1 Basic Principles - Intro

Pharmacology and Therapeutics
A.Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY UNIVERSITY OF SANTO TOMAS
General Principles of Pharmacology

PHARMACOLOGY
Body of knowledge concerned with the action of chemicals on biologic systems, especially by binding to regulatory molecules (receptors) and (receptors) activating or inhibiting normal body processes

MEDICAL PHARMACOLOGY
Area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease, especially in humans

TOXICOLOGY
Area of pharmacology concerned with the undesirable effects of chemicals on biologic systems

MOLECULAR BIOLOGY

Identifies the exact mechanism of action of one particular drug Identifies the receptors
DRUG
Any substance that brings about a change in biologic function through chemical actions

RECEPTOR
Specific molecule in the biologic system that plays a regulatory role
THE NATURE OF DRUGS

Inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates Found in plants or animals, many are partially or completely synthetic

PHYSICAL NATURE OF DRUGS
Solid Liquid Gas Drugs are given at a site distant from the intended site of action

DRUG SIZE AND MOLECULAR WEIGHT (MW)

Vary in size MW 7 (lithium) MW 50,000 (thrombolytic agents) Majority have MW between 100 and 1000

DRUG SIZE AND MOLECULAR WEIGHT (MW)

100 MW For selective binding 1000 MW For traversing to different barriers of the body >1000 MW Cannot move within the body Given directly at the site of action

DRUG RECEPTOR BONDS

Chemical forces or bonds through which the drug interacts with the receptors Weaker bonds are more selective bonds

DRUG RECEPTOR BONDS
COVALENT BONDS Strongest Irreversible
DRUG RECEPTOR BONDS

ELECTROSTATIC BONDS More common Weaker Eg, between cation and an anion

DRUG RECEPTOR BONDS

HYDROPHOBIC BONDS Weakest Highly lipid soluble drugs

THE MOVEMENT OF DRUGS IN THE BODY

To reach its receptors and bring about biologic effect A drug molecule (eg, sedative) must travel from the site of administration (eg, gastrointestinal tract) to the site of action (eg, brain)

A.
PERMEATION
Movement of drug molecules into and within the biologic environment

A.
PERMEATION
1. AQUEOUS DIFFUSION Movement of molecules through the watery extracellular and intracellular spaces Membranes of capillaries with small waterwaterfilled pores Passive process Governed by Ficks law

A.
PERMEATION
2. LIPID DIFFUSION Movement of molecules through membranes and other lipid structures Most important factor for drug permeation Large lipid barriers that separate the compartments of the body Passive process Governed by Ficks law

A.
PERMEATION
3. TRANSPORT BY SPECIAL CARRIERS Drugs transported across barriers by mechanisms that carry similar endogenous substances Amino acid carriers, weak acid carriers Capacity limited Not governed by Ficks law

A.
PERMEATION
3. TRANSPORT BY SPECIAL CARRIERS ACTIVE TRANSPORT Needs energy Against a concentration gradient FACILITATED DIFFUSION No energy required Downhill

PERMEATION
A.
4. ENDOCYTOSIS Binding to specialized components (receptors) on cell membranes Internalization by infolding of the area of the membrane and contents of the vesicle are subsequently released into the cytoplasm

PERMEATION
A.
4. ENDOCYTOSIS Permits very large or very lipid-insoluble lipidchemicals to enter the cell Eg, B12 with intrinsic factor and iron with transferrin

PERMEATION
A.
5. EXOCYTOSIS Reverse process Expulsion of membrane-encapsulated membranematerial from the cell

B.

FICKS LAW OF DIFFUSION

Predicts the movement of molecules across a barrier Drug absorption is faster in organs with larger surface areas (eg, small intestine) than from organs with smaller absorbing areas (eg, stomach)

B.

Drug absorption is faster from organs with thin membrane barriers (eg, lungs) than those with thick barriers (eg, skin)

Area x Permeability coefficient ______________________________ Thickness
(C1C2)
C1-higher conc C2-lower conc Permeability coefficient-measure of the mobility coefficientof the drug in medium of the diffusion path ThicknessThickness-thickness (length of the diffusion path)

C.
WATER AND LIPID SOLUBILITY OF DRUGS
1. AQUEOUS DIFFUSION Aqueous solubility of a drug is a function of the electrostatic charge (degree of ionization, polarity) of the molecule Water molecules are attracted to charged drug molecules forming an aqueous shell around them Lipid solubility of a molecule is inversely proportional to its charge

C.
2. LIPID DIFFUSION Many drugs are weak bases or weak acids pH of the medium determines the fraction of molecules charged (ionized) versus uncharged (nonionized) Fraction of molecules in the ionized state can be predicted by means of the H-H equation H-

THE HENDERSON-HASSELBACH EQUATION HENDERSON(protonated) ___________ = pka - pH (unprotonated)
log
Protonated means associated with a proton (a hydrogen ion)

C.
3. Ionization of Weak Acids and Weak Bases WEAK BASE Neutral molecule that can form a cation (+ charged) by combining with a proton (hydrogen ion) Ionized, more polar, more water soluble when they are protonated

C.
3. Ionization of Weak Acids and Weak Bases WEAK ACID Neutral molecule that can reversibly dissociate into an anion (- charged) and (a proton ( hydrogen ion) Not ionized, less polar, less water soluble when they are protonated
RNH3+ protonated weak base (charged, more water-soluble) waterRCOOH protonated weak acid (uncharged, more lipid-soluble) lipid-
RNH2 + unprotonated weak base (uncharged, more lipidlipid-soluble) RCOO_ + unprotonated weak acid (charged, more waterwater-soluble)
H+ proton
H+ proton

The Henderson-Hasselbach Equation HendersonClinically important when it is necessary to estimate or alter the partition of drugs between compartments of different pH

The Henderson-Hasselbach Equation Henderson
When a patient takes an overdose of a weak acid drug, excretion maybe accelerated by alkalinizing the urine Weak acids dissociate to its charged, polar form in alkaline urine and cannot readily diffuse back from the renal tubule back to the blood
Large number of drugs are weak bases with amine containing molecules Nitrogen of a neutral amine has 3 atoms associated with it plus a pair of unshared electrons

Primary H .. R:N: .. H Secondary Tertiary R .. R: N : .. H R .. R:N: .. R Quaternary R .. R:N:R .. R

ABSORPTION OF DRUGS
A. ROUTES OF ADMINISTRATION Drugs usually enter the body remote from the target tissue or organ and require transport by the circulation to the intended site of action BIOAVAILABILITY amount absorbed into the systemic circulation amount of drug administered

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 1. ORAL (swallowed) Maximum convenience Absorption maybe slower, and less complete Some drugs have low bioavailability when given orally
A.

ABSORPTION OF DRUGS
A.
ROUTES OF ADMINISTRATION 1. ORAL (swallowed) Subject to first-pass effect (significant amount firstof the agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation)

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 2. INTRAVENOUS (IV)/PARENTERAL Instantaneous and complete absorption Bioavailability by definition is 100% Potentially more dangerous, high blood levels reached if administration is too rapid
A.

ABSORPTION OF DRUGS
A.
ROUTES OF ADMINISTRATION 3. INTRAMUSCULAR (IM) Absorption is often faster and more complete (higher bioavailability) than oral Large volumes (>5 ml into each buttock) if the drug is not irritating

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 3. INTRAMUSCULAR (IM) FirstFirst-pass effect is avoided Heparin cannot be given by this route, causes bleeding in the muscle
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 4. SUBCUTANEOUS Slower absorption than IM route FirstFirst-pass effect is avoided Heparin can be given by this route, does not cause hematoma
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 5. BUCCAL AND SUBLINGUAL Buccal route (in the pouch between gums and cheeks) Permits absorption direct into the systemic circulation, bypassing hepatic portal circuit and first-pass metabolism firstA.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 5. BUCCAL AND SUBLINGUAL Slow or fast depending on formulation of the product Sublingual route (under the tongue) offers the same features
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 6. RECTAL (suppository) Partial avoidance of first-pass effect first(not completely as the sublingual route) Suppositories tend to migrate upward in the rectum where absorption is partially into the portal circulation
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 6. RECTAL (suppository) Larger amounts of unpleasant drugs are better administered rectally May cause significant irritation
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 7. INHALATION For respiratory diseases Delivery closest to the target tissue Results into rapid absorption because of the rapid and thin alveolar surface area
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 7. INHALATION Drugs that are gases at room temperature (eg, nitrous oxide), or easily volatilized (anesthetics)
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 8. TOPICAL Application to the skin or mucous membrane of the eye, nose, throat, airway, or vagina for local effect
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 8. TOPICAL Rate of absorption varies with the area of application and drugs formulation Absorption is slower compared to other routes
A.

ABSORPTION OF DRUGS
ROUTES OF ADMINISTRATION 9. TRANSDERMAL Application to the skin for systemic effect Rate of absorption occurs very slowly FirstFirst-pass effect is avoided
A.
ABSORPTION OF DRUGS
B.
BLOOD FLOW Influences absorption from IM, subcutaneous, and in shock High blood flow maintains a high drug depotdepotto-blood concentration gradient to Maximizes absorption
ABSORPTION OF DRUGS
C.
CONCENTRATION Concentration gradient Major determinant of the rate of absorption (Ficks law)

DISTRIBUTION OF DRUGS
A.
DETERMINANTS OF DISTRIBUTION 1. Size of the organ Size of the organ determines the concentration gradient between blood and the organ Eg, skeletal muscle and brain

DETERMINANTS OF DISTRIBUTION 2. Blood flow Important determinant of the rate of uptake WellWell-perfused organs Brain Heart, kidneys Splanchnic organs
A.

DETERMINANTS OF DISTRIBUTION 3. Solubility If the drug is very soluble in cells, the concentration in the perivascular space will be lower and diffusion from the vessel into the extravascular tissue will be facilitated
A.

DETERMINANTS OF DISTRIBUTION 4. Binding Binding of drugs to macromolecules in the blood or tissue compartment will tend to increase the drugs concentration in that compartment
A.

B.
APPARENT VOLUME OF DISTRIBUTION
Vd

Amount of drug in the body to the concentration in the plasma

METABOLISM OF DRUGS
A.

AS MECHANISM OF TERMINATION OF DRUG ACTION Action of many drugs is terminated before they are excreted Metabolized to biologically inactive derivatives Conversion to a metabolite is a form of elimination

METABOLISM OF DRUGS
B.
AS MECHANISM OF DRUG ACTIVATION PRODRUGS Inactive as administered and must be metabolized in the body to become active Eg, levodopa, minoxidil Many drugs are active as administered and have active metabolites as well Some benzodiazepines
General Principles of Pharmacology METABOLISM OF DRUGS

C.

DRUG ELIMINATION WITHOUT METABOLISM Drugs not modified by the body Continue to act until they are excreted Eg, lithium

ELIMINATION OF DRUGS
Determinants of the duration of action for most drugs Dosage Rate of elimination following the last dose Disappearance of the active molecules from the bloodstream

Drug elimination is not the same as drug excretion A drug maybe eliminated by metabolism long before the modified molecules are excreted from the body


For most drugs, excretion is by way of the drugs, kidneys (except anesthetic gases-lungs) gasesFor drugs with active metabolites (eg, diazepam), elimination of the parent molecule by metabolism is not synonymous with termination of action For drugs that are not metabolized, excretion metabolized, is the mode of elimination


A small number of drugs combine irreversibly with their receptors, disappearance from the bloodstream is not equivalent to cessation of drug action Very prolonged action Eg, phenoxybenzamine, irreversible inhibitor of alpha receptors is eliminated from the bloodstream in 1 h or less after administration, drugs action lasts for 48 h

A.
FIRST ORDER ELIMINATION Rate of elimination is proportionate to the concentration (ie, the higher the concentration, the greater the amount eliminated per unit time) Drugs concentration in plasma decreases exponentially with time

A.

FIRST ORDER ELIMINATION HalfHalf-life of elimination is constant regardless of amount of drug in the body Concentration of such drug in the blood will decrease by 50% for every half-life halfMost common process Followed by most drugs

FIRST ORDER KINETICS
5 units/h
Plasma conc. (Cp)
2.5 units/h 1.25 units/h
Time (h)

B.
ZERO ORDER ELIMINATION Rate of elimination is constant regardless of concentration Occurs with drugs that saturate their elimination of mechanism at concentrations of clinical interest

B.
ZERO ORDER ELIMINATION Concentration of such drugs in plasma decrease in linear fashion over time With higher doses, there will be bigger chances of toxic effect because the patient may not be able to eliminate it Eg, alcohol, phenytoin, aspirin

ZEROZERO-ORDER KINETICS
2.5 units/h
2.5 units/h
Plasma conc. (Cp)
2.5 units/h
Time (h)

1 Basic Principles - Intro

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Pharmacology and Therapeutics

A.Q. Sangalang, MD, FPOGS

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

THE NATURE OF DRUGS

General Principles of Pharmacology

General Principles of Pharmacology

DRUG SIZE AND MOLECULAR WEIGHT (MW)

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

DRUG RECEPTOR BONDS

General Principles of Pharmacology

HYDROPHOBIC BONDS Weakest Highly lipid soluble drugs

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

5. EXOCYTOSIS  Reverse process  Expulsion of membrane-encapsulated membranematerial from the cell

General Principles of Pharmacology

FICKS LAW OF DIFFUSION

General Principles of Pharmacology

FICKS LAW OF DIFFUSION

General Principles of Pharmacology

General Principles of Pharmacology

WATER AND LIPID SOLUBILITY OF DRUGS

General Principles of Pharmacology

WATER AND LIPID SOLUBILITY OF DRUGS

General Principles of Pharmacology

Protonated means associated with a proton (a hydrogen ion)

General Principles of Pharmacology

WATER AND LIPID SOLUBILITY OF DRUGS

General Principles of Pharmacology

WATER AND LIPID SOLUBILITY OF DRUGS

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

General Principles of Pharmacology

5. EXOCYTOSIS Reverse process Expulsion of membrane-encapsulated membranematerial from the cell