (of plasma presumably) per unit time
that would be completely freed of the drug
– CL = ve/[drug] = Vd/ke
• ve – rate of drug elimination
• Vd – volume of distribution
• kel – elimination constant = ln2/t½
– Additive
• CLt = CLrenal + CLhepatic + CLpulmonary + CLother
Prodrugs
Pharmacologically inactive compounds, designed
to maximize the amount of the active species
that reaches its site of action
Examples:
Cyclophosphamide
Levodopa
Valaciclovir
Famciclovir
Renal clearance
Kidneys most important excretory organ
Corellated with exogenous creatinin clearance
or serum creatinin concentration
Influencing factors:
– Glomerular filtration binding to plasma proteins
– Tubular secretion affinity for transporter
mechanisms
– Passive tubular reabsorption lipid solubility (eg.
thiopental), pH, rate of urine flow
9
Hepatic clearance
Drug elimination
Excretion with bile intestine
– some drugs deconjugated and reabsorbed enterohepatic circulation
Various transporters in liver cells
Conjugation
• blood hepatocyte
• hepatocyte bile duct
Influencing factors:
–
–
–
–
(Elimination) half-life (t1/2) – the time it
takes for the plasma concentration, or
the amount of drug in the body, to be
reduced by 50%.
Biliary duct
molecular weight (+)
genetic factors
polarity (+)
protein binding
Pharmacokinetic parameters
SUMMARY
bioavailability
volume of distribution
clearance
elimination half-life
t1/2= 0.693 Vd / CLtotal
Deconjugation
Some drugs designed for biliary excretion
Problems - examples
Morphine has a pKa of about 8. Would you
expect morphine to be mainly ionized or
nonionized in the stomach pH?
Drug X has a half life of 4 hours and is
administered as an intravenous bolus dose to
produce a concentration of 100 mcg/ml. How
long after administration of the dose of Drug
X will the concentration drop to 25 mcg/ml?
10