How do drugs work? | Nearly all drugs act by interfering or inhibiting natural processes which are required for normal physiological function but which may have been disrupted by disease. | Paul Ehrlich 1845-1915 ? | Observed that certain chemicals or drugs bound in a selective manner to some but not all cells. He recognised that the cells must have chemical recognition sites for these drugs.
The concept of a “receptor” was bornOver the last 100 years we have identified the recognition sites for many known drugs This information has been used to: -design new drugs -understand the biological impact of chemicals -Allowed better understanding of physiological function and disease | Regulatory proteins are the targets 1 Carriers/ transporters2 Enzymes 3 Ion channels 4 Receptors The exception: DNA | There are thousands of known targets and many more to be discovered.
| Target 1 Carriers | The body has to move nutrients and waste products into and out of cells and organs This function is often carried out by specialised proteins which sit in cell membranesAlso known as a transporter protein The movement of ions and small organic molecules across cell membranes generally occurs either through channels (see above), or through the agency of a transport protein, because the permeating molecules are often too polar (i. e.insufficiently lipid soluble) to penetrate lipid membranes on their own.
Examples of particular pharmacological importance include those responsible for the transport of ions and many organic molecules across the renal tubule, the intestinal epithelium and the blood-brain barrier, the transport of Na+ and Ca2+ out of cells, and the uptake of neurotransmitter precursors (such as choline) or of neurotransmitters themselves (such as noradrenaline, 5-hydroxytryptamine [5-HT], glutamate and peptides) by nerve terminals, and the transport of drug molecules and their metabolites across cell membranes and epithelial barriers.
| | Target 2 Enzymes | Enzymes: important in regulating protein concentrations and producing bioactive products ? Drugs which inhibit enzymes are used in many situations ? Drugs which promote enzyme activity are rare; eg MAO inhibitors Many drugs are targeted on enzymes. Often, the drug molecule is a substrate equivalent that acts as a competitive inhibitor of the enzyme (e. g. captopril, acting on angiotensin-converting enzyme)Drugs may also act as false substrates, where the drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway.
An example is the anticancer drug fluorouracil, which replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate, thus blocking DNA synthesis and preventing cell division. | | Target 3 Ion channels? | Ion channels1 are essentially gateways in cell membranes, which selectively allow the passage of particular ions, and which are induced to open or close by a variety of mechanisms. Two important types are ligand-gated channels and voltage-gated channels.
The former open only when one or more agonist molecules are bound, and are properly classified as receptors, since agonist binding is needed to activate them. Voltage-gated channels are gated by changes in the transmembrane potential rather than by agonist binding. | In general, drugs can affect ion channel function either by binding to the channel protein itself (to the ligand-binding site of ligand-gated channels, or to other parts of the channel molecule), or they may affect channel function by an indirect interaction, involving a G-protein and other intermediaries (see below).
In the simplest case, exemplified by the action of local anaesthetics on the voltage-gated sodium channel, the drug molecule plugs the channel physically, blocking ion permeation. | Small ions are important in maintaining the function of many cells Systems where drugs target ion channels: Nerves, brain, kidney and the cardiovascular system ? | Target 4 Receptors ? Main drug target ?
?| Proteins that recognise: -Drugs -endogenous compoundsReceptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body, the chemical messengers being the various hormones, transmitters and other mediators Many therapeutically useful drugs act, either as agonists or antagonists, on receptors for known endogenous mediators. ?Role in regulating cell function 1000’s + receptors 4 superfamilies / types of receptors defined mainly on the basis of structure 1. Linked to ion channels: neurotransmitters 2.
G-protein linked: wide range of ligands 3. Linked to kinase enzymes: growth factors 4. Nuclear: steroid | Receptors and effectors | | G-protein coupled receptors: GPCRs | | GPRC coupling | | What does all this mean? ?How do changes in the targets in disease change response? | Changes in the function / expression of these proteins can change drug responses | Tachyphylaxis? | Tachyphylaxis is a medical term describing an acute (sudden) decrease in the response to a drug after its administration. [1] Tachyphylaxis can occur both after an initial dose of medication or after an inoculation with a series of small doses.
Increasing the dose of the drug may be able to restore the original response. [2]This can sometimes be caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug’s effect, or by the depletion of receptors available for the drug or neurotransmitter to bind to. This depletion is caused by the cell’s reducing the number of receptors in response to their saturation. | Upregulation, Downregulation & Desensitization| Receptor proteins are synthesised by the cells that express them, and the level of expression is itself controlled, via the pathways discussed above, by receptor-mediated events.
Short-term regulation of receptor function generally occurs through desensitisation. Long-term regulation occurs through an increase or decrease of receptor expression. Examples of this type of control include the proliferation of various postsynaptic receptors after denervation (see Ch. 12), the upregulation of various G-protein-coupled and cytokine receptors in response to inflammation (see Ch. 17), and the induction of growth factor receptors by certain tumour viruses (see Ch. 5).
Long-term drug treatment invariably induces adaptive responses, which, particularly with drugs that act on the central nervous system, are often the basis for therapeutic efficacy. They may take the form of a very slow onset of the therapeutic effect (e. g. with antidepressant drugs; see Ch. 46), or the development of drug dependence (Ch. 48). It is likely that changes in receptor expression, secondary to the immediate action of the drug, are involved in delayed effects of this sort-a kind of ‘secondary pharmacology’ whose importance is only now becoming clearer.
The same principles apply to drug targets other than receptors (ion channels, enzymes, transporters, etc. ) where adaptive changes in expression and function follow long-term drug administration, resulting, for example, in resistance to certain anticancer drugs (Ch. 55)Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable. An increase of a cellular component is called upregulation.
An example of downregulation is the cellular decrease in the number of receptors to a molecule, such as a hormone or neurotransmitter, which reduces the cell’s sensitivity to the molecule. This phenomenon is an example of a locally acting negative feedback mechanism. An example of upregulation is the increased number of cytochrome P450 enzymes in liver cells when xenobiotic molecules such as dioxin are administered (resulting in greater degradation of these molecules). Most receptor agonists downregulate their respective receptor(s), while most receptor antagonists upregulate their respective receptor(s).
The disequilibrium caused by these changes often causes withdrawal when the long-term use of a medication or drug is discontinued. | Introduction to Pharmacology III Pharmacodynamic concepts Mar 12 Overview Drug targets Methods and technologies Receptor types Structure Tr a n s d u c t i o n Regulation | | Organ Bath Tissue Writing lever Oxygenated salt solution Organ bath (37 degrees C) Chart| Dose response studies are typically conducted to assess concentration-response relationships in isolated tissue preparations.
Traditionally, tissue-organ baths are used for in vitro dose response experiments to investigate the physiology and pharmacology of tissue preparations from various species (e. g. chick, toad, rabbit, rat, guinea-pig, etc. ). Tissue-organ baths are used to maintain the integrity of the tissue for several hours, in a temperature-controlled environment, while physiological measurements are performed. Typical experiments involve the addition of drugs to the organ bath or direct/field stimulation of the tissue.
The tissue reacts by contracting/relaxing and an isometric or isotonic transducer is used to measure force or displacement, respectively. From the experimental results dose-response curves are generated (tissue response against drug dosage or stimulus potency). | Agonists | Drugs which activate receptors, mimic effects of endogenous ligand ? Majority of drugs are not agonists, but are: Essential tools to develop new drugs There is an important distinction between agonists, which ‘activate’ the receptors, and antagonists, which combine at the same site without causing activation, and block the effect of agonists on that receptor.
The distinction between agonists and antagonists only exists for receptors with this type of physiological regulatory role; we cannot usefully speak of ‘agonists’ for the more general class of drug targets described above. If a drug binds to the receptor without causing activation and thereby prevents the agonist from binding, it is termed a receptor antagonist. The tendency of a drug to bind to the receptors is governed by its affinity, whereas the tendency for it, once bound, to activate the receptor is denoted by its efficacy.
Drugs of high potency generally have a high affinity for the receptors and thus occupy a significant proportion of the receptors even at low concentrations. Agonists also possess significant efficacy, whereas antagonists, in the simplest case, have zero efficacy. Drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is submaximal, are known as partial agonists, to distinguish them from full agonists, the efficacy of which is sufficient that they can elicit a maximal tissue response. | Occupation theory: Agonist vs Antagonist| |.
Dose response curves:| The maximum effect is called the Emax. The concentration at which the effect is 50% of the maximum is called the EC50. | Potency & Efficacy| Potency: A > B Amount required for effect, depends on affinity & efficacy Efficacy: A & B > C Once bound, how much effect? | Potency & Efficacy Selectivity ? | The more selective drug is for specific target / receptor: ? Easier to use therapeutically ? Good selectivity important aim when designing drugs | Antagonists ? | HAS AFFINITY TO FIT INTO ELECTRICAL SOCKET BUT LIGHT DOES NOT TURN ONBlock or diminish normal receptor function Most drugs that act on receptors are antagonists They action can be: -Reversible -irreversible| Antagonism: competitive | Shift to right ? Same slope Same max Figure 2.
6 Effects of irreversible competitive antagonists on agonist concentration-effect curves. [A] Rat stomach smooth muscle responding to 5-hydroxytryptamine at various times after addition of methysergide (10-9 mol/l). [B] Rabbit stomach responding to carbachol at various times after addition of dibenamine (10-5 mol/l)| Affinity & Efficacy| Important drug characteristics that effects how we use them.
?Affinity: how strong drug binds to receptor ? Efficacy: max effect drug can have ? Often determined experimentallyHOW WELL A KEY FITS IN A LOCK| Partial Agonists | Mixed action: Agonists at low concentrations Antagonists at high concentrationsFigure 2. 7 Partial agonists. [A] Log concentration-effect curves for a series of ? -adrenoceptor agonists causing contraction of an isolated strip of rabbit aorta. Phenylephrine is a full agonist. The others are partial agonists with different efficacies. [B] The relationship between response and receptor occupancy for the series.
Note that the full agonist, phenylephrine, produces a near-maximal response when only about half the receptors are occupied, whereas partial agonists produce submaximal responses even when occupying all of the receptors. The efficacy of tolazoline is so low that it is classified as an ? -adrenoceptor antagonist (see Ch. 14). In these experiments, receptor occupancy was not measured directly, but was calculated from pharmacological estimates of the equilibrium constants of the drugs. The ability of a drug molecule to activate the receptor is actually a graded, rather than an all-or-nothing, property.
If a series of chemically related agonist drugs acting on the same receptors is tested on a given biological system, it is often found that the largest response that can be produced by the drug in high concentration differs from one drug to another. | Inverse Agonist| An inverse agonist vs partial agonistA partial agonist has a weaker preference than an agonist for the same receptor and shift the equilibrium to a smaller extent than an agonist. Conversely, an inverse agonist has all the properties of a full agonist except that is shifts the equilibrium in the opposite direction to a full agonist.
An antagonist reduces the effect of an agonist by preventing it from binding to receptors. Both antagonists and inverse agonists reduce the activity of a receptor and, in the presence of an agonist, reduce its activity. However, unlike inverse agonists, antagonists do not have any effect in the absence of an agonist. Common Inverse AgonistsAs the definition of inverse agonists became clearer, more and more molecules that exhibit inverse agonism with clinical applications have been established.
Inverse agonism was first discovered when B-carbolines and other compounds that were shown not only to have an antagonistic effect at benzodiazepine receptors but also to elicit an effect that was the opposite of the benzodiazepine in the absence of benzodiazepines. Currently there are a number of well established true inverse agonists including antipsychotics, antidepressants and other psychopharmacological drugs that have inverse agonist activity at serotonin, dopamine, histamine, opioid, cannabinoid and muscarinic receptors. |
Basic Pharmacokinetic Concepts pharmacodynamicspharmacokinetics| What the drug does to the body VS What the Body does to the drug| What is Pharmacokinetics? | The branch of pharmacology that studies the fate of drugs within the bodyIncludes factors that govern drug Concentrations at the site of action as a function of time:•Absorption•Distribution•Metabolism•Excretion“ADME” We explain how drug clearance determines the steady-state plasma concentration during constant-rate drug administration and how the characteristics of absorption and distribution (considered in Ch. 8) plus metabolism and excretion (considered in Ch.9) determine the time course of drug concentration in blood plasma during and following drug administration.
The effect of different dosing regimens on the time course of drug concentration in plasma is explained| Overview of Pharmacokinetic Phase| Total clearance (CLtot) of a drug is the fundamental parameter describing its elimination: the rate of elimination equals CLtot multiplied by plasma concentration. CLtot determines steady-state plasma concentration (CSS): CSS = rate of drug administration/CLtot. For many drugs, disappearance from the plasma follows an approximately exponential time course.
Such drugs can be described by a model where the body is treated as a single well-stirred compartment of volume Vd. Vd is an apparent volume linking the amount of drug in the body at any time to the plasma concentration. Elimination half-life (t1/2) is directly proportional to Vd and inversely proportional to CLtot. With repeated dosage or sustained delivery of a drug, the plasma concentration approaches a steady value within three to five plasma half-lives. In urgent situations, a loading dose may be needed to achieve therapeutic concentration rapidly.
The loading dose (L) needed to achieve a desired initial plasma concentration Ctarget is determined by Vd: L = Ctarget ? Vd. A two-compartment model is often needed. In this case, the kinetics are biexponential. The two components roughly represent the processes of transfer between plasma and tissues (? phase) and elimination from the plasma (? phase). Some drugs show non-exponential ‘saturation’ kinetics, with important clinical consequences, especially a disproportionate increase in steady-state plasma concentration when daily dose is increased.
| Drug Absorption| The process by which unchanged drug proceeds from the site of administration into the blood. Note: An important factor for all routes of administration with the exception of intravenous administration| Drug Absorption Across Biological Membranes| •Lipid-rich biological membranes are the main barriers encountered by drugs•Generally, fat-soluble (lipophilic) drugs cross barriers easily•Water-soluble (hydrophilic) & ionised drugs cross membranes poorly.
•Some very small drugs (e.g. ethanol, MW < 100) cross membranes through small pores•Most drugs cross membranes by passive diffusion•i. e drugs diffuse down concentration gradient•Some drugs are actively transported across membranes (energy-requiring process)| Factors Influencing Drug Absorption| •Nature of Absorbing Surface (e. g. single layer of epithelial cells in GIT easier than skin)•Blood Flow (a rich blood flow e. g.sublingual/under tongue) enhances drug absorption compared to skin)•Solubility of Drug (lipid solubility is important for drugs given orally)
Formulation of Drug (drugs can be manufactured with enteric coatings to delay absorption)•Ionisation of Drug– most drugs are either weak acids (H-donating) or weak bases (H-accepting) •exist as either unionised (lipid soluble) or ionised (H2O soluble) species| Drug Excretion by the Kidneys| The relation between dose rate, drug clearance and plasma concentration is illustrated by the cylinder model.
Dose rate is represented by tap flow, drug clearance by outlet size, and plasma concentration by the height of the water column. Adjust the tap flow, and the size of the outlet to see what happens to the height of the water column. | Drug clearanceAmount of eliminationFigure 10. 1 Plasma drug concentration-time curves. [A] During a constant intravenous infusion at rate X mg/min, indicated by the horizontal bar, the plasma concentration (C) increases from zero to a steady-state value (CSS); when the infusion is stopped, C declines to zero.
[B] Following an intravenous bolus dose (Q mg), the plasma concentration rises abruptly and then declines towards zero. [C] Data from panel B plotted with plasma concentrations on a logarithmic scale. The straight line shows that concentration declines exponentially. Extrapolation back to the ordinate at zero time gives an estimate of C0, the concentration at zero time, and hence of Vd, the volume of distribution. | Plasma concentration (Cp) is directly proportional to the dose rate, and inversely proportional to the clearance (CL). i. e.
Cp = Dose rate/CLThe steady state concentration (Cpss) is thus determined by the maintenance dose rate and the clearance. Clearance of a drug can be defined analogously as the volume of plasma from which all the drug molecules would need to be removed per unit time to achieve the overall rate of elimination of drug from the body. Subsequently, as mentioned in Chapter 9, creatinine rather than urea clearance has become the routine clinical measure of renal functional status because it more closely reflects the glomerular filtration rate.
Van Slyke introduced the equation given in Chapter 9 for estimating renal clearance (CLren). This follows from the law of conservation of mass, and is written: where Cu is the urine concentration of the substance of interest (whether endogenous such as urea or creatinine, or exogenous as in the case of an administered drug), Cp its concentration in plasma and Vu the urine flow rate in units of volume/time. Cu and Cp are expressed in the same units of mass/unit volume (e. g. mg/l) so their units cancel out and CLren has the same units as V, namely volume/unit time-e.
g. ml/min or l/h. The overall clearance of a drug (CLtot) is the fundamental pharmacokinetic parameter describing drug elimination. It is defined as the volume of plasma containing the total amount of drug that is removed from the body in unit time by all routes. Overall clearance is the sum of clearance rates for each mechanism involved in eliminating the drug, usually renal clearance (CLren) and metabolic clearance (CLmet) plus any additional appreciable routes of elimination (faeces, breath, etc. ).
It relates the rate of elimination of a drug (in units of mass/unit time) to Cp: Drug clearance can be determined in an individual subject by measuring the plasma concentration of the drug (in units of, say, mg/l) at intervals during a constant-rate intravenous infusion (delivering, say, X mg of drug per h), until a steady state is approximated (Fig. 10. 1A). At steady state, the rate of input to the body is equal to the rate of elimination, so: Rearranging this, where CSS is the plasma concentration at steady state, and CLtot is in units of volume/time (l/h in the example given).
| For many drugs, clearance in an individual subject is the same at different doses (at least within the range of doses used therapeutically-but see the section on saturation kinetics below for exceptions), so knowing the clearance enables one to calculate the dose rate needed to achieve a desired steady-state (‘target’) plasma concentration from equation 10. 3. | | Drug Clearance, kidneys and liver| Drugs are eliminated by excretion unchanged through the kidneys, or by metabolism to an inactive product usually in the liver.
The fraction excreted unchanged (fu) defines the renal elimination, while (1-fu) describes the metabolic elimination. Drug elimination is the irreversible loss of drug from the body. It occurs by two processes: metabolism and excretion. Metabolism consists of anabolism and catabolism, i. e. respectively the build-up and breakdown of substances by enzymic conversion of one chemical entity to another within the body, whereas excretion consists of elimination from the body of chemically unchanged drug or its metabolites.
The main routes by which drugs and their metabolites leave the body are: * the kidneys * the hepatobiliary system * the lungs (important for volatile/gaseous anaesthetics). Most drugs leave the body in the urine, either unchanged or as polar metabolites. Some drugs are secreted into bile via the liver, but most of these are then reabsorbed from the intestine. | Steady State| The steady state concentration (Cpss) is determined by the maintenance Dose rate and the CL. | Volume distribution (Vd) The major compartments are:plasma (5% of body weight)interstitial fluid (16%)intracellular fluid (35%)transcellular fluid (2%)fat (20%).
| Volume of Distribution is considered in relation to body “compartments”. Vd determines the distribution of drugs between the blood and the rest of the body. Some highly polar drugs, such as penicillins, distribute mainly into “central” compartments and have a small Vd, while highly lipid soluble drugs, such as tricyclic antidepressants, distribute far more widely and have a large Vd. Drugs with small Vd stay mainly in the central compartment. Volume of distribution “dilute” as concentration enters ECF (extra-cellular fluid), ICF (intracellular fluid), muscle and fat.
Amount in body = Vd x plasma concentrationAb = Vd x CpVd = Ab/Cp Volume of distribution (Vd) is defined as the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma. Lipid-insoluble drugs are mainly confined to plasma and interstitial fluids; most do not enter the brain following acute dosing. Lipid-soluble drugs reach all compartments and may accumulate in fat. For drugs that accumulate outside the plasma compartment (e. g. in fat or by being bound to tissues), Vd may exceed total body volume.
The apparent volume of distribution, Vd, (see Ch. 10) is defined as the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma, Cp: Values of Vd have been measured for many drugs (see Table 8. 1). 3 It is important to avoid identifying a given range of Vd too closely with a particular anatomical compartment. For example, insulin has a measured Vd similar to the volume of plasma water but exerts its effects on muscle, fat and liver via receptors that are exposed to interstitial fluid but not to plasma (Ch.30). | | Effect of pH on Drug Absorption| If acid is added, eg. H+Cl-, the equilibrium moves to the right.
If alkali is added, eg. Na+OH-, then OH- ions and H+ ions neutralise each other to form water, and the equilibrium moves to the left. Unionized drug crosses lipid biological barriers (e. g. membranes) better than ionized drug. One important complicating factor in relation to membrane permeation is that many drugs are weak acids or bases, and therefore exist in both unionised and ionised form, the ratio of the two forms varying with pH.
For a weak base, the ionisation reaction is: and the dissociation constant pKa is given by the Henderson-Hasselbalch equation For a weak acid: In either case, the ionised species, BH+ or A-, has very low lipid solubility and is virtually unable to permeate membranes except where a specific transport mechanism exists.
The lipid solubility of the uncharged species, B or AH, depends on the chemical nature of the drug; for many drugs, the uncharged species is sufficiently lipid soluble to permit rapid membrane permeation, although there are exceptions (e.g. aminoglycoside antibiotics; see Ch. 50) where even the uncharged molecule is insufficiently lipid soluble to cross membranes appreciably. This is usually because of the occurrence of hydrogen-bonding groups (such as hydroxyl in sugar moieties in aminoglycosides) that render the uncharged molecule hydrophilic. | pH partition and ion trapping | Ionisation affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments, if a pH difference exists between them. Figure 8.
3 shows how a weak acid (e. g. aspirin, pKa 3. 5) and a weak base (e. g. pethidine, pKa 8. 6) would be distributed at equilibrium between three body compartments, namely plasma (pH 7. 4), alkaline urine (pH 8) and gastric juice (pH 3). Within each compartment, the ratio of ionised to unionised drug is governed by the pKa of the drug and the pH of that compartment. It is assumed that the unionised species can cross the membrane, and therefore reaches an equal concentration in each compartment. The ionised species is assumed not to cross at all.
The result is that, at equilibrium, the total (ionised + unionised) concentration of the drug will be different in the two compartments, with an acidic drug being concentrated in the compartment with high pH (‘ion trapping’), and vice versa. The concentration gradients produced by ion trapping can theoretically be very large if there is a large pH difference between compartments. Thus, aspirin would be concentrated more than four-fold with respect to plasma in an alkaline renal tubule, and about 6000-fold in plasma with respect to the acidic gastric contents. Such large gradients are not achieved in reality for two main reasons.
First, the attribution of total impermeability to the charged species is not realistic, and even a small permeability will attenuate considerably the concentration difference that can be reached. Second, body compartments rarely approach equilibrium. Neither the gastric contents nor the renal tubular fluid stands still, and the resulting flux of drug molecules reduces the concentration gradients well below the theoretical equilibrium conditions.
The pH partition mechanism nonetheless correctly explains some of the qualitative effects of pH changes in different body compartments on the pharmacokinetics of weakly acidic or basic drugs, particularly in relation to renal excretion and to penetration of the blood-brain barrier. | pH partition is not the main determinant of the site of absorption of drugs from the gastrointestinal tract.
This is because the enormous absorptive surface area of the villi and microvilli in the ileum compared with the much smaller surface area in the stomach is of overriding importance. Thus, absorption of an acidic drug such as aspirin is promoted by drugs that accelerate gastric emptying (e. g.metoclopramide) and retarded by drugs that slow gastric emptying (e. g. propantheline), despite the fact that the acidic pH of the stomach contents favours absorption of weak acids. Values of pKa for some common drugs are shown in Figure 8. 4. | There are several important consequences of pH partition:
* Free-base trapping of some antimalarial drugs (e. g. chloroquine, see Ch. 53) in the acidic environment in the food vacuole of the malaria parasite contributes to the disruption of the haemoglobin digestion pathway that underlies their toxic effect on the parasite.
* Urinary acidification accelerates excretion of weak bases and retards that of weak acids. * Urinary alkalinisation has the opposite effects: it reduces excretion of weak bases and increases excretion of weak acids. * Increasing plasma pH (e. g. by administration of sodium bicarbonate) causes weakly acidic drugs to be extracted from the CNS into the plasma. Conversely, reducing plasma pH (e. g. by administration of a carbonic anhydrase inhibitor such as acetazolamide) causes weakly acidic drugs to become concentrated in the CNS, increasing their neurotoxicity.
This has practical consequences in choosing a means to alkalinise urine in treating aspirin overdose: bicarbonate and acetazolamide each increase urine pH and hence increase salicylate elimination, but bicarbonate reduces whereas acetazolamide increases distribution of salicylate to the CNS. | | Weak Acids| •may contain –COOH group•are nonionised at acidic gastric pH, ionised at alkaline pH (e. g. urine)•e. g. aspirin, penicillin, warfarin|
Weak Bases| •may contain –NH2 or -NH group•are ionised at gastric pH, nonionised at alkaline pH•e. g.amphetamine, chloroquine, morphine| Effect of pH on Ionisation of Benzoic Acid & Aniline| Klaassen et al(1996)| Drug Bioavailability| Def’n: The proportion of an orally-administered drug dose reaching the systemic circulation intact. |
2. Drug Distribution| Def’n: The reversible transfer of a drug from one location (e. g. blood) to another (e. g. heart or lung tissue)•Drug distribution initially greatest to organs receiving high blood supply (e. g. heart, liver, kidney)•Distribution to tissues receiving lower blood supply occurs more slowly (e. g.skeletal muscle, fat)•The major body compartments are:•Plasma (5% of total body weight)•Interstitial fluid (16%)•Intracellular fluid (35%)
•Transcellular fluid (2%)•Fat (20%)| Drug-Protein Binding in Plasma| Certain drugs often strongly bind to proteins within plasma (e. g. warfarin is 99. 9% bound to albumin)•Acidic drugs mainly bind to albumin, while basic drugs prefer ? 1- acid glycoprotein•Protein-drug binding is a reversible & dynamic (bound and unbound drug are in equilibrium)•Only free drug is active in pharmacological terms•Drug doses may need to be altered in patients with diseases that alter plasma protein profiles (e. g.hypoalbuminemia)| Binding Properties of Plasma Proteins|.
The physical processes of diffusion, penetration of membranes, binding to plasma protein and partition into fat and other tissues underlie the absorption and distribution of drugs. These processes are described, followed by more specific coverage of the process of drug absorption and related practical issue of routes of drug administration, and of the distribution of drugs into different bodily compartments. There is a short final section on special drug delivery systems designed to deliver drugs efficiently and selectively to their sites of action. At therapeutic concentration.