Download Principles of Pharmacology

Noppamas Rojanasthien, MD
PHCO 320301 : General Principles of Pharmacology
Noppamas Rojanasthien M.D.
Pharmacology “drugs and the body ”
I Pharmacokinetics
II Pharmacodynamics
What the body does to the drug
- Absorption
- Distribution
- Biotransformation (Metabolism)
Excretion
What the drug does to the body
- Drug receptors
- Effects of drug
- Responses to drugs
- Toxicity and adverse effects of drugs
Transfer of drugs across cell membranes
1. Passive diffusion (from high to low concentrations)
Diffusion rate depends on concentration gradient, lipid solubility, degree of ionization and size of
drug, area of the absorptive surface because cell membranes = Semipermeable phospholipid
bilayer
Drug molecule that favor drug transport across membrane
1. Lipid soluble drugs (uncharged, nonpolar)
2. Small molecules
Most drugs are weak acids or weak bases
Degree of ionization of drugs
Weak acid (proton donor, e.g., aspirin )
AH ←→ A- + H+
Acid environment (gastric pH, 1.4) = ↑ Nonionized form
Plasma pH, 7.4 = ↑ Ionized form
Weak base (proton acceptor e.g., quinidine)
BH+ ←→ B + H+
(Acid = ↑ Ionized form)
(Alkaline = ↑ Nonionized form)
Non-ionized form of drug is lipid soluble.
Influence of pH on drug absorption
Stomach e.g. salicylic acid (weak acid) ↓ ionized form in stomach (acid pH)
! cross readily in the stomach to plasma but cross hardly from plasma to stomach
(plasma pH = 7.4 , ↑ ionized form)
Is the drug lipid or water soluble ?
Drug absorption takes place at the small intestine (large surface area).
Effects of food, antacids, blood flow, bile etc.
Controlled-release preparations
Effects of pH on drug elimination (distal renal tubule)
Alkalinized urine (sodium bicarbonate)
↑ excretion of acidic drugs (e.g. salicylate, uric acid)
Acidified urine (ammonium chloride)
↑ excretion of basic drugs (e.g. amphetamine)
2. Active transport : (renal tubule, biliary tract, blood-brain barrier, GI tract)
Require energy, selectivity, limited specific membrane carrier ! saturation kinetics
e.g., ions, vitamins, sugars, amino acid
3. Facilitate passive diffusion
e.g., glucose (low lipid solubility) rate of diffusion > expected
carrier-mediated diffusion (selectivity, saturability, does not require energy, does not transport
against concentration gradient
4 . Pinocytosis
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Noppamas Rojanasthien, MD
Drug absorption, Bioavailability and Routes of administration
Factors that modify absorption
1. drug solubility (aqueous solution absorb faster than oily solution or solid form)
2. rate of dissolution (solid form)
3. concentration of drug
4. circulation to sites of absorption and area of absorbing surface
5. first-pass metabolism
Bioavailability = the fraction of drug that reaches the systemic circulation.
= the rate and extent of drug reaches its site of action
Determine as the ratio of the AUC’s obtained after oral and IV doses
Bioavailability (F) =
AUCoral
Doseiv
x
AUCiv
Dose oral
Bioequivalence = drugs with the same rate and extent of bioavailability
Bioequivalence =
Dosereference
AUC test
x
AUCreference
Dose test
Routes of drug administrations
1. Alimentary routs : oral administration (sublingual, buccal, rectal, etc.)
2. Parenteral routes : intravenous, intramuscular, subcutaneous, etc
3. Others : Topical (skin, eye), Inhalation
Some Characteristics of Common Routes of Drug Administration*
ROUTE
ABSORTION PATTERN
SPECIAL UTILITY
Oral
ingestion
Variable; depends
upon many factors
May show first-pass
effect
or presystemic
extraction
Intravenous
Absorption
circumvented
Potentially immediate
effects
Intramuscular
Prompt, from aqueous
solution
Most convenient and
Requires patient
economical; usually more safe
cooperation
Availability
potentially erratic and
incomplete for drugs
that are poorly soluble,
slowly absorbed,
unstable, or
extensively
metabolized by the
liver and/or gut
Immediate onset
Increased risk of
(for emergency use, low BP
adverse effects
or shock)
Must inject solutions
Complete drug availability
slowly, as a rule
Not suitable for oily
(no first-pass effect)
solutions or insoluble
Permits titration of dosage
substances
Usually required for high
molecular weight protein
and peptide drugs
Suitable for large volumes
and for irritating substances,
when diluted
Suitable for moderate
Precluded during
volumes, oily vehicles, and
anticoagulant Rx,
some irritating substances
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LIMITATIONS AND PRECAUTIONS
Noppamas Rojanasthien, MD
Slow and sustained,
from repository
preparations
Subcutaneous
Prompt, from aqueous Suitable for some insoluble
suspensions and for
solution
implantation of solid pellets
Slow and sustained,
from repository
preparations
*See text for more complete discussion and for other routes.
bleeding tendency
or low BP (shock)
May interfere with
interpretation of
certain diagnostic
tests
(e.g., creatine kinase)
Not suitable for large
volumes
Possible pain or
necrosis from irritating
substances
Distribution of drugs
1. Physiological factors
Cardiac output & blood flow & size of the organ
(brain, liver, kidney, heart >> muscle, viscera, skin, adipose tissue)
CNS (blood-brain barrier), Placenta
2. Physicochemical properties of drugs
Solubility ( lipid or water solubility, degree of ionization)
Drug reservoir (plasma proteins, cellular reservoirs)
Drug displacement from binding sites and change in drug levels
Distribution of drug influence its site of action and duration of action
Redistribution [e.g. (IV) thiopental, diazepam distribution to brain ! action
and redistribution to peripheral tissue! terminate action]
Anatomical barrier : Blood-brain barrier (permit only lipid-soluble drugs)
Meningitis or inflammation (more permeable to antibiotics)
Placental transfer of drug (lipid-soluble, nonionized drugs)
Acid drugs with highly protein bound (Warfarin 8 L / 70kg, Aspirin 12 L / 70Kg)
Basic drug avidly taken up by tissue (Amphetamine = large Vd)
Apparent volume of distribution (Vd)
- determine amount of drug in the body
- determine a loading dose
- Estimate feasibility of using dialysis in case of drug overdose
Vd =
Amount of drug in the body
F(dose)
=
Plasma drug concentration
Co
Loading dose = Cp x Vd
Drug Biotransformation (Metabolism)
Why is drug biotransformation necessary?
To eliminate the drug
Lipophilic drug ! filtered through glomerulus ! reabsorbed by renal tubule
Lipophilic drug ! biotransformed to more polar compound
! more readily excretable by the kidney
Where do drug biotransformation occur ?
Liver, Kidney, GI, Skin, Lung (mostly occur in the liver)
Phase I Oxidations ! liver CYP450 (Microsomal mixed function oxidase system)
Enzyme inducers :
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Noppamas Rojanasthien, MD
Chronic alcohol ingestion, Cigarette smoker
Barbiturates, Carbamazepine, Estrogen, Rifampin
Enzyme inhibitor :
Acute alcohol ingestion
Cimetidine, Erythromycin, Ketoconazole, Verapamil, INH
Reductions ! Flavin enzyme
Hydrolysis ! Esterase
Phase II Acetylation, Glucuronidation, Conjugations, Methylation
Is the drug activated or inactivated by the liver enzymes ?
an active drug ! inactive metabolite
an active drug ! active metabolite (morphine, spironolactone)
an active drug ! toxic metabolite (acetaminophen, lidocaine)
PRODRUG ! active metabolite (enalapril, simvastatin, cyclophosphamide)
First-pass effect and Extraction ratio
High extraction ratio ! required larger oral dose or parenteral administration
e.g. lidocaine, verapamil, nifedipine, propranolol, nitroglycerine, isosorbide, morphine,
amitryptyline
Hepatic blood flow-limited elimination
Shunting of blood past hepatic site ! result in increasing drug availability
Clinical relevance of drug metabolism
Marked individual differences in drug concentrations
1. Age, Gender (sex)
2. Genetic factors: Fast and slow acetylators (INH), Oxidation (TCA)
3. High or low first-pass metabolism
4. Enzyme induction or inhibition (drug interactions)
5. Disease affecting drug metabolism : Liver disease, heart failure,
6. Diet & environmental factors, smoking
Drug Excretion (elimination)
Drug clear by the kidney or the GI ?
MW > 300 ! Gall bladder ! Bile
MW < 300 ! Kidney
Biliary excretion and fecal excretion (conjugated metabolites, MW > 300)
! enterohepatic recycle (Benzodiazepine, Digoxin, Estrogen, chloramphenicol)
(deconjugate by GI bacteria ! GI reabsorption)
Renal excretion of drug :
1. Glomerular filtration : Plasma concentration (Cp) & Free form, MW < 20,000
2. Active tubular secretion : Competitive secretion
cation : penicillin and probenecid
anion : amiloride, ethambutol, cimetidine
3. Passive tubular reabsorption : probenecid and uric acid
Effect of urine pH
alkaline urine ↑excretion of acidic drug
acidified urine ↑excretion of basic drug
Clearance = total amount of blood which a drug is completely removed per unit time
Clearance (Cl) =
F(Dose)
AUC
First-order and Zero-order elimination
First-order
rate of elimination is proportion to the concentration of drug (apply to most drugs)
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Noppamas Rojanasthien, MD
Zero-order :
drug is cleared at constant rate regardless of its concentration
occurs if the elimination process is saturated or at high concentrations
Half-life (t1/2)
is the time required for the plasma concentration of a drug to be reduced by 50 %
For first-order elimination : the t1/2 is constant
4 -5 t1/2 > 90 % of the drug is eliminated.
Half - life (t 1/2 ) =
0.7 (Vd)
Cl
Multiple dosing, drug accumulation and steady state concentration
The time to reach steady-state is 4 - 5 times t1/2 for most of the drugs
At steady state : Rate in (dosing rate) = Rate out (elimination)
Therefore :
Maintenance dose = CL x Cp
Steady-state concentration (Css)
Css =
Dosing rate
Cl
Rate at which steady-state achieved is the rate of accumulation and is the same as the rate of
elimination
The time required to obtain steady state equal the time required for drug elimination
(4-5 times of the half-life)
Drug intervals should be less than the half-life to avoid inter-dose fluctuation.
To achieve a more constant plasma level, multiple dose (D) are given at fixed time interval (T).
Shorter intervals lead to more constant plasma levels (smaller inter-dose fluctuation)
Reference:
1. Benet LZ, Kroetz DL and Sheiner LB. Pharmacokinetics : the dynamics of drug absorption,
distribution and elimination. In Hardman JG, editors. The Goodman & Gilman’s the
pharmacoligical basis of therapeutics. 9th edition. McGraw-Hill companies, Inc, 1996 : 328.
2. Holford NHG and Benet LZ. Pharmacokinetics & pharmacodynamics : rational dose
selection & the time course of drug action. In Katzung BG, edittor. Basic and clinical
pharmacology. 6th edition. Prentice-Hall International, 1995 : 33-47.
3. Correia MA. Drug biotransformation. In Katzung BG, edittor. Basic and clinical
pharmacology. 6th edition. Prentice-Hall International. 1995 : 48-59.
4. Lullman H, Mohr K, Ziegler A, editors. Color atlas of pharmacology. New York: Thieme,
1993.
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Noppamas Rojanasthien, MD
Pharmacodynamic
Drug receptors : specific macromolecules (proteins, DNA) which drugs interact to produce
changes in the system functions.
Determine the relations between doses and pharmacologic effects (affinity, number of receptor)
Responsible for selectivity of drug actions
Mediate the action of pharmacological antagonist
Effectors : molecules that translate the drug-receptor interaction into a change in cellular activity
Receptor-effector signaling mechanisms:
1. Intracellular receptors
Nitric oxide, hormones (steroids, thyroid, sex hormones), Vitamin D
Lipid-soluble agent crosses the membrane
Response element (gene-active receptor) in the nucleus
Stimulate transcription of genes
Delay onset of action (lag period 30 min – hours, synthesis of new proteins)
Effects can persist for hours or days (slow turnover of protein-enzyme)
2. Transmembrane enzymes
Insulin, growth factors, ANF etc.
Acts on protein kinase enzyme (tyrosine, serine, guanyl cyclase)
Altered membrane transport (glucose, amino acid)
Down regulation of receptor
3. Transmembrane ion channels (ligand-gated channels)
Regulate flow of ion through plasma membrane
Alter electrical potential across membrane
e.g. Ach = Nicotinic receptor, benzodiazepine = GABA receptor
4. G proteins & second messengers
Drug-receptor activate coupling proteins (G protein)
Alter effector element (enzyme or ion channel)
Change concentration of intracellular second messenger
(cAMP, Ca, phosphoinositides, cGMP)
e.g. sympathomimetic drugs ! activation of G protein (+/- adenylyl cyclase)
Relation between drug concentrations and responses
Concentration-Effect Curves
Agonists : fully activating the effector
Partial agonists : lower maximal efficacy than full agonist (≈ competitive inhibitor)
Antagonist
Competitive antagonists
Reversibly bind to receptor without activating the effector
The log dose-response curve is shift to higher dose but the maximal effect is reached
The effect can be overcome by adding agonist
e.g., histamine – antihistamine, beta-receptor antagonist (beta-blocker)
Irreversible antagonists
Downward shift of the maximum effect with no shift of the curve on the dose axis
(unless spare receptors are present)
The effect cannot be overcome by adding agonist
e.g., phenoxybezamine (alpha-receptor antagonist)
Physiologic antagonist :
Bind to different receptor producing opposite effect
e.g. bronchoconstrictor action of histamine vs bronchodilator action of epinephrine
glucocorticoid and insulin (blood suger)
Chemical antagonist :
Interact directly remove or prevent drug from reaching the target
e.g. protamine-heparin, dimercaprol (chelator of lead and toxic metals)
Spare receptors and Kd : persist effects of drug-receptor interaction
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Noppamas Rojanasthien, MD
actual number of receptors >> effector molecule available
↑ sensitivity to agonist
Receptor desensitization
Down regulation of the number of receptors
Relation between drug dose and clinical response
1. Graded dose-response curves
(Response VS Drug concentration)
Efficacy : Maximal efficacy (Emax)
measure with a graded dose-response curve
maximal effect of an agonist
Potency : EC50 determine Potency
amount of drug needed to provide a given effect
affinity of the receptor for the drug
Shape of dose-response curves
Steep dose-response curve
2. Quantal dose-response curves
(Percent of population response VS Dose of the drug)
Median effective dose ED50 ,
Median toxic dose TD50 and Median lethal dose LD50
Toxic dose 50
Therapeutic index =
Effective dose 50
(estimate margin of safety of the drug)
Therapeutic window : dose range between the minimum effective therapeutic
concentration and the minimum toxic concentration
Potency : amount of drug needed to provide a given effect
Variation in drug responses
Idiosyncratic reaction (genetic differences in drug metabolism, allergic reactions)
Hypo-reactive, Hyper-reactive
Hypersensitivity (allergic reaction)
Tolerance (↓ response after continued drug administration)
Tachyhylaxis (rapid ↓ response after drug administration)
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Noppamas Rojanasthien, MD
Basic & Clinical Evaluation of New Drugs
1. Drug discovery & Drug screening
2. Preclinical safety & toxicity testing
In vitro studies
Animal studies
Acute, subacute and chronic toxicity
Teratogeninity
Carcinogenicity
Mutagenicity
3. Evaluation of drug in humans
Phase I
Phase II
Phase III
Postmarketing surveillance
Evaluation of drugs in humans
To obtain safety and effectiveness data of drug
The Food and Drug Administration (FDA)
Drug evaluation process
Grants approval for marketing of drugs
Ethical Committee
Institutional Review Boards (IRB)
The IND & NDA
Investigational New Drug Application (IND)
New Drug Application (NDA)
Phases of a Clinical Trial
Phase I ( First human administration )
Phase II ( Initial administration to patients )
Phase III ( Broad double blind clinical trial )
Phase IV (Postmarketing surveillance)
Phase I (Human pharmacology study )
Evaluation of safety / Pharmacokinetics (PK)
Healthy adults volunteers, 25-50 cases
Except AIDS & Cancer drugs
Single dose / dose escalation / repeated dose
Phase II (Therapeutic exploratory study)
Evaluation of efficacy / safety / PK
First introduction of a drug into patients (10-200)
Single-blind placebo controlled
Dosage range (safety, dose/response)
Monitor side effects
Phase III (Therapeutic confirmatory study)
Confirm efficacy and safety in patient population
Determine efficacy for specific indications
Large sample of specific patients (1,000)
Randomized double-blind placebo controlled
Monitor side effects
Rate of common adverse effects
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Noppamas Rojanasthien, MD
Phase IV
After drug approval for marketing
Monitor the safety of the new drug in patients
Determine patterns of drug utilization and
additional efficacy
Monitor rare, severe side effects / toxicity
Documents submit to IRB
Study protocol (and any amendments)
Consent form and subject information sheets
Subject recruitment procedures
Investigator Brochure and safety information
Information about indemnity/compensation
Investigator’s current curriculum vitae
Consent Form
Eighth grade reading level (Lay language)
Purpose and background
Procedures (treatment/compensation for injury)
Benefits and Risks & discomforts
Confidentiality
Costs/Reimbursement/Compensation
Questions and Signature
Obtaining informed consent
Purpose of the trial (experimental aspects)
Trial treatment(s), random assignment
Trial procedures (invasive procedure)
Subject’s responsibility
Risks, inconveniences
Clinical benefit
Compensation/treatment available in the event of trial-related injury
Payment or expenses for participating the trial
Participation is voluntary and may withdraw
from the trial anytime without penalty
Confidentiality of the medical record
Inform new information updates
Person to contact for further information
The reason to terminate subject’s participation
Expected duration of participation
Approximate number of subjects in the trial
Data management
Enter the result into the subject file
Completion of case report form (CRF)
Correcting data in a CRF
Source data verification (Pt file, lab test,etc)
Clinical fraud carries severe penalties
Adverse events report
Record ALL adverse events
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Noppamas Rojanasthien, MD
Is the event drug-related ?
Is the event unexpected ?
Serious adverse event (die, life threatening
hospitalization, significant disability birth
defect, overdose, cancer, pregnancy
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