Introduction To Pharmacology
September 1999

Pharmacology review Goodman and other references 1

Rate constant & t ½ – rates of elimination, absorption, and distribution are proportional ti cibcebtratuin, but zero order kinetics is not concentration dependent. When the process becomes saturated, the rate of metabolism becomes independent of concentration. If mechanisms for elimination of a drug become saturated, the kinetics become zero order – a constant amount of drug is eliminated per unit of time which means that CL becomes variable

ED50 is RT potency – and potency is the dose of drug required to achieve 50% of desired therapeutic effect which is the effective dose( which is the measure of dose required to produce a response.

Efficacy is the maximal response that a drug can produce and is represented as a % on the graph.

Drugs pass through cells rather than between them - < 100-200 D can pass through with water, urea, etc.

Receptors – cell membrane receptors are embedded in the bilayer and elicit electric or chemical signal pathway and provide selective targets for drug actions.

Bulk flow through IC clefts is the major mechanism of passage of drugs across most capillary endothelial membranes except for the CNS, so diffusion is limited by bloos flow and not only solubility of drugs or pH gradients. Pinocytosis is involved but not as much as bulk flow.

Carrier mediated transport – charac of active transport – selectivity, competative inhibition, saturability overcome by movement against e/c gradients

Bioavailibility is > important than absorption, but factors that impair absorption can change bioavailability. Aq solns are more rapidly absorbed into circ.

Distribution of drug reflects on CO and other organs functions.

Reasons for dec distribution are 1) thight clefts which restrict bulk flow, poorly permeating into tissues, absorption problems and 2) binding of drug to PP, reseviours – fat, bone, transcellular – ie GI tract

Acidic drugs bind to albumin & and basic drugs bind to alpha acid glycoproteins

BIOTRANSFORMATION = metabolism, which generates > polar inactive metabolites.

Biotransformation occurs in the liver mostly at the mitochondria, nuclear envelop, plasma membrane, and biotransformation is usually enzymatic. 2 drugs can compete for the enzyme receptor site and the drug with the lowest affinity will be metabolized less quickly.

Phase 1 – introduces or exposes a functional group upon parent, and the drug usually loses pharm activity. Occurs in the SER via CP450 generally in the liver, but can happen almost anywhere.

Phase 2 – is cytosolic. Covalent bonding which occurs between functional group and parent( functional group is usually glycouronbic acid, SO4, glutathione, AA, acetate) thru drug reacting with endogenous compounds à water sol conjugate.

1st order kinetics – drugs disappear from plasma by processes which are conc dependent, and as plasma conc inc rate of elimination inc, because elimination is usually a 1^st order process. See a constant fraction of drug (weight of drug)eliminated per unit of time. The order of a reation refers to the way in which the conc of a drug or reactant influences the rate of a chemical reaction. The elimination rate varies with the 1^st power of the concentration. Any 1^st order process is RT t ½

0 order kinetics – is dose dependent. The rate of elimination is independent of concentration. Follows a linear time course Ko. Liver metablolism – one of the most important factors that contributes to Ko. A constant amount of drug is lost /unit time, the t1/2 is not constant since it depends on concentration.

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Excretion – via lung, breast milk, GI and most importantly th ekidney – tubular urine is acid usu, excretion occurs via glomerular filtration, active tubular secretion, and passive tubular secretion of nonionized product, since tubular cells are < permeable to ionized forms of weak acids and lytes; passive reabsorption of these substances is pH dependent. When tubular urine is made > alkaline, weak acids are excreted > rapidly because they are watersoluable(ionized), and passive reabsorption is decreased.

CLEARENCE – CL - is a measure of the bodys ability to eliminate a drug. Total body clearance is the sum of the clearances from various metaboling and eliminatory organs. CL is additive – CL hep + CL ren …= CL system.

• its RT rate of elimination and drug presentation to organs RT (flow of blood to organ + arterial conc of drug) and (flow or exit of of drug from organ flow + venous concentration of drug). The difference between these rates at steady state is the rate of drug elimination, Q(Ca – Cv).
• is a term that indicates the rate at which a drug is cleared from the body – but think of it as the volume of biological fluid that is completely freed of drug to account for elimination
• CL is given in units of volume/time
• Another way to think of CL defined as the volume of plasma from which all drug is removed in a given time ( the volume of fluid cleared of a drug per unit time)
• CL becaome variable when the mechanisms for elimination of a drug become saturated – zero order kinetics.
• The t ½ increases as CL decreases in disease states, as long as disease does not change the volume of distribution.
• Changes in protein binding may change CL and Volume of distribution à unpredictable changes ie hepatitis dec t ½ of tolbutalide

T ½ – halflife – is thetime it takes for the conc of drug to dec to ½ the value it had at the start of the time interval.

• it’s a dependent pharmacokinetic parameter derived from th eindependent parameters of CL and Vd
• its constant and is RT Ke for 1^st order kinetic drugs, because its concentration dependent
• it dies provide a good indication of time required to reach steady state after dosage initiated

Dosing the patient – and adjustments of dosage depend on the pharmacokinetic parameters, and the 3 most important parameters are:

• CL – for long term – a measure of the bodys ability to eliminate the drug – phase 1&2
• Volume of distribution Vd- – a measure of apparent space in the body available to contain a drug
• Bioavailability – the fraction of drug absorbed into circulation
• 2&3 are less important than 1.

Steady state – Css – when multiple dosing or a continuous infusion of drug will accumulate until the amount administered per unit time is = to the amount eliminated per the same unit time, and is usually achieved after @ 4.3 t ½

Parameters to consider:

• CL read previous entries
• Vd relates amount of drug in the body to the conc of drug in plasma depending of the fluid measured
• Vd can vary widely depending on pKa of drug , degree of binding to PPs and other tissues, partition coefficient of drug in fat, age, gender, disease, body composition, etc.

RECEPTORS ( R )

• are enzyme like molecules or complexes which are found in cells or in cell membrane which are responsible for triggering, modulating or inhibiting biological processes, thus altering cell physiology. They are also found on organelles and in cytoplasm. 2. Any cellular macromolecule to which a drug binds to initiate its effects. 3. The R , its cellular target, and any intermediary molecule is referred to as a "receptor – effector system" or "signal transduction pathway". 4. R great properties of catalyzing make it a good target for drugs, the catalyzing effect allows biochemical signaling/ amplification. 5. All Rs are formally catalysts ie : a R which is an ion channel à channel opens and drug binds to hormone R à transcription of mRNA à protein synthesis occurs.

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• are often protein in structure but can contain CHO, lipids, and inorganic ions in their structure

some nucleic acids are receptors (they are complex long chain compounds of high molecular weight which forms genetic material of cell and direct synthesis of protein in cell)

• when chemical/drug/hormone bind to R à stims cascade of chemical reactions or nerve impulse à physiological action
• Hydrogen bonding is involved in the binding of substrates to R sites
• R subtypes – nicotinic = ligand binding controls it – NMJ, all autonomic ganglia, CNS, role – is to convert the NTMS to an electrical signal in the target organ. There are 5 subunits of the nicotinic R which are all glycosalated – alpha, beta, delta, gamma . The channel opens when 2 achs bind in a low affinity conformation, (the channel cant be opened in a high affinity conformation), anyway, prolonged contact with ach results in inactivation (desensitization) of the receptor.
• Glutamine receptors – (new drugs, anticonvulsants, analgesics, neurodegenerative agonists) via ion channel, ligand gating and voltage gating
• GABA type A receptor – ligand gatyed ion channel receptor, GABA is primary endigonous and inhibits NTMS in vertebrates CNS, and is enhanced by barbiturates
• G protein coupled receptors – Gsi, Gi, Gt, Gg, G12,h3 – agonists to G protein generates IC 2^nd msgrs that regulate cell function; effectors(membrane bound proteins) are regulated by G proteins are adenylate cyclase & phsophodiasterase. 2^nd msgr cAMP, ID3, DAG à activate protein kinases which produce cellular response by increasing phosphoralylation state of important regulatory proteins in target cells.
• Receptors with intrinsic tyrosine kinase activation involve phosphorilation of proteins on tyrosine residues
• The # of receptors /cell are finite – receptor mediated responses plateau upon or before receptor saturation.
• When a ligand binds to a receptor – the 1. ion channel opens 2. cytoplasmic 2^nd biochemical msgrs cAMP, cGMP, Ca, PIPs are activated à initiate series of chemical reactions with in cell which transduce the signal stimulated by the drug - therefore a high cellular function is physically inhibited ie DNA and protein synthesis, bacterial wall production. 3. Cell function is turned on eg steroid promotion of DNA transcription.

Functional families of receptors exist. 2 functions of receptors are 1. Ligand binding (ligand binding domain) 2. Message propagation ( effector domain)

R as enzymes – protein kinase for peptide hormone that regulates growth & development of different tissues, are frequent plasma membrane bound protein kinase that act by phosphorilating target proteins.

R are subject to regulatory and homeostatic controls –

• continuous stimulation with agonists à desensitization which can be charac by refractoriness or down regulation – ie beta agonists for broncodilation

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Desentization can occur when - stimulation of R à attenuated(weaker) signal secondary to covalent modification via phosphorylation of R, destruction of R, or relocation of R in the cell - synthesis of R is subject to feedback regulation, cell resets itself after the drug is withdrawn

Examples of receptor malfunction are myesthenia gravis, insulin resistant diabetes mellitus, and testicular feminization syndrome.

Classification of receptors and drug effects are identified and classified primarily by effect and relative potency of selective agonist and antagonist acitvity ie: ach mimicked by muscarine and are selectively antagonized by atropine – and this is termed as muscarinic effects.

Other effects if ach mimicked by nicotine and are not readily antagonized by atropine but selectively blocked by the other agents are described as nicotinic effects.

There are drugs that do not use receptors – they react with molecules in the body ie: mannitol, antacids, mesna.

CELLULAR EVENTS OF PHARMACOLOGY

AFFINITY is 1) # of cell receptors occupied by the drug as a function of an equilibrium between drug bound to R and drug that is free. A high affinity agonist or antagonist is < likely than a low affinity drug to dissociate once bound. Kd is the dissociation constant, and it measures the drugs affinity for a given R, it’s the concentration of drug in solution to achieve 50% of occupancy of its R. 2) affinity is the measure of the strength of binding between drug and R and cant easily be measured. 3) a low affinity agonist may produce a response > or = than that produced by a high affinity agonist, but I don’t know why?? 4) cant compare affinity with efficacy and potency.

Receptor affinity is determined by 1.absorption 2. Plasma protein binding 3. Distribution 4. Metabolism 5. Excretion. (1-5 affect the dose response curve)

AGONIST – drug that binds to physiological receptors and mimick the effect of the endogenous regulatory compounds (EMAX reached through minimal receptor binding) its an agonist which causes maximal effects even though it may occupy a small fraction of R on a cell.

WEAK AGONIST – (EMAX reached thru much receptor binding) an agonist which must be bound to many receptors than a strong agonist would, inorder to produce the same effect.

PARTIAL AGONIST – (EMAX never reached) a drug which fails to produce maximal effects even when all the receptors are occupied by the partial agonist

ANTAGONISTS – non competative, competative, irreversable. Agonists do not have efficacy since they do not produce responses. 1. Compuonds devoid of intrinsic regulatory activity, but which produce effects by inhibiting the action fo an agonist. 2. Drugs which bind to R and do not mimick but interfere with.

SUBTLETIES OF DRUG CLASSIFICATION – 1. drugs that are only partly as effective as agonists are termed partial agonists. @. Negative or inverse agonists ( antagonists) stabilize receptor from undergoing productive binding to agonist by causing conformational changes to R, thus not allowing agonist to bind to R.

RECEPTOR DRUG BINDING occurs these types of binding – ionic, hydrogen, hydrophobic, VanDer Waals attraction, covalent, and usually there are bonds of multiple types involved. 1. With covalent bonding the drug action is usually prolonged. 2. Non covalent interactions of high affinity may appear essentially irreversable.

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PROPERTIES THAT ARE REQUIRED FOR OPTIMAL ACTION ATH THE RECEPTOR are size, shape; position & orientation of charged groups or hydrogen bond donar. Through modeling the receptor de novo design of drugs is done with improved selectivity, affinity, aor regulatory effect.

CELLULAR SITES OF DRUG ACTION – sites of action and extent of action are determined by 1. Locality and functional capacity of specific R with which the drug interacts with 2. Concentration of drug to which R is exposed. 3. Selective locality doen not depend upon delective distribution. If drug acts on receptor which serves functions common to all cells, then the effects of the drug are wide spread. If the function is a vital one, th edrug can be difficult one to use ie digoxin – works on Na pump in heart but also affects all Na pumps in body. The digoxin could be toxic.

A drug may react with R unique to a few types of different cells à therefore the effects of the drug are > specific thus minimizing side effects , BUT some drugs are very specific and also very toxic through primary local action à widespread effects. Ie botulism

EFFICACY – effect to which a drug is able to induce maximal effects. It is usual to compare drugs with different mechanisms ie: narcs and NSAIDS rt post op pain.

POTENCY 1. The amt of drug necessary to produce 50% of max response that a drug is capable of inducing. 2. Used to compare drugs in a chemical class ie narcs or corticosteroids – these drugs have similar max efficacy if a high enough dose is given

GRADED DOSE RESPONSE CURVE 1. Graphs the magnitude of drug action against the conc(dose) of drug required to induce those actions. 2. The curve represents effects and dose of drug with in an individual animal or tissue rather than a population

PHARMACOLOGY AT THE POPULATION ( AGGREGATE) LEVEL

Tests of efficacy and safety are tested on the population and data are presented via:

EC50, LD50, Therapeutic Index [LD50 / ED50] where ED = EC, Margin of Safety ( margin between therapeutic and lethal doses of drug.

PHARMACODYNAMICS - Goodman

What the drug does to the body.. It’s the study of the biochemical and physiological effects of drugs and their mechanisms of action ( effects result from interaction with macromolecule components). Objectives of the drug action are to 1. Delineate chemical and or physical interactions between drug and target cell, 2. Characterize full sequence and scope of action of each drug

The receptor is the component of the organism with which the chemical agent was presumed to interact.

Drugs alter the rate at which any body function proceeds, drugs do not create effects, but do modulate functions.

R the most important class are proteins ie hormones, growth factors, NTMS, all rely on enzymes of crucial metabolic regulatory paths. Transport proteins include Na/K/ATPase pump, structural proteins, and nucleic acids are important for CA & chemo