basic principles
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Basic PrinciplesIntroduction
the body of knowledge concerned with the action of chemicals (drugs) on biologic systems
Medical Pharmacology – use of drugs in the prevention, diagnosis, and treatment of disease, especially in humans
Toxicology – undesirable effects of drugs on biologic systems
Pharmacology
Commonly include: inorganic ions nonpeptide organic molecules small peptides and proteins nucleic acids lipids Carbohydrates
Often found in plants and animals Many partially or completely synthetic
THE NATURE OF DRUGS
Vary from MW 7 (Li) to over MW 50,000 (thrombolytic enzymes)
Majority have MW 100-1000
A. Size and MW
Very strong covalent bonds
Weaker electrostatic bonds
Much weaker interactions (H-bonds, van der Waals, hydrophobic bonds)
B. Drug-Receptor Bonds
1. AQUEOUS DIFFUSION – passive movement through the extracellular and intracellular spaces (usually through water-filled pores)
2. LIPID DIFFUSION – passive movement through membranes
MOVEMENT OF DRUGS IN THE BODY (PERMEATION)
3. FACILITATED DIFFUSION – transport by special carriers across barriers
- capacity-limited - may be inhibited
4. ENDOCYTOSIS, PINOCYTOSIS – permit transport of very large (peptides) or very lipid-insoluble molecules or complexes (small, polar molecules combined to special proteins)
MOVEMENT OF DRUGS IN THE BODY (PERMEATION)
Predicts the rate of movement of molecules across a barrier
Rate = (C1 – C2) x Permeability coefficient x Area
Thickness
FICK’S LAW OF DIFFUSION
Weak bases – ionize when protonated; more water-soluble
RNH3+ ⇋ RNH2 + H+
Water-sol. Lipid-sol.
Weak acids – do not ionize when protonated; more lipid-soluble
RCOOH ⇋ RCOO- + H+
Lipid-sol. Water-sol.
IONIZATION OF WEAK ACIDS AND BASES
can predict the fraction of molecules in the ionized state (water-soluble) if the pKa of the drug and the pH of the medium are known
pKa - pH = log Protonated form Unprotonated form
Clinically important when it is necessary to estimate or alter the partition of drugs between compartments of differing pH
HENDERSON-HASSELBALCH EQUATION
“Trapping” is a method for accelerating excretion of drugs.
Nonionized form diffuses readily across the lipid barriers of the nephron
Protonation will occur within the blood and urine
Example: Pyrimethamine – pKa 7.0 >
NH3
NH4+NH4+
NH3
BloodpH 7.4
UrinepH 6.0
Membranes of the nephron
Lipid diffusion
H+
H+
ROUTES OF ADMINISTRATION
Rate and efficiency of absorption differ depending on a (1) drug’s route of administration, (2) blood flow, (3) concentration of drug at site of administration
Bioavailability = The amount absorbed into systemic circulation divided by the amount of drug administered
Oral (swallowed) maximum convenience slower absorption and less complete drugs are subject to first-pass effect (a
significant amount is metabolized in the gut wall, portal circulation, and liver before reaching systemic circulation)
ROUTES OF ADMINISTRATION
Intravenous
Instantaneous and complete absorption Potentially more dangerous if administration
is too rapid (high blood levels is reached)
ROUTES OF ADMINISTRATION
Intramuscular
Often faster and more complete than oral Large volumes may be given if drug is not
too irritating First-pass metabolism is avoided NOT applicable to anticoagulants (heparin)
as this may cause bleeding
ROUTES OF ADMINISTRATION
Subcutaneous
Slower absorption than intramuscular First-pass metabolism is avoided Large-volume bolus doses are less feasible Applicable to heparin
ROUTES OF ADMINISTRATION
Buccal and sublingual
Permits direct absorption into systemic venous circulation
Bypasses hepatic portal circulation and first-pass metabolism
Fast or slow depending on physical formulation of drug
ROUTES OF ADMINISTRATION
Rectal (suppository)
Partial avoidance of first-pass effect (absorption from this location is partially into portal circulation)
May cause significant irritation Drugs with unpleasant tastes may be
administered rectally
ROUTES OF ADMINISTRATION
Inhalation
Offers delivery closest to the target tissue (respiratory diseases)
Rapid absorption Convenient for drugs that are gases at room
temperature (NO, N2O) or easily volatilized (anesthetics)
ROUTES OF ADMINISTRATION
Topical
Application to skin or mucous membrane of the eye, nose, throat, airway, or vagina for local effect
Rate of absorption varies with area of application and drug’s formulation
Usually slower than any of the previous routes listed
ROUTES OF ADMINISTRATION
Transdermal
Involves application to the skin for systemic effect
Absorption usually occurs very slowly First-pass effect is avoided
ROUTES OF ADMINISTRATION
SIZE OF THE ORGAN – determines the concentration gradient between blood and the organ
- larger organs can take up more (eg. muscles)
DETERMINANTS OF DRUG DISTRIBUTION
BLOOD FLOW – determines the rate of uptake, although it may not affect the steady-state amount of drug in the tissue
- well-perfused tissues (eg. brain, heart, kidneys, splanchnic organs) will often achieve high tissue concentrations sooner than poorly-perfused tissues (eg. fat, bone)
DETERMINANTS OF DRUG DISTRIBUTION
SOLUBILITY – influences the concentration of the drug in the extracellular fluid surrounding the blood
- example: some organs (like brain) have a high-lipid content; thus, very lipid-soluble anesthetic will diffuse into the brain tissue more rapidly and to a greater extent than a drug with low lipid-solubility
DETERMINANTS OF DRUG DISTRIBUTION
BINDING – binding of a drug to macromolecules in blood or tissue compartment will tend to increase its concentration in that compartment
DETERMINANTS OF DRUG DISTRIBUTION
Occurs primarily in the liver
Conversion to a metabolite terminates drug action (a form of elimination)
Prodrugs ( eg. Levodopa, minoxidil) are metabolized to become active
Some drugs are not metabolized and continue to act until they are excreted
METABOLISM OF DRUGS
Not the same as drug excretion Excretion is primarily by way of the kidneys,
except anesthetic gases (lungs) Some drugs (diazepam) have active
metabolites For drugs that are not metabolized, excretion
is the mode of elimination A few drugs combine irreversibly with
receptors, so disappearance from the bloodstream is not equivalent to termination of action
ELIMINATION OF DRUGS
FIRST-ORDER ELIMINATION
Rate of elimination is proportionate to concentration
Plasma concentration decreases exponentially with time
Drugs have a characteristic half-life
ELIMINATION OF DRUGS
FIRST-ORDER ELIMINATION
ELIMINATION OF DRUGS
ZERO-ORDER ELIMINATION
Rate is constant regardless of concentration Plasma concentration decreases linearly Typical of ethanol and aspirin at toxic levels
ZER0-ORDER ELIMINATION
PHARMACODYNAMICS Deals with effects of drugs on biologic
systems
RECEPTOR – specific molecules in the biologic system to which a drug binds to bring about change in function of the system
AGONIST – drug that activates its receptor upon binding
EFFECTOR – channel or enzyme that accomplishes the effect after activation by the receptor
INERT BINDING SITE – component to which a drug binds without changing any function
ANTAGONIST – drug that binds to receptor without activating it
PHARMACODYNAMICS
1. Competitive – can be overcome by increasing the dose of the agonist
2. Irreversible – cannot be overcome by increasing the dose of the agonist
3. Physiologic – counters the effects of another by binding to a different receptor and causing opposing effects
4. Chemical - counters the effects of another by binding the drug and preventing its action
5. Partial – binds to its receptor but produces a smaller effect at full dosage than a full agonist
Antagonists
Maximal efficacy (Emax)
The maximum effect an agonist can bring about regardless of dose
Determined mainly by the nature of the receptor and its associated effector system
Efficacy
Dose or concentration required to bring about 50% of a drug’s maximal effect (EC50) – in graded-dose response
Determined mainly by affinity of the receptor for the drug
Typical variables in *quantal dose-response:ED50 – median effectiveTD50 – median toxicLD50 – median lethal
*minimum dose required to produce a specific response in each member of the population
Potency
THERAPEUTIC WINDOW
index of safety
Dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose.
Eg. Theophylline: 8 – 18 mg/mL
Distribution - the process by which a drug diffuses or is transferred from intravascular space to extravascular space (body tissues). These spaces are described mathematically as volume(s) of distribution.
Volume of distribution is that volume of bodily fluid into which a drug dose is dissolved
PHARMACOKINETICS
The body is usually divided into two spaces, a central and a tissue compartment.
Central volume (Vc) = blood in vessels and tissues which are highly perfused by blood.
Vc = Dose / Peak serum level
Peak = Dose / Vc
DISTRIBUTION
Peripheral volume (Vt) = sum of all tissue spaces outside the central compartment
Vc + Vt = Vd
Distribution volumes are important for estimating: Amount of drug in the body, Peak serum levels, and Clearance
DISTRIBUTION
Volume of distribution (Vd)
Vd = Amount of drug in the body
Plasma drug concentration
Clearance (CL)
CL = Rate of elimination of drug Plasma drug concentration
DISTRIBUTION
PHASE I REACTIONS- oxidation, reduction, deamination, and
hydrolysis
PHASE II REACTIONS - synthetic reactions that involve addition (conjugation) of subgroups to –OH, -NH2, and –SH on the drug molecule;
- subgroups include glucoronate, acetate, glutathione, glycine, sulfate, and methyl groups
DRUG METABOLISM: Types
Liver
Kidneys
Other tissues (blood, intestinal wall)
DRUG METABOLISM: Sites