lecture 1 pharm advanced.doc

NEUROPHARMACOLOGY:504

ABERCROMBIE

LECTURE 1: INTRODUCTION TO GENERAL PHARMACOLOGY – Pharmacokinetics and Pharmacodynamics

How drugs work and how their effects are measured. Drugs can act to increase or decrease the normal function of tissues or organs, but they do not confer any new functions on them; effects of drugs are quantitative, never qualitative. A particular effect measured as a change in a definite physiologic process may be brought about in several ways.

Nomenclature

Pharmacology - the study of the effects of drugs on the body. However, given the broad nature of this subject area, pharmacology includes a number of subdisciplines:

Neuropharmacology - the subdiscipline devoted to the study of the effects of drugs on cells of the nervous system.

Psychopharmacology - the subdiscipline devoted to the study of the effects of drugs on psychological processes and behavior.

Clinical Psychopharmacology - the subdiscipline of psychopharmacology concerned mainly with the use of drugs to treat abnormal human behaviour.

Clinical Neuropsychopharmacology - you guessed it, a combination of all three subdisciplines of pharmacology, i.e. the subdiscipline concerned with the study of the effects of drugs on the nervous system, their effects on psychological and behavioural processes, and their use in the treatment of abnormal human behaviour.

PHARMACOKINETICS AND PHARMACODYNAMICS

Nomenclature

Pharmacokinetics - the study of the absorption, distribution, and elimination of drugs, that is, what the body does to the drug.

Pharmacodynamics - the study of the action of drugs at cellular receptors, that is, what the drug does to the body.

Drug - any chemical agent that affects living processes via actions at receptor sites and include exogenous chemicals that are ingested deliberately or inadvertently, and also endogenous chemicals such as neurotransmitters and hormones.

Drug absorption - the process by which a drug gets from the site of administration to the blood plasma (the fluid of the blood minus the red and white blood cells; blood serum is the plasma minus the blood protein, fibrinogen).

Drug distribution - degree to which a drug reaches its receptor targets or a biological fluid (e.g., blood plasma). Once in blood plasma, it is distributed throughout the body via circulation. How much drug will be available to the CNS depends on how well the drug crosses the Blood brain barrier- a term used to describe the low permeability of capillaries that supply the CNS with blood and the amount of drug that binds to blood proteins. Some drugs cannot be used clinically because of low blood brain barrier permeability, while others bind to proteins.

Drug elimination - two processes by which drugs are eliminated from the body: (a) metabolism, performed mainly by the liver; and (b) excretion, performed mainly by the kidneys.

Drug clearance - ability of the body to eliminate a drug. Elimination half-life is time required for drug concentration to decay 50% of initial peak concentration. Drugs usually stay in body for ~4-5 half-lives.

PHARMACOKINETICS AND PASSAGE ACROSS BIOLOGICAL BARRIERS (relevant reading: Chapter 1 M & Q)

Drugs must move from where they are administered to the tissues or cells where they will act. Selectivity of migration of drug is consequence of physicochemical properties and structural configuration of barrier and of molecule. Transport defined as translocation of a solute from one phase to another. Passive diffusion, Facilitated diffusion, Active transport. PASSIVE DIFFUSION: directed movement of solute through a biologic barrier from the phase of higher concentration to the phase of lower concentration, the process requiring no direct expenditure of energy by system. Concentration gradient & permeability.

DRUG ABSORPTION - drug must be absorbed and be transported to site of action, target site; transport often over very large distances. Bloodstream as carrier. How and where drug is administered will determine how quickly drug is absorbed and how completely it gets into bloodstream (definition of absorption). Disparities in movement of materials across different biological barriers must lie in anatomical arrangement of barriers themselves.

E.G., drugs entering the body by way of the GI tract, skin, or lungs must first traverse an epithelial barrier before entering the interstitium. Drugs given S.C. or I.M. bypass the epithelial barrier. Drugs given by any route except I.V. must traverse the capillary wall in order to enter circulation. Vascularity at site of absorption thus an important variable. ENTERAL ADMINISTRATION (via GI tract)

1) Sublingual - thin epithelium, high vascularity, and slightly acid pH make oral mucosa very conducive to absorption. Compound must dissolve rapidly and be effective in small amounts. Advantage that drug gains access to general circulation without first traversing liver (also true of lower rectum).

2) Oral administration -Stomach fluid is very acidic, thus absorption of weak acids (like aspirin) is promoted, weak bases (e.g. nicotine) not absorbed to any significant degree. Major factor is rate of stomach emptying into small intestine. Small intestine exquisitely suited for absorption because of enormous surface area, true whether substance is lipid soluble or is a weak electrolyte. Enormous quantitative difference in area available for absorption. Along length of intestine, pH changes from slightly acidic to barely alkaline. PARENTERAL ADMINISTRATION (bypass GI tract) 1) Transdermal application - very slow. Sustained release preparations, blood level achieved never very high. 2) Inhalation - Very large surface area and high degree of vascularization of lungs. Lungs receive half of blood pumped from heart. Most effective absorptive area of body. Gases are almost always small molecules of high lipid solubility and are almost instantaneously absorbed when inhaled. Aerosol preparations.

3) Subcutaneous injection - Bypass epithelial layer and must pass endothelial layer of capillaries to enter bloodstream. Rate of capillary blood flow/vascularization main determinant. Some drugs too irritating.

4) Intramuscular injection - Again, barrier is capillary wall. Muscle somewhat more blood flow, especially when active. Larger volumes, more irritating substances can be administered. 5) Intravenous injection - most rapid and precise since barriers are eliminated and therefore exact quantity of drug administered is amount absorbed. Can be used for drugs otherwise too irritating. Least safe, large variations in blood level.

DIFFUSION ACROSS MEMBRANES DEPENDS ON RELATIVE LIPID SOLUBILITY (lipid/water partition coefficient)

The rate of passive diffusion is dependent on the degree of lipid solubility. Compounds that are highly soluble in lipids diffuse rapidly, whereas those that are relatively lipid insoluble diffuse more slowly. Size also a factor. See NEURONAL MEMBRANE (below).

MOST AGENTS OF PHARMACOLOGICAL INTEREST ARE WEAK ELECTROLYTES. They ionize, but only partially such that they are present in aqueous solution as both undissociated and dissociated entities.

Weak acids: substance that is a proton donor, net negative charge (aspirin)

Weak bases: substance that ionizes by accepting a proton, net positive charge.

Ammonium ion type coordinate bond formation important for many biologically active molecules (ionization of amines e.g.) Majority of commonly used drugs are weak bases. Tendency to ionize for a given weak electrolyte = ionization constant.

HA = H+ + A- HA is the undissociated acid

B + H+ = BH+ B is the unionized base

Fractions are in equilibrium.

DRIVE THESE REACTIONS BY CHANGING HYDROGEN ION CONCENTRATION, pH.

pH is expression of reciprocal of H+ ion concentration.

1) degree of ionization of a weak electrolyte is dependent on its ionization constant and on the pH of the aqueous medium in which it is dissolved.

2) degree of ionization of a weak acid tends to be greater at higher pH and lower at lower pH.

3) degree of ionization of a weak base tends to be greater at lower pH and lower at higher pH.

THE RATE OF PASSIVE DIFFUSION OF WEAK ELECTROLYTES IS DEPENDENT ON THEIR DEGREE OF IONIZATION: THE GREATER THE FRACTION THAT IS NONIONIZED, THE GREATER THE RATE OF DIFFUSION, SINCE THE RATE OF DIFFUSION IS MAINLY DETERMINED BY THAT OF THE UNDISSOCIATED PORTION.

ASPIRIN EX.,

Stomach: pH~1.0 Small intestine: pH=5.0-6.6 Blood: pH~7.4 Urine: pH=4.5-7.0

Aspirin is a weak acid. If we put aspirin into the stomach (increase H+, low pH of stomach) we drive reaction to left, or increase non-ionized form of drug. This increases the amount of aspirin that can be absorbed through stomach lining into blood, where it is carried to target site to reduce pain. Absorption is relatively lessened in small intestine, where reaction is driven to the right and more aspirin is in the ionized form. pK is pH at which 50% of compound is ionized (e.g. catecholamines are weak bases with pK of 9.0; caffeine is weak base with pK of 0.5).

TRANSPORT: Specialized transport processes give membrane flexibility and selectivity to control movement of specific substances.

FACILITATED DIFFUSION- movement of lipid insoluble drugs down a concentration gradient via a carrier, thus has a limiting or maximal value (# carriers in membrane). No energy is required. GLUCOSE. Temporary binding to transporters (proteins) involves same kind of bond formation as drug-receptor interactions.

ACTIVE TRANSPORT- movement of lipid insoluble compounds against a concentration gradient via a carrier thus requiring energy from the cell to perform the work.

DRUG DISTRIBUTION -High endothelial surface area (capillary wall) conducive to penetration and compounds will distribute throughout body. Penetration of drugs into CNS is a special case.

BLOOD-BRAIN-BARRIER: Rate of penetration of water-soluble and ionized compounds into CNS relatively slow compared with rate of distribution into peripheral tissue. Lipid soluble drugs distribute relatively fast since brain receives one-sixth total blood leaving heart. Endothelial cells of brain capillaries appear to be more firmly joined to one another than periphery. Also, surrounding brain capillaries are astrocytic processes, or glial feet, that form an additional membrane barrier.

DRUG INACTIVATION - absorption and distribution determine the speed of onset of drug effect. Processes of excretion and biotransformation terminate the actions of drugs.

EXCRETION: process whereby materials are removed from body to external environment. Drugs eliminated unchanged or as metabolites.

The two major organs of excretion of water-soluble drugs are the kidney and the liver. KIDNEYS are pair of organs that filter out products of metabolism and maintain appropriate blood levels of various ions and other substances. Functional unit of kidney is nephron. 1 to 2 million nephrons per kidney, each consists of a knot of capillaries through which blood flows from renal artery to renal vein. Single layer of epithelial cells lines lumen of nephron throughout entire length. The capillary endothelium contains large pores that discriminate against the passage of blood constituents on the basis of molecular size; hydrostatic pressure of blood supplying kidney is high. Fluid filters out of the capillaries into Bowman’s capsule -ultrafiltrate, filtrate of plasma lacking only the plasma proteins. 99% of original filtrate is reabsorbed and returned to body via a second capillary bed. Driving force for reabsorption is either passive diffusion down a concentration gradient or active transport across tubular epithelium. Nutrients such as glucose, amino acids and some vitamins are reclaimed by active transport. Active removal of Na+ in exchange for H+ (acidification of urine). Passive diffusion of water down osmotic gradient established by active transport of Na+.

EXCRETION OF DRUGS - Because of concentration gradient, kidney itself is insufficient for eliminating drugs from body - reabsorption into bloodstream must be prevented. Drugs will passively diffuse back into the circulation in accordance with their lipid/water partition coefficients, degree of ionization and molecular size. Distal segments, urine is more acidic - reabsorption of weak acids and excretion of weak bases.

BIOTRANSFORMATION: metabolism, process by which chemical reactions carried out by body convert a drug into a different compound. Generally yields products more readily excreted than parent compound. Excretion and biotransformation determine the duration of action of a drug.

LIVER allows metabolism into substance that is less lipid soluble and less capable of being reabsorbed. Conversion of fat-soluble drugs into water-soluble metabolites that can be excreted by kidney -biotransformation. Biotransformation usually, but not always, decreases pharmacological activity of the drug. Drug biotransformations are catalyzed reactions - carried out by special system of enzymes in liver cells. These microsomal enzymes are interesting in that they can only catalyze reactions of compounds which are lipid soluble. Many drugs can increase the rate at which the microsomal enzyme system metabolizes drug. Induce an increase in both enzyme activity and total amount of enzyme - one mechanism for producing pharmacological tolerance.

TOLERANCE: Diminished response to drug administration after repeated exposure to that drug. Increasingly larger doses must be administered to obtain the same magnitude of pharmacological effect observed with the original dose. Tolerance is reversible.

Drug Disposition Tolerance - reduction in concentration of drug at receptor with repeated administration (metabolic tolerance). Increase in rate of drug metabolism, e.g. by induction of liver microsomal enzymes. Effect of this type of tolerance on blood drug level depends on route of administration.

Pharmacodynamic (cellular) Tolerance - Cannot be explained on the basis of altered metabolism or altered concentration of drug reaching brain. Some change in receptor: Change in number of receptors or in their sensitivity (affinity).

Cross-Tolerance - development of tolerance to one drug administered over a period of time can diminish the pharmacological effectiveness of a second drug. Ex., alcohol and barbiturates.

Individual Variation in Drug Effect and Change in Drug Effect Over Time

Contributing factors :

• Drugs do not affect everyone in the same way, even given exactly the same dose by the same route of administration.

• Differences in the way individuals respond to a drug may be due to pharmacokinetic or pharmacodynamic factors, or both.

• Pharmacokinetic explanations for variation in drug effect between individuals include differences in the absorption, distribution, and metabolism of a drug.

• Differences in drug metabolism are particularly important because the capacity to metabolise a specific drug can vary with genetic history, age, disease, pregnancy, and environmental factors that alter liver enzyme induction.

• Differences in drug metabolism are important in geriatric populations in whom liver function may be reduced, resulting in substantially longer half-lives for some drugs.

• The distribution of a drug can be affected if other drugs are being taken concurrently.