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1

INTRODUCTION TO PHARMACOLOGY

PHARMACOLOGY is the study of the interaction of chemicals with living organisms to produce biologicaeffects. Drugs are any substances that bring about changes in the rate of a biological function. In most casesdrugs produce these effects through their interactions with a specific molecule that plays a regulatory role i.e. areceptor.

DRUG LEGISLATION has evolved in order to protect the consumer from 1) false claims of beneficial effects2) harmful effects and 3) inappropriate administration.

Standardization: relationship between drug dose and biological effect. Codes have been adopted fostandardizing drug content. In the USA, drugs must comply with standards in the United StatesPharmacopeia (USP) and/or the National Formulary. Standardization of doses is one of the biggestconcerns with alternative therapies/health remedies.

USP: contains chemical, physical and biological information on all the active ingredients used in medications(e.g. USP aspirin (325 mg) must contain between 95% (309 mg) and 105% (341 mg) of the amount of aspirinindicated on the label.

Comprehensive Drug Abuse Prevention Act (Controlled Substance Act): Defined drug dependency andaddiction, classified drugs into Schedules based on medical usefulness and abuse potential.

SCHEDULE CHARACTERISTICS RESTRICTIONS EXAMPLES

I high abuse potential; no accepted medical use;severe physical and/or psychological dependence

approved protocolnecessary

heroin, marijuana, LSD

II high abuse potential; accepted medical uses; severephysical and/or psychological dependence

written Rx required; norefills; warning label oncontainer

morphine, meperidine,codeine, secobarbital

III less abuse potential than II; accepted medical uses;moderate/low physical dependence or highpsychological dependence

written or oral Rx required;Rx expires in 6 months; 5refills in 6 months; warninglabel on container

preps with limited quantitiesof codeine, non-opioids(barbiturates) except thoselisted in another schedule

IVlower abuse potential than III; accepted medicaluses; limited physical/psychological dependence

written/oral Rx; expires in6 months; 5 refills in 6months; warning label oncontainer

some barbiturates (e.g.,phenobarbital) andbenzodiazepines (e.g.,diazepam, alprazolam)

V low abuse potential compared to IV; acceptedmedical uses; limited physical/psychologicaldependence

may require Rx; dependson state law

Contain limited quantities ofcertain opioid substances(e.g., IMODIUM, AD)

DRUG DEVELOPMENT and ASSESSMENT OF SAFETY and EFFICACYWhy test and control (placebo) groups in phase II studies? If only the sickest patient receive the

drug (ones where other drugs have failed) the new drug being screened would appear less effective thanplacebo, even if it is not, simply because the patients receiving the drug are sicker to begin with. Converselyadministering the drug to healthier patients might make it look more effective than it really is. In addition, thesimple act of taking something contributes to the therapeutic response (placebo effect).

What is informed consent? It is an explanation of the potential risks to healthy volunteers or patientsbefore their enrollment in a clinical trial. An Institutional Review Board (IRB) must consent to a clinical trial andcan stop a trial if it becomes concerned with results. It can also request changes in procedure.

Compassionate use: Drugs that are made available to extremely ill patients OUTSIDE of clinical trialsBUT, such use comes with NO assurances that the drug/procedure will help nor that it is safe.

TRIALS TYPE PURPOSE LENGTH COST

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2

OVER-THE-COUNTER DRUGS AND SELF-MEDICATION

Properties of OTC Medications

1. for a drug to be available OTC, it must be safe for self-medication, must clearly indicate thecontents, dosage, precautions and possible drug interactions.

2. low doses (sometimes less than therapeutic amounts)

3. combinations of ingredients - fixed combination products. Thus if an increase in oneingredient is needed, more of the other ingredients must be consumed as well, even if they arenot needed.

Names of Drugs

1. chemical- precise description of a drug's chemical composition, i.e. S-6-Methoxy-E-methyl-2naphthaleneacetic acid sodium salt

2. generic- general class of pharmacologically similar drugs (e.g. naproxen sodium)3. trade (brand; proprietary) - name of a drug designated by the drug company which makes and

markets it (e.g., ALLEVE). ALLEVE is the registered trade name of Bayers form of naproxensodium while Naprosyn is made by Roche Pharmaceuticals.

Importance of knowing the generic name: there are many trade names for the same drug (e.gpropranolol, a beta (F) antagonist (blocker), is known by trade names such as DETENSOL, INDERALIPRAN, NOROPRANOL etc...). Therefore it becomes difficult to remember all the trade names and mistakescan and do occur. Such errors occurred when prescribing the drug omeprazole (LOSEC) for people withulcers. Instead of prescribing omeprazole (LOSEC), furosemide (LASIX) was ordered. These two drugshave vastly different uses, omeprazole is a H+ pump inhibitor used to treat ulcers and furosemide is a diureticused to control edema and hypertension. As a result of this confusion, LOSEC was renamed PRILOSEC.

Substitution of a generic drug for a brand name drug depends a great deal on the formulation of thegeneric drug. By law, generic drugs must contain all the active ingredients present in the brand name

preparation and must be present at concentrations of 80-120% of that amount indicated on the labe

PRECLINICALin at least 2

animal species

Acute1. short-term effects of high doses2. identify target of toxicity

~5 years millionsChronic

1. effects of prolonged drug exposure atseveral doses

2. males, females, and pregnant females (?)File an Investigational New Drug (IND) application with the FDA

CLINICAL

Phase Iscreening for safety

(20-100 people)

1. usually performed in healthy volunteers orin patients on an older medication

2. determine dosing guidelines3. compare human data with animal data

~1.5 years $10,000,000

Phase IIestablishing protocols

(50-300 patients)

1. preliminary estimates of drug doses andduration of treatment2. homogeneous population of patients3. establishing end-points to determine exactly

what the drug can do4. first use of a control group (double-blind

studies)5. selecting patients for phase III studies

~2 years $20,000,000

Phase IIIdefining efficacy and

side effects(300-30,000 patients)

1. FDA releases drug into limited circulation2. validates phase II efficacy3. monitor nature and incidence of side effects

~3.5 years $45,000,000

File a New Drug Application (NDA) with the FDA

Review by the FDA ~1.5 years

Phase IVpost-marketing

surveillance

monitor long-term effectiveness and cost-effectiveness compared to other drugs on themarket. Phase IV studies ultimately forcedVIOXX off the market

ongoing

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3However, absorption of a drug depends greatly on its formulation including its inactive ingredients. Thereforenot all generic drugs have the same bioavailability even though they may contain the same amount of drugGeneric drugs can be substituted for trade name drugs unless the prescription reads DISPENSE AS WRITTEN(DAW). For example, Parke-Davis phenytoin (DILANTIN) is considered an extended action drug while somegeneric formulations of phenytoin are not. Thus, DILANTIN and generic phenytoin may not be therapeuticallyequivalent.

Study Questions

1. What is the purpose of drug legislation?DRUG LEGISLATIONhas evolved in order to protect the consumer from 1) false claims of

beneficial effects, 2) harmful effects and 3) inappropriate administration.

2. What does it mean when a drug carries the USP label?Drug complies with the US Pharmacopeia in that it contains 95-105 percent of the drug inquestion.

3. Compare the characteristics of drugs in Schedules I-V.All schedules require a prescription except schedule I; Schedules 2-5 placement on scheduledepend on the amount of drug; #1 has no accepted medical use;1>2>3>4>5

4. What is the purpose of drug testing in animals?To determine the short term affects of high doses, identify target of toxicity, effects ofprolonged drug exposure at several doses, and the comparative effects on malesfemales, and pregnant females.

5. What kinds of studies are performed in phases 1-IV clinical trials?1Healthy volunteers; compares human verses animal data; dosing guidelines detrmn.2homogenous pop. of patients; control grp.double blind;select for phase 33FDA limited circ. Release;validation of phase 2 rslts;monitor side effectsNew drug app filed4 monitor long term and cost efxtvns.

6. Drugs can be described by 3 different names; what are they and what does each indicate?

Chemical name- drugs precise chemical compositionGeneric name- general class of pharmacologically similar drugsTrade/Brand name- name designated by drug company which makes and markets it

7. What are the characteristics of over-the-counter drugs?for a drug to be available OTC, it must be safe for self-medication, must clearly indicate thecontents, dosage, precautions and possible drug interactions.low doses (sometimes less than therapeutic amounts)combinations of ingredients - fixed combination products. Thus if an increase in one

ingredient is needed, more of the other ingredients must be consumed as well, even if they are notneeded.

their benefits outweigh their risks the potential for misuse and abuse is low consumer can use them for self-diagnosed conditions they can be adequately labeled health practitioners are not needed for the safe and effective use of the product

What determines whether a drug will be available over the counter?For a drug to be available OTC, it must be safe for self-medication, must clearly indicate thecontents, dosage, precautions and possible drug interactions.

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4

PHARMACODYNAMICS

PHARMACODYNAMICS: Biochemical and physiological effects of drugs and their mechanisms of actioni.e. what they do to you. Determines 1) primary action of a drug, 2) its chemical interaction with the cell and 3characterizes its actions and effects which can provide a basis for rational therapeutic use and design of newtherapeutic agents.

RECEPTORS are reactive sites with which drugs interact. Activation of receptors by drugs mediates thedrugs effects. Drugs change the RATE of a given function, or modulate ongoing functions; they DO NOTconfer new functions on cells. There are two general categories of drugs that bind to receptors.

1) agonists: drugs which bind to receptors and mimic at least some of the effects of the endogenousregulatory compound.

full: Drugs which produce all the possible responses associated with activating that receptorpartial: produce only some of those responses i.e. are partly as effective as a full agonistinverse: Produce effects opposite of those produced by a full agonist

2) antagonists: bind to agonist receptors, have no pharmacological activity of their own and cannoactivate the receptors. However, when antagonists bind to receptors agonists cannot. So antagonistscan prevent the effects of agonists.

competitive: Effects can be reversed by high concentrations of agonist

non-competitive: Effects are essentially irreversible

RECEPTORS CHARACTERISTICS: Receptors are selective not specific for the ligand they bind.1) chemical properties: protein, DNA, membrane lipids, transporters, etc....2) structure-activity relationships: the affinity of a drug for its receptor and its intrinsic activity are

closely related to its structure such that even small changes in a drugs structure can alter its agonistproperties or even convert it to an antagonist.

3) cellular sites of drug action include:a. common molecules present in most cells (i.e., Na pump, DNA/RNA, AChE).

Drugs interacting with these molecules cause wide-spread effects and if that functionis vital, the drug may be dangerous and difficult to use (e.g., cardiac glycosides)

b. receptors for physiological regulatory molecules (hormones and neurotransmitters)

c. actions not mediated by receptors (e.g., antacids)4) drug-receptor interactionsa. covalent interactions - characterized by the sharing of pairs of electrons between

atoms and are not easily reversible e.g. phosphorylationb. electrostatic interactions - include strong interactions between + and charges, H+

bonds and weak dipole interactionsc. hydrophobic bonds weak interactions of lipid-soluble drugs with membrane lipid

DOSE-RESPONSE RELATIONSHIPS: The easiest way to increase the response to any drug is toincrease the dose. Thus, of all of the controllable variables in drug action, dose is crucially important. Themagnitude of a drug effect is proportional to the dose administered; dose-response curves are ways oquantitating drug responses and help define drug responses by illustrating the effects of a drug as a function of

its concentration. Semi-log dose-response curves have two advantages: (1) the response to a wideconcentration of a drug can be illustrated and (2) the response is linear over a wide portion of the curve.

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5Fig. 1 represents a linear dose response curve. Notice that this graph is very difficult to read at low

doses, and at high doses, it is difficult to see small changes in drug response. In the graph on the right, drugdose has been converted to a log scale. Thus, 3 Qg = 100.5, 10 Qg =101, 30 Qg=101.5, 100 Qg is 102 Qg, 300 Qg =102.5, 300 Qg = 102.5, etc Converting doses to log doses makes a portion of the graph easy to read (i.emakes it linear). Thus we can easily compare the response to 100 Qg; log=2.0, 500 Qg, log=2.7, and 1000Qglog=3.

CHARACTERISTICS OF DOSE-RESPONSE CURVES (fig. 2)1. EC5

0

: Effective Concentration50 (EC50) is that concentration of a drug producing a 1/2 maximal (or50% of the maximal) response. In Fig 2, each drug produces the same maximal effect, but the concentrationsproducing that increase are different. Since it is hard to compare drug concentrations producing a maximaresponse, we instead compare the doses producing a half-maximal (50% response).These concentrations aredifferent for each drug.

2. POTENCY: A term used to compare concentrations of several drugs. The EC50 is used as anindication of potency; the smaller the EC50, the more potent the drug. Thus it takes 1 mg/kg of ISO, 3 mg/kgEPI 10 mg/kg NE and ~20 mg/kg dobutamine to produce a half-maximal response. Thus, ISO is the mostpotent drug while dobutamine is the least potentand ISO>EPI>NE>dobutamine (rank order of

potency).REMEMBER: Potency is a comparativeterm.

3. EFFICACY: An indication of how wella drug works and reflects the maximumresponse a drug can produce. It is indicated bythe height of the dose-response curve and is

proportional to the number of receptorsactivated. This is also a comparative term and ismore important clinically than POTENCY. SinceISO, EPI and NE produce the same maximalresponse, they are equally efficacious (they allproduce the same maximal response) and are allfull agonists. In contrast, dobutamine does notproduce the same maximal response; it is apartial agonist.

4. SLOPE: The slope of the dose responsecurve reflects the degree of receptor occupancy. Asteep slope indicates that very few receptors need to beoccupied to produce a response. A drug with a steepslope may not be as safe to use as a drug with ashallow slope. Since the slopes of the ISO, EPI, and NEcurves are about equal, in theory they are about equallysafe to use.

DOSE-RESPONSE CURVES IN THE PRESENCEOF ANTAGONISTS (fig 3): Epinephrine (EPI) is anagonist which increases blood pressure. When 1 mgprazosin is used in the presence of EPI there is anapparent decrease in EPIs potency (EC50 EPI = 0.1mg/kg; EC50 EPI+1 mg/kg prazosin = 0.3 mg/kg).Increasing the dose of prazosin to 10 mg reduces EPIspotency even further (to 1 mg/kg). Prazosin bindsreversibly to the same site on EPI receptors that EPIdoes, but cannot activate these receptors (i.e. it has noefficacy). When EPI receptors are occupied by prazosin(notice that prazosin by itself produces no response),

0 0.1 0.3 1 3 10 30 100 3000

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6low concentrations of EPI cannot compete with prazosin for bindingto EPI receptors. However, increasing concentrations of EPI canovercome the antagonism of prazosin, Thus, prazosin is describedas a COMPETITIVE ANTAGONIST. The maximal effect of theagonist (EPI) can still be achieved if the dose of agonist is highenough. Also notice that prazosin shifts the dose-response curvefor EPI to the right. This shift depends ONLY on the concentrationof the antagonist and its affinity for the receptor

When EPI is used in the presence of phenoxybenzamine, thereis an apparent decrease in EPIs efficacy. This is becausephenoxybenzamine covalently binds to EPI receptors preventingEPI from binding and does so irreversibly. Thus, EPI cant bind, nomatter how high the EPI concentration (notice thatphenoxybenzamine by itself produces no response). Since EPIcannot compete with phenoxybenzamine, phenoxybenzamine istermed a NON-COMPETITIVE ANTAGONIST. This results in a decrease in the number of receptors availablefor agonist activation and thus a decrease in efficacy (REMEMBER:efficacy is proportional to the number oreceptors activated).

Basal activities of agonists, antagonists and inverse agonists: Figure 4 compares receptoactivation by agonists, antagonists and inverse agonists. Notice that agonists increase basal activity

antagonists have no activity and that inverse agonists produce the opposite effect of an agonist because thereis some level of basal activity in the system in the absence of any drug.OTHER TYPES OF DOSE-RESPONSE CURVES: In Quantal Dose-Response Curves (fig 5a), an

experiment was performed on 14 groups of rats with100 rats/group (a total of 1400 rats) and an all-or-none response is produced (e.g. a seizure iscontrolled or not). The dose of drug vs % opopulation responding at each dose is then plottedFrom this, an Effective Dose50 (ED50) can becalculated and indicates the dose where 50% of the

population is responding. Most individuals wilrespond to a drug dose lying between 0.5 and 2 x the

ED50. Quantal dose-response curves can then beused to compare two drugs OR to define thetherapeutic index of a drug. In Graded Dose

Response Curves(Fig 5b)a single animal receives increasing doses and a complete dose-response curve isproduced in each animal. An EC50 is determined for each animal and variability is reflected in the family odose-response curves. Means of responses are calculated at each dose, then a mean EC50is calculated.

QUANTAL DOSE-RESPONSE CURVES TO DETERMINE THERAPEUTIC INDEX (fig 6): Therapeutic indexis a reflection of a drugs selectivity or its margin of safety. It is determined by comparing the dose-responserelationship for therapeutic effects and toxic effects. Therapeutic index = Lethal Dose50 (LD50)/Effective Dose50

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7(ED50) or better the ED50 for the side effects/ED50 for the therapeutic effects )

. The further apart the 2 curves,the safer the drug (i.e. the larger the ratio, the safer the drug). In fig. 6 the TI of two drugs used to treat hearfailure are compared. Digoxin (left graph) has a TD50 of 5 and LD50 (or better Toxic dose50) where theappearance of arrhythmias is half-maximal of 17. 17/5=3.4 so digoxin has a TI of 3.4. Digitoxin (right graphhas a TD50 of 5 and a toxic dose50 of 80. So its TI= 80/5=16. Thus Digitoxin is safer to use.

DRUGS DO NOT HAVE A SINGLE THERAPEUTIC INDEX.

1. aspirin has a greater margin of safety for headache relief than arthritis relief (since lower dosesare needed to relieve headache pain)

2. drugs can be both selective and non-selective; e.g. antihistamines block the effects of histamineand cause sedation (an anticholinergic effect)

3. margin of safety is a meaningless measurement in an individual allergic to the drug

TIME-COURSE OF DRUG ACTION (Fig 7)

1. onset - time it takes to achieve aconcentration of a drug whichproduces a response

2. peak effect- time it takes a drug to

achieve its highest concentration inthe blood

3. duration - time during which there issufficient drug in the circulation toproduce a response

4. half-life (t1/2) - time it takes forelimination processes to decreasedrug concentration in the body by1/2

Study Questions:

1. Define pharmacodynamics. Define receptors.2. Describe the similarities and differences between agonists and antagonists.3. What does the ED50 of a drug indicate? The efficacy? The slope of a dose-response curve?4. Describe the relationship between the agonists

and antagonists in the graph to the right.5. Differentiate between competitive and non-

competitive antagonists and inverse agonists6. Describe the similarities and differences between

quantal and graded dose-responses curves.What information can be obtained from each?

7. What does the therapeutic index of a drugindicate? How is it calculated?

8. Define the following characteristics of the time-course of a drugs action.

onset of drug actiontime to peak effectduration of actionhalf-life

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20

40

60

80

100EPI + yohimbineEPI

yohimbine alone

0 1 3 10 30 100 300 1000

ephedrine

phenylephrine

[agonist], mg/kg body weightINCREASEIN

BLOODPRESSURE

%maximalresponse

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8

PHARMACOKINETICS

For a drug to activate receptors and produce a response, it must be transported from its site ofadministration to its site of action. In addition, to produce a finite response, the drug must be

inactivated and/or excreted to terminate its actions. The intensity of a biological response produced bya drug is related to the concentration of the drug at its site of action. Drug concentration actuallyattained at the site of action depends on many factors and the examination of these factors =PHARMACO INETICS (drug movement throughout the body orwhat your body does to drugs). Thereare 4 phases:

1. ABSORPTION2. DISTRIBUTION3. BIOTRANSFORMATION4. EXCRETION

ABSORPTION is the ability of a drug to enter the blood stream without chemical alteration.Absorption is expressed as a rate (amount/time) and indicates the speed with which a drug leaves its

administration site and the degree to which this occurs. A number of factors affect drug absorptionincluding:1. physiochemical properties ofthe drug: In order to interact with its receptor, a drug must

be the correct size, shape, charge, composition, and solubility. Distribution of a drug acrossmembranes is determined by its p a (i.e. relative acidity or alkalinity) and the pH gradient across themembrane. The term pH refers to the negative log of the hydrogen ion (H+) concentration. pH valuesrange from 1 (extremely acidic) to a value of 14 (extremely basic). An acidic solution with a pH of 3 hasa H+ concentration of 10-3M (0.001 M) while a basic solution with a pH of 9 as a H+ concentration of 10-9

M (0.000000001 M).Effect of pH on solubility: Most drugs are weak acids or weak bases. For weak acids and

bases, the ability to move from an aqueous to a lipid environment varies with the pH of the mediumbecause charged molecules attract water molecules.

Acids are defined as H

+

(proton) donors; a neutral molecule that can reversibly dissociate into an anionand a proton (H+). When weak acids are dissolved in water they lose a proton and become negativelycharged.

Bases are defined as proton acceptors; a neutral molecule that forms a cation by combiningwith a proton (H+). When weak bases are dissolved in water they gain a proton and become positivelycharged.

Why is this important? Because uncharged drugs are lipid soluble and able to move acrossmembranes while charged drugs are water soluble and easier to excrete in the urine.

RCOOH RCOO- + H+

RNH2 RNH3+

RCOOH RCOO- + H+

basic environmenthigh pHlow [H+]

acidic environmentlow pH

high [H+]

-OH

H+

LIPID

SOLUBLE

WATER

SOLUBLE

RNH2 RNH3+

acidic environmentlow pH

high [H+]

basic environmenthigh pHlow [H+]

H+

-OH

LIPID

SOLUBLE

WATER

SOLUBLE

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9The excretion of a weakly acidic drug can be enhanced by keeping it in a charged, water

soluble form. To keep the negative charge on an acidic drug we must prevent H+ from re-associatingwith RCOO-. This can be accomplished by addingH+ acceptors or bases (-OH) to the system. Thus,you enhance the excretion of a weakly acidicdrug by increasing the pH (i.e. alkalinizing) of theurine with a base (e.g. sodium bicarbonate).Conversely, to enhance the excretion of a weaklybasicdrug you must prevent H+ dissociation fromRNH3

+. This is accomplished by adding H+donors or acids to the system (i.e. lowering urinepH oracidifying the urine with an acid such asascorbic acid). Although not done therapeutically,you could enhance the absorption of a weaklyacidic drug by making it more lipid soluble. Thiscan be accomplished by reducing the drugscharge by acidifying the system. Conversely toenhance the lipid solubility of a weakly basic drug,you reduce its charge (i.e. remove the H+) byalkalinizing the system with a H+ acceptor (i.e. a

base).2. types oftransport

a. passive transport - no energy required; movement from an area of [high] to [low]; this is theprimary means of drug absorptionb. carrier-mediated

1. active transport- energy-dependent moving from [low] to [high]-selective(structural analogs can compete)-saturable-movement vs electrochemical gradients

2. facilitated diffusion - movement from [high] to [low]-no energy required-saturable

-selective (structural analogs can compete)-moves compounds whose

rate of movement across membranes would otherwise be too slow3. nature ofthe absorbingsurface - the greater the surface area, the greater the absorption4. blood flowto the absorption site (i.e. perfusion) the greater the blood flow to the site of

application, the greater the absorption5. drugconcentration - in general, the higher the concentration, the more rapid the absorption. A

loading dose is a single large dose used to rapidly increase blood concentrations into thetherapeutic range. A loading dose is followed by repeated or continuous infusion to maintain bloodconcentrations.

6. dose form - affects the rate of dissolution and drugs must be in solution to be absorbed (timerelease capsules; enteric coating). Regardless of the site, absorption depends on drug solubility.

7. route of administrationa. enteral- administered by any portion of the GI tract

subject to 1. ORAL most common, safest, cheapest convenient. Also most unreliablefirst pass and slowest absorption due to pH changes in the gut, GI motility, gastricmetabolism enzyme and first pass metabolism in the liver.in the liver 2. GASTRIC

3. SMALL INTESTINE4. RECTAL-slow absorption5. SUBLINGUAL rich vasculature under the tongue provide a large absorbing

surface and rapid absorption.

ATP

ADP[low]

[low]

[low]

[high]

[high]

[high]

DIFFUSION

FACILITATEDDIFFUSION

ACTIVE

TRANSPORT

Carrier-

mediated

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10b. parenteral- by injection. Absorption occurs by diffusion from the injection site.

1. SUBCUTANEOUS (s.c. or sub q.) - small volume; slow sustained effect2. INTRAMUSCULAR (i.m.) - larger volume; faster absorption due to larger

blood supply to skeletal muscle (compared to s.c.)3. INTRAVENOUS (i.v.) - immediate effect (within 1 circulation time)4. INTRATHECAL - into the subarachnoid space; cerebrospinal fluid

c. pulmonary- large surface area; primarily local effects. Hard to regulate dose.d. topical- skin and mucous membranes

8. bioavailability - fraction of unchanged drug reaching the systemic circulation followingadministration by any route (Compared with the amount absorbed after i.v. administration).

Affected by solubility, incomplete absorption, rapid first pass metabolism. Differences inbioavailability of oral preps result from inactive ingredients and tableting process.

e.g., oral drug stomach small intestine hepatic portal liver bloodbioavailable

DISTRIBUTION is the movement of drug throughout the body to various tissue sites. It depends on:1. physiochemical properties of the drug2. cardiac output and blood flow (Initially, the most well-perfused tissues receive most of drug

brain, kidney, liver, etc)

3. drug reservoirs4. blood-brain barrier: distribution of drugs to the CNS is unique because drug entry is

restricted by this barrier

Drug Reservoirs allow the accumulation of drugs by binding to specific tissues, primarily plasmaprotein (albumin) but also mineralized tissues such as bone and teeth, skeletal muscle and liver. Largereservoirs that fill rapidly can alter distribution to such an extent that large initial concentrations of adrug are required to produce a therapeutic effect. There are two general types of drug pooling: 1)plasma protein binding and 2) tissue binding. Binding is reversible and in dynamic equilibrium

albumin-drug albumin + drug drug-receptor

cant cross blood vessels bound to albumin small enough to diffuse across bloodvessels

Why is this important?1. only drug free in solution is therapeutically active; a drug bound to protein does not have access

to its sites of action2. small changes in the amount of free drug are not a concern with most drugs, but if a drug has a

low TI the small changes in free drug concentration can produce toxic effects3. binding of a drug in drug reservoirs allows a drug to be available for a long time4. several drugs can compete for protein binding, changing the therapeutically active concentration

of both drugs (see figure).5. most assays measure total drug concentration

6. limits glomerular filtration and thus excretion

Depot prepsproviding

sustained effects

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11Competition for plasma protein binding(see figure): When warfarin is administeredalone, 75% is bound to albumen and 25% isfree in solution and available for therapeuticeffects. Aspirin when administered alone it isalso 75% bound/25% free. But when they areadministered together, they compete for bindingto a finite amount of plasma protein, increasing

the free concentration of both from 25% to 50%.This effectively doubles the free concentrationof each drug in the circulation. Reservoirs alsoinclude fat (storage for lipid soluble drugs),mineralized tissues such as bones and teeth(antibiotics like tetracyclines), and skeletalmuscle (a large reservoir for digitalis).

Blood-brain barrier (BBB): The BBB is the result ofendothelial cells lining blood vessels in the brain forming a barrierbetween the circulation and the brain. A thin basement membranesurrounds the endothelial cells and associated pericytes, providing

mechanical support and barrier function. The BBB prevents entranceof blood-borne immune cells, pathogens and charged chemicals intothe CNS and protects the neuronal network from chemical andimmune response damage.

Re-distribution is the movement a drug from its site of actioninto other sites. For example, the lipid-soluble barbiturate thiopentalrapidly enters the brain (within 1 min following injection) due to thebrains high perfusion. After the injection is completed theconcentration of thiopental in the brain rapidly drops as it comes out ofthe brain, back into the circulation and distributes to other tissues likemuscle.

BIOTRANSFORMATION is the alteration of the chemical structure of a drug. It occurs primarily inthe liver, but also in plasma, lungs, and kidney. The majority of the changes occur as a result ofinteraction with enzyme systems in the liver. Phase I reactions (non-synthetic) are usuallyoxidation/reduction in the smooth endoplasmic reticulum. These reactions convert parent drugs to morepolar metabolites by introducing/unmasking functional groups (e.g. OH, -NH2, -SH) Phase II reactions(synthetic) couple endogenous substances to Phase I reaction products or parent drugs. Thesemolecular are large and polar (acetate, sulfate, methyl, phosphate)

1. OXIDATIONintroduce new functional 2. REDUCTION may/ may not inactivategroups into the parent 3. HYDROLYSISdrug 4. CONJUGATION causes inactivation. Joins polar (i.e. charged drug

with endogenous substances like glucuronic acid,acetate, sulfate

Biotransformation reactions can transform:1) active drugs into inactive metabolites,

active barbiturates inactivate metabolites(produces a therapeutic response) (cause no therapeutic response)

2) active drugs into active metabolites, andactive benzodiazepine active metabolites(produces a therapeutic response) (each metabolite causes a response)

lar

marin

aspirin

Warafn o alone

75% bound

25% free

Aspirin alone

75% bound

25% free

Warafin and aspirin administered

togeter reduces t

e amount

ofeach drug bound to 50% andincreases the free amountto 50%

effectively doubling the

therapeutically effective dose.

albumen

BLOOD BLOOD

BLOOD

BRAINBLOOD

Blood-brain barrier

lipid-soluble drugs

water-soluble drugs

transporter-mediated influx

transporter-mediated efflux

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123) inactive drugs into active metabolites. When a metabolite is active, the parent drug is said to beaprodrug.

inactive aspirin active metabolite(produces no therapeutic deacetylation (produces a therapeutic response)

response)

Factors Modifying Biotransformation

1. genetically determined enzyme polymorphisms e.g. the enzyme metabolizing thiopurineused to treat some cancers are well-known to have mutations that greatly reduce theiractivity. In some patients only 1% of the normal dose is needed to produce atherapeutic response!

2. environmental influences including drug interactions3. liver disease

EXCRETION is the removal of drugs and biotransformation products from the body. Excretoryorgans eliminate unchanged drugs or drug metabolites. Excretory organs (except the lungs) eliminatepolar (charged) compounds more easily than non-polar (uncharged) compounds. Excretion includes allprocesses that terminate the presence of a drug in the body(renal, biliary, lungs, sweat and saliva).

1. biliary excretion: enterohepatic cycle. Metabolites formedin the liver can be excreted in bile. Breakdown compounds inliver, transport to gall bladder (into bile) resulting in fecalexcretion.

2 renal excretion: primary route, consisting of filtration,reabsorption, and active secretion.

a. filtration depends on free [drug], size of molecule andpH.

b. reabsorption can be affected by pH.1. increase pH with sodium bicarbonate

(NaHCO3)

2. decrease pH with NH4Cl or ascorbic acid3. changes in ionization change lipid solubility

and reabsorption

Study Questions:

1. Define pharmacokinetics. What are the 4 phases of pharmacokinetics?2. What factors alter the absorption of a drug?3. How would you increase the charge on a weakly acidic drug? On a weakly basic drug? How would

you enhance the excretion of a weakly acidic drug? A weakly basic drug?4. What are the characteristics of the 5 routes of enteral drug administration and which are affected by

first pass metabolism in the liver?

5. What are the characteristics of the 4 parenteral routes of drug administration?6. Define drug distribution. What can affect drug distribution? What are drug reservoirs and how do

they affect drug distribution? What happens when 2 highly protein bound drugs are administeredtogether?

7. Define biotransformation. Do biotransformation reactions always inactivate drugs?8. Define excretion.

Filtration

reabsorption

T B EB OOD

secretion

B OO

Filtration

reabsorption

T B EB OOD

secretion

B OO

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13

ADVERSE EFFECTS AND DRUG INTERACTIONS

Drug responses are subject to individual variability and present the greatest challenge to using drugstherapeutically. All drugs have the potential for altering more than one function. These responses canbe 1) PREDICTABLE, 2) IATROGENIC, or 3) UNPREDICTABLE.

PREDICTABLE ADVERSE RESPONSES: These adverse responses are extensions of a drugs

pharmacological actions. The best way to minimize predictable adverse responses is to minimize drugdosage. For example, barbiturates produce sleep by CNS depression. Since respiration is controlledin the CNS, respiratory depression is a predictable side effect of barbiturate use.1. Side effects vs toxic effects: Side effects are unavoidable secondary drug effects produced at

therapeutic doses. Toxic effects are adverse reactions caused by excessive levels of a drug.2. Factors allowing for the prediction of adverse responses

a. age: children and the elderly with differences in metabolism and excretionb. body mass and drug dose: dose is adjusted for body size, mass and water content.

The mean adult dose is the amount which produces a response in 50% of people between18-65 years old weighing 150 lbs.

c. sex: differences in size, percent body composition of fat and water, pregnancyd. time of administration: absorption is easier on an empty stomach but irritating drugs should

be taken with food. Often drugs are administered to mimic biorhythms (e.g. glucocorticoidsin the morming).e. disease states which alter pharmacokinetics: e.g., heart and kidney diseasef. genetic factors: inherited deficiencies in drug metabolism (e.g., lack of metabolizing

enzymes producing prolonged effects).

IATROGENIC DRUG RESPONSES: Iatros (physician) genic(to produce). The best definition is adisease produced by drugs. For example, cortisol and other glucocorticoids are used as anti-inflammatories to control severe inflammation in patients with rheumatoid arthritis. This requires theuse of high doses of these drugs which then mimics hypersecretion of cortisol from the adrenal cortex(CUSHINGS SYNDROME) a condition called iatrogenic CUSHING'S SYNDROME. This form ofCushing's is 1) drug-induced and 2) is nearly identical to the naturally-occurring disease caused by

hypersecretion of cortisol from the adrenal cortex. Also:1. antipsychotics and Parkinson's disease2. amphetamines and schizophrenia-like psychoses

UNPREDICTABLE RESPONSES:

1. hypersensitivity (allergy): requires prior sensitization and is largely independent of dose. Itcan be as simple as hives, runny nose, and mild hypotension to anaphylaxis (an immediate,severe allergic reaction). Mediated by the immune system.

2. hyperorhyporeactive: effects at unusually low or high concentrations of drugs, respectively.3. tolerance: a reduced response to repeated administration of a drug. This is drug-induced

hyporeactivity acquired as a result of continued drug exposure. Overcoming tolerance requires

the administration of larger and larger drug doses. Tolerance does not usually develop equallyto all effects of a drug. e.g. tolerance to the sedative effects of a barbiturate occur beforetolerance develops to its anticonvulsant effects.

4. tachyphylaxis: rapid development of tolerance5. idiosyncratic: genetically determined abnormal reactivity to a chemical that results in extreme

sensitivity or insensitivity to a drug. e.g., succinylcholine and prolonged muscle paralysis inpeople who are "poor acetylators"

6. cumulative: drug is not metabolized before another dose is administered

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14DRUG INTERACTIONS: Concomitant use of drugs is often essential to produce the desiredtherapeutic effect. However, drugs often alter each others pharmacokinetic or pharmacodynamicproperties.

Pharmacokinetic Mechanisms

1. chemical/physical interactions: Drugs interact resulting in insoluble complexes (e.g., Ca andMg antacids interact with tetracycline; antacids increase gastric pH enhancing the breakdown ofenteric coatings and affecting drug absorption).

2. competition for plasma protein binding: Minor changes in the free concentration of a drugcan result in large changes in its therapeutic effectiveness.

3. lack of specificity:Drugs are selective not specific for the receptors with which they interact.For example, some older antihistamines like diphenhydramine (BENADRYL) are alsoanticholinergic, making them useful as OTC sleep preparations.

4. enzyme induction: Exposure to a drug increases (i.e. induces) the amount or activity ofbiotransforming enzymes resulting in accelerated metabolism and a shorter t1/2. For example.the hyperforin in St Johns wort induces the activity of the enzyme CYP3A.

5. enzyme inhibition: a decrease in the amount or activity of biotransforming enzymes resulting ina reduction in drug metabolism and a longer t1/2. For example, the furanocumarins in grapefruit

juice inhibit the activity of CYP3A.

6. changes in renal excretion: one drug may affect the excretion of a second by competing forthe same transport mechanism

Pharmacodynamic Mechanisms

1. changes in receptor number: the magnitude of a drug response is proportional to the numberof receptors it activates. Therefore changes in receptor number affect a drugs efficacy.

2. genetic polymorphisms:small changes in the amino acid sequence of a receptor can affectligand binding; it can increase or decrease affinity for the ligand. Increases in affinity wouldreduce the dose required to produce a particular effect while a reduction in affinity wouldincrease the dose requirement

3. receptor mutations: mutations may change receptor- drug interaction (e.g. affinity of receptor

for agonist/antagonist) and the ability of the receptor to initiate signaling important in theregulation of cellular function.

4. disease-related changes: Diseases and drug treatment of disease often produce changes inthe expression and function of receptors (up- or down-regulation).

DRUG TRANSFER TO THE FETUS

1. Volume expansion (increases in extracellular fluid volume) during pregnancy results in areduction in plasma protein and an increase free [drug] in circulation. Also metabolism

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16

OVERVIEW OF THE AUTONOMIC NERVOUS

The nervous system is broadly divided into the CENTRAL NERVOUS SYSTEM (CNS)composed of the brain and spinal cord and the PERIPHERAL NERVOUS SYSTEM composed of theAUTONOMIC and SOMATIC NERVOUS SYSTEMS. The autonomic nervous system is "involuntary"or "self-governing" and is further subdivided into the PARASYMPATHETIC (PNS) and SYMPATHETIC(SNS) NERVOUS SYSTEMS. Autonomic nerves have ganglia outside the CNS and are composed of

two neurons termed preganglionic and post-ganglionic, named with respect to their location relative tothe ganglion. Preganglionic fibers exit the CNS, form a synapse with the cell body of post-ganglionicfibers which then send axons to effector organs. Somatic nerves innervate skeletal muscles and do nothave ganglionic junctions. In autonomic ganglia (both PNS and SNS pathways), the neurotransmitter isacetylcholine (ACh) and the receptor on the cell body of the post-ganglionic fiber is nicotinic (R N). Inthe PNS, the post-ganglionic fiber is a cholinergic pathway, ACh is the neurotransmitter and AChinteracts with muscarinic (RM) or RN receptors. In the SNS, the post-ganglionic fiber is an adrenergicpathway, norepinephrine (NE) is the neurotransmitter and NE interacts with E or F receptors. Oneganglion in the SNS does not have post-ganglionic fibers. Instead, activation of pre-ganglionic nervesinnervating the adrenal medulla cause the release of the hormone epinephrine (adrenaline). In Fig 1.all autonomiccholinergic fibers are red and all adrenergic fibers are blue

PARASYMPATHETIC NERVOUS SYSTEM: This is the Restand Digest nervous system. The pre-ganglionic fibers are long and the post-ganglionic fibers are short. The ratio of pre-ganglionic to post-ganglionic fibers is small (1:1 or 1:2). Activation causes a discrete, local response.

SYMPATHETIC NERVOUS SYSTEM: This is the FightorFlightnervous system. The pre-ganglionicfibers are short and the post-ganglionic fibers are long. The ratio of pre-ganglionic to post-ganglionicfibers can be a great as 1:20 and activation produces a generalized response in many tissues.

SOMATIC NERVOUS SYSTEM: The somatic nervous system has no ganglia. Motor neurons arise inthe spinal cord and terminate at special cholinergic synapses termed the neuromuscular junction (NMJ)

ACh

RNAChE

ACh

RNAChE

ACh

RNAChE

CNS

ACh

ACh

NE

NE

NE

NE

NE

NE

TARGET

TARGET

NMJSOMATIC

ACh

Pre-ganglionicPost-ganglionic

Adrenal medulla

epinephrine

P

N

S

S

NS

A

N

S

Motor neuron

E

andF

receptors

RN

RM

AChE

AChE

re-uptake

SYNAPSE (ganglion)

SYNAPSE (ganglion) pre-synaptic post-synaptic

SYNAPSE

(neuroeffector junction)

motor end plate

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17

NEUROHUMORAL TRANSMISSION: passage of impulse across a synapse or neuroeffector junction withthe use of a chemical. Sequence of events

1. biosynthesis of neurotransmitter2. storage in vesicles3. release autonomic drugs affect one/more of these processes4. action (interaction with receptor)5. inactivation

CHOLINERGIC TRANSMISSION:

1. Synthesis choline acetyltransferaseacetyl CoA + choline acetylcholine + CoA

acetylcholinesterase (AChE)

2. Storage into vesicles at nerve terminal. Vesicular storage ensures regulated (quantal) release; i.e. adepolarization of a certain size releases a fixed number of synaptic vesicles containing a fixed amount of ACh.3. Release: depolarization results in the influx of Ca2+ and vesicles fuse with the synaptic membranereleasing ACh. ACh binds to RN or RM postsynaptically, resulting in excitation/inhibition of post-synaptic cell4. Action by activation of ACh receptors: Nicotinic receptors (RN) are located at autonomic ganglia (both

PNS and SNS), the neuromuscular junction (NMJ) and the adrenal medulla. Muscarinic receptors (RM) arelocated on smooth and cardiac muscle, glands etc...5. Inactivationof ACh enzymatically by ACh esterase (AchE) and by diffusion away from the synapse. AChst1/2 is very short.

MUSCARINIC andNICOTINIC

CHOLINERGICSYNAPSES

ACh Receptors:muscarinic (G protein coupled)

M1: Ca2+ signalM2: inhibit cAMP productionM3: Ca2+ signal

nicotinic: ligand-gated ion channels

NG: opens Na+

,+

channelsNM: opens Na+, + channels

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18

ADRENERGIC TRANSMISSION: catecholamines (norepinephrine, dopamine )

1. synthesis:rate-limiting step

tyrosine dopa dopamine F methyltyrosine Dopa

DA NE EPI

hydroxylase decarboxylase hydroxylase transferase

2. storage: DA taken up into vesicles where conversion to NE occurs3. release:depolarization results in Ca2+ influx, fusion of vesicles and release of NE into the

junction4. action: NE binds to E, Eand Freceptors but not to F5. inactivation by re-uptake (primary), enzymatic transformation (monoamine oxidase-MAO and

catechol-O-methytransferase- COMT) and diffusion.-

Functional Organization: An understanding of the organization of the ANS activity is essential forunderstanding the actions of ANS drugs and the significant reflex responses they cause. For example:

ORGAN SNS RECEPTOR PNS RECEPTOR

Heart: SA node

contractility

increased activity

increased forceF1/F2F1/F2

decreased activity

decreased contractilityM2M2

GI smooth muscle relaxes E2/F2 contracts M3bronchiole smooth muscle relaxes F2 contracts M3eye (ciliary muscle) relaxes F contracts M3

1. Integration of cardiovascular function: the primary controlled variable is mean arterial pressure. Anyaspect of cardiovascular function that changes mean arterial pressure (e.g. heart rate, peripheral vascularresistance (PVR), venous return to the heart etc)

a. F1 agonist causes increased heart rate resulting in reflex activation of PNS pathwaysb. F1 antagonist decreases heart rate cause?

cytoplasm vesicle

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19

c. muscarinic agonist decreases heart rate causingSNS activation

d. muscarinic antagonist increases heart causing?2. presynaptic regulation: presynaptic receptors, whenactivated, reduce the rate of further neutortransmitter release(e.g. E2 receptors for NE). Also called auto-receptors since theyregulate neurotransmitter release by being activated by thatneurotransmitter.

3. postsynaptic regulation: activity modulated bya. prior history (i.e. desensitization/downregulation orupregulation). For example, cutting the nerve to a skeletal musclefibers results in an increase in AChRN receptors over the wholemuscle fiber

b. temporal events: the same neurotransmitter actingthrough two different receptors produced distinct responses dueto the speed of receptor activation/signaling

Study Questions

1. Briefly describe the anatomy of the peripheral nervous system (i.e. what nervous systems are included,

which have ganglia, etc)2. Where are nicotinic ACh receptors located? Where are muscarinic receptors located? What terminatesACh actions at all cholinergic synapses?

3. NE is the neurotransmitter at what synapses (i.e. ganglionic or post-ganglionic ) and what kind of receptorsare present at these synapses. What is the primary way NE actions are terminated?

4. How is autonomic nervous system function (i.e. SNS and PNS function) integrated? Why is this important?

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20

CHOLINERGIC AGONISTS AND ANTAGONISTS

PARASYMPATHOMIMETICS: drugs producing acetylcholine (ACh)-like effects. ACh is not usedtherapeutically due to its lack of selectivity, its very short half-life, and its susceptibility to breakdown byacetylcholinesterase (AChE) and plasma cholinesterases. Responses to PNS activation are all related to Resand Digest. The direct effects of ACh are mediated by AChRM and AChRN. ACh can also work indirectly byinhibiting the release of other neurotransmitters.

Receptors: The actions of ACh are mediated by muscarinic and nicotinic receptors.1. nicotinic ACh receptors (ACh RN): Nicotinic receptors mediate ACh action at autonomic ganglia

the NMJ and some sites in the CNS. Activation of ganglionic receptors results in increased heart rate andblood pressure (via the SNS), increased GI tone and motility and acid secretion (via the PNS), vomiting andCNS stimulation. At the NMJ AChRN receptor activation causes skeletal muscle contraction.

2. muscarinic ACh receptors (ACh-RM): Muscarinic receptors are found on most cells innervated byPNS post-ganglionic fibers. They are also found in the brain, ganglia, blood vessels and the adrenal medulla

All organs are regulated by the PNS, and in general, activation of muscarinic receptors results in themodulation of ongoing mechanical and/or electrical activity.

Activation of muscarinic receptors produces the following:1) increases in gastrointestinal (GI) smooth muscle tone and motility

and gastric acid secretion2) increases in urinary bladder smooth muscle tone and motility3) increases in exocrine gland secretion including increased

salivation, sweating (diaphoresis), lacrimation and increasedtracheobronchial secretions

4) in the cardiovascular system, RM cause vasodilation (decreasedblood pressure),decrease heart rate ( - chronotropic) andconduction velocity at the SA/AV nodes (-dromotropic) anddecrease the force of contraction

5) in the respiratory system, RM cause bronchiole smooth musclecontraction and increased tracheobronchial secretions.

DIRECT-ACTING MUSCARINIC RECEPTOR AGONISTS: Drugs that interact with and activate muscarinicreceptors. Most produce effects very similar to ACh with the primary differences lying in their potency anddurations of action. The best-studied members are highly charged molecules that have long t1/2 due toresistance to AChE and plasma cholinesterases [e.g. bethanechol (URECHOLINE) and pilocarpine(PILOPTIC)]. Most have little or no effect at AChRN at therapeutic doses.

Uses: delivered subcutaneously for acute responses and orally for chronic responses..1. GI disorders - post-operative decreases in tone and motility; atony2. urinary bladder disorders - urine retention/inadequate emptying3. xerostomia - dry mouth due to disease or radiation therapy4. eye - glaucoma; stimulates contraction of the ciliary body and the outflow of aqueous humor5. CNS - Alzheimers disease

INDIRECT-ACTING CHOLINERGIC AGONISTS inhibit AChE, prolonging the effect of ACh at virtually alcholinergic synapses (i.e. AChRM and AChRN ) to which they have access. Thus they can cause muscarinic

AND nictotinic effects and are used to treat conditions where muscarinic or nicotinic activation can contribute tocontrolling symptoms.

Pharmacological Effects:1. In the CNS: if accessible, these drugs cause stimulation followed by depression2. at AChRM: increased exocrine gland secretion, increased GI and urinary bladder tone and motility,

bradycardia and bronchial constriction.

motility

tone

increased motility

increased tone

Fig. 1: changes in tone and motility

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pharmacological effects are opposite to those produced by muscarinic agonists. They have little effect aganglionic ACh RN except at high doses or at NMJ ACh RN except at extremely high doses. Most are moreeffective at blocking the effects of exogenously administered muscarinic agonists than in preveting the effectsof endogenous ACh release. The tissues most sensitive to the effects of AChRM antagonists are the salivarylacrimal and sweat glands.

Dose-dependent Effects: low doses (0.5 mg) atropine can reduce salivation, decrease heart rate(transient and seems to be related to blockade of post-ganglionic fibers that release Ach) and reduce sweating1.0 mg atropine causes dry mouth, increased heart rate and pupil dilation. Moderate doses (2.0 mg) cause

rapid heart rate, markedly reduce salivation, dilate pupils and blur near vision, decrease acid secretion andproduce bronchodilation. High doses (5.0 mg) can produce all of the above as well as disturbed speechswallowing difficulty, hot dry skin, difficult urination and decreased intestinal peristalsis. Therefore, eventhough hypersecretion of acid can be reduced by atropine, people with gastric ulcers do not routinely receivethis drug because at the doses which must be used, there would be effects on glandular secretion andcardiovascular function.

Uses: The primary limitation to atropine use is the failure to achieve a therapeutic effect without producingside effects.

1. ocular exams - mydriasis (dilation) and cycloplegia (paralyzes accommodation)2. MI-induced bradycardia (increases rate without affecting pressure)3. antispasmodic, antidiarrheal, anti-emetic (motion sickness)

4. Parkisons disease5. chronic obstructive pulmonary diseases (COPD; asthma, emphysema)

GANGLIONIC AChRN AGONISTS AND ANTAGONISTS: Ganglionic receptors are nicotinic. Ganglionicstimulation influences nerve impulses in the PNS and the SNS and therefore ganglionic drugs have limitedtherapeutic value.

Ganglionic Agonist: nicotine, a plant alkaloidwith no therapeutic uses except for withdrawal ofsmoking.

Pharmacological Effects: Peripherallyvirtually all of the drugs cause transien

stimulation and subsequent persistent depressionof ANS ganglia. At the NMJ, they causecontraction followed by paralysis due to persistentdepolarization and receptor desensitization.1. low doses result in stimulation, high doses

in receptor blockade.2. increase blood pressure due to NE

release(SNS ganglia) and EPI release from theadrenal gland

3. increased GI T/M and activation secretion(PNS ganglia)

4. CNS stimulation: low doses produce aweak analgesia and high doses causetremor and convulsions and vomiting dueto activation of the emetic center(chemoreceptor trigger zone).

ACh

RNAChE

ACh

RNAChE

ACh

RNAChE

CNS

ACh

ACh

NE

NE

NE

NE

NE

NE

TARGET

TARGET

N

SO ATICACh

Pre-ganglionicPost-ganglionic

Adrenal medulla

epinephrine

P

N

S

S

N

S

A

N

S

Motor neuron

E

andF

receptors

RN

RM

AChE

AChE

re-uptake

SYNAPSE (ganglion)

SYNAPSE (ganglion)pre-synaptic post-synaptic

SYNAPSE(neuroeffector junction)

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Ganglionic Antagonists (Blockers): These drugs work as receptor antagonists or as ion channeblockers. The responses to these drugs depends upon whether the PNS or the SNS is the dominant controlleof various organs. For example, blood pressure is primarily under the control of SNS thus ganglionic blockadecauses vasodilation and decreased blood pressure. These drugs are of limited therapeutic usefulness

because1) the net effect depends upon theSNS/PNS balance prior to use,2) orthostatic hypotension that they

cause,3) decreased GI T/M and4) impaired micuritionMechanism of Action: competitiveantagonist at ACh RN at autonomicganglia affecting both PNS and SNS.Pharmacological Effects: majority oorgans are under the influence of PNStone. Ganglionic blockers produceeffects similar to muscarinic antagonists.

Therapeutic Uses: initial control of blood pressure in patient with dissecting aortic aneurysms because theyreduce blood pressure and limiting further tearing and they also block reflex increases in SNS activity. They

provide acute control only.

NEUROMUSCULAR BLOCKING AGENTS (interact with AChRN) are used primarily to producemuscle relaxation for surgery. All can produce some effect at autonomic ganglia and the adrenal medulla.

Control of muscle contraction: an action potential (wave of depolarization) arrives at the terminal of amotor neuron, causing the influx of Ca2+ and the subsequent release of ACh. ACh binds to AChRN on themotor end plate (MEP) of the muscle, opening channels and allowing Na+, + movement and end platedepolarization. End plate depolarization causes an action potential in the muscle, the release of Ca2+ andmuscle contraction (fig 4a). There are 2 classes of NMJ blocking drugs

1. Non-depolarizingagents are curare-like drugs such as pancuronium (PAVULON)anddoxacurium(NUROMAX). These drugs are highly charged competitive antagonists. These drugs bind to ACh RN at MEPswithout stimulating an action potential or initiating a contraction (see Fig 4b). Since the drug binds to thereceptor but produces no response (i.e. no contraction) it is a receptor antagonist. The muscle remainsrelaxed as long as pancuronium remains at the NMJ in sufficient quantities to prevent ACh binding. At high

anhidrosis

Dry mouth (xerostomia)

Urine retention

Reduced T/M

Tachycardia

Dilation

Vasodilation

Effect of

ganglionic blockers

SNSSweat glands

PNSSalivary glands

PNSUB

PNSGI tract

PNSHeart

SNSVeins

SNSAterioles

Dominant

ToneSite

anhidrosis

Dry mouth (xerostomia)

Urine retention

Reduced T/M

Tachycardia

Dilation

Vasodilation

Effect of

ganglionic blockers

SNSSweat glands

PNSSalivary glands

PNSUB

PNSGI tract

PNSHeart

SNSVeins

SNSAterioles

Dominant

ToneSite

nerve

muscleAChRN

AChE

motor end plate

myelin

contraction

contraction contraction

ASE

ASE

Non-depolarizing

Depolarizing

Fig 4: Effects of neuromuscular blocking agents on the neuromuscular junction. (A)The structure of theneuromuscular junction. (B) mechanism of action of neuromuscular blocking agents.

AB

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concentrations they may also block the channels. These drugs cause flaccid paralysis with the smallesmuscles affected first (eyelids, fingers, jaws) followed by the trunk (limbs and abdomen) and finally therespiratory muscles (intercostals and then the diaphragm). Recovery occurs in the reverse order. Thesedrugs produce paralysis but not unconsciousness nor analgesia.

Uses: The margin of safety between therapeutic doses and dose-induced respiratory paralysis is small.1. produce surgical muscle relaxation2. muscle relaxation for mechanical ventilation3. muscle relaxation for electroconvulsive therapy (weakens muscle contractions in seizures)

2. DepolarizingBlockingAgentsare receptor agonists (e.g. succinylcholine (ANECTINE). Theybind to ACh RN at NMJ, depolarizing the MEP (Phase I). They also enters the channel and causes channeflickering. Since these drugs bind to receptors and produce a response (an initial contraction), they arereceptor agonists. Drugs remain bound producing long-lived depolarization resulting in transient musclefasiculations followed by blockade of transmission and flaccid paralysis (Phase II) due to receptodesensitization. These drugs have a higher affinity for RN than does ACh and is more resistant to AChE than

ACh, causing more prolonged depolarization. Plus, released ACh binds to AChRN on an already depolarizedend plate.

Uses: These drugs cause paralysis within minutes and recovery within 4-10 min and are most valuablewhen a short-lived paralysis is required They are rapidly degraded by plasma pseudocholinesterases (mospeople have high levels of plasma cholinesterase; those that don't can be paralyzed for much longer -an

IDIOSYNCRATIC response).1. produce surgical muscle relaxation2. muscle relaxation for mechanical ventilation3. muscle relaxation for electroconvulsive therapy (weakens muscle contractions in seizures)4. orthopedic - fracture reduction5. insertion of endotracheal tubes

Study Questions

1. What are the 4 general responses to activation of muscarinic ACh receptors? What could a muscarinicreceptor agonist be used for therapeutically? What side effects would be associated with its use?

2. What are the physiological responses to a muscarinic ACh receptor antagonist? What could it be used fo

therapeutically? What would its side effects be?3. How do indirect-acting cholinergic agonists work? Do they affect muscarinic synpases, nicotinic synapsesor both? What are they used for and what are the signs of overdose?

4. Drugs acting at autonomic ganglia affect what type of ACh receptor? How selective are these drugsfor parasympathetic vs sympathetic ganglia? What are these drugs used for?

5. Describe how non-depolarizing and depolarizing neuromuscular blocking agents cause muscleparalysis.

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ADRENERGIC AGONISTS AND ANTAGONISTS

SYMPATHOMIMETIC DRUGS: mimic the effectsof SNS stimulation. Three classes1. direct-acting (receptor agonists; EPI, NE, DA)2. indirect-acting (cause NE release prevent NE

reuptake; amphetamine)3. dual acting(bind to receptors AND cause NE

release; ephedrine)CATECHOLAMINES aredirect-acting adrenergic agonistswhich are released fromsympathetic nerves (theneurotransmitters NE and DA),the adrenal medulla (the hormone

EPI) and also includes the synthetic catecholamineisoproterenol. They are particularly important inintegrating stresses that threaten homeostasis. Allcatecholamines: 1)have short durations of action, 2)are ineffective orally, 3) are subject to first-passmetabolism in the liver (MAO and COMT) and todegradation by MAO and COMT in the intestine and 4) are highly charged and do not cross the blood-brainbarrier. The actions of catecholamines are mediated by adrenergic receptors. Their actions include:

1. peripheral excitation of vascular smooth muscle and glands2. peripheral inhibition of GI, bronchial and skeletal muscle arteriole smooth muscle3. cardiac excitation [increase force (+ inotropic) and rate (+chronotropic)]4. metabolic actions including glycogenolysis and lipolysis (mobilization of energy)5. endocrine effects on insulin secretion, renin production and pituitary hormone secretion6. CNS effects including respiratory stimulation, enhanced wakefulness, appetite suppression

(peripheral catecholamines do not cross the blood-brain barrier)7. presynaptic enhancement or inhibition of neurotransmitter release

ADRENERGIC RECEPTORS AND RESPONSES: Net effect of a given adrenergic agonist depends on:

1. relative receptor affinity: NE is primarily an Eagonist causing vasoconstriction (E1) and has little effecon bronchial smooth muscle or skeletal muscle arterioles (where Freceptors predominate); EPI interacts withboth E and F receptors therefore causing vasoconstriction and vasodilation and dilation of bronchiole smoothmuscle; ISO interacts only with F receptors. Also, most vascular smooth muscle has Eadrenergic receptors-thus EPI and NE cause vasoconstriction while the F selective agonist ISO has no effect.

RECEPTOR and SIGNAL LOCATION/RESPONSEECa2+

EPI > NE >> DA >>>ISO

vascular smooth muscle (nerve ending)/ vasoconstrictionradial smooth muscle/ pupil dilationuterine smooth muscle/ contractionGI smooth muscle/decreased tone and motility

E2 - q cAMPEPI > NE >> DA >>>ISO

vascular smooth muscle (blood-borne (EPI)/vasoconstrictionpre-synaptic/ inhibits NE releasepancreas/ inhibits insulin secretion

F1 - ocAMPISO > EPI = NE >DA

Hear/ increase rate, force, conduction velocityadipose tissue/ lipolysis

F2 - ocAMPISO> EPI >>>NE>DA

bronchiole smooth muscle/ bronchiole dilationskeletal muscle arterioles/ vasodilationuterine smooth muscle/relaxationGI smooth muscle/ relaxationLiver/ stimulates glycogenolysis

DAD1, D5 - ocAMP; D2-D4 - q cAMP

vasculature (kidney, coronary, mysentary)/ vasodilation

cathecol

o

t

at

c cell

e

o

o

e

oe

ecto

e

a

t

c cell

o

t

a

l

o

c

e

YY

YY

YY

YY

Y

a

e

e

ta

e

ta

o

te

U

e

a

t

cE2 receptor

MAOCOMT

Neurotransmitter

(NE, DA, 5HT) Post-synapti c

recept

o

1

2

5

4

3

5

4

Fig 1: sites forSNSdrug action

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2. relative density ofE andF receptors in a given tissue.For example, the pancreas has Eand F receptors, but EPIdecreases insulin secretion because there are more Ereceptors present (What effect would ISO have?)3. compensatory reflexes evoked (see Fig2). EPI causesvasoconstriction and elevates blood pressure. This results indecreased SNS tone and increased PNS (vagal) tonecaused by the hearts baroreceptor system. (This would not

occur in heart transplant recipients - why?)

SYMPATHOMIMETIC DRUGS: SNS AGONISTS

1. CATECHOLAMINES: All have rapid onsets, shortdurations of action and are metabolized in the liver by MAO(monoamine oxidase) and COMT (catecho-O-methyltransferase). Based on these properties, none areadministered orally but can be administered i.v., s.c., topically or by inhalation (EPI).

a. epinephrine (adrenalineEE2, F1 and F2. A non-selective adrenergic agonist. ActivationofE1, E2 and F1 receptors all contribute to the increase in blood pressure.

1. E1 effects: vasoconstriction resulting in increased blood pressure, nasal decongestion,mydriasis (pupil dilation), decreased insulin secretion (predominates) and contraction of

uterine smooth muscle.2. E2 effects: vasoconstriction, inhibition of insulin secretion3. F1 effects: increased heart rate and force of contraction and increased lipolysis4. F2 effects: bronchiole dilation, arteriole dilation in skeletal muscle, increased insulin

secretion, relaxation of uterine smooth muscle and stimulation of liver glycogenolysis.. EPI isused as a bronchiole dilator, in the treatment of anaphylaxis, as a topical hemostatic agentand to delay absorption of local anesthetics

b. norepinephrine (noradrenalin, LEVARTERENOL)Acts atE1, E2 andF1. It differs from EPI in itsefficacy at E and F2 receptors. Used for acute hypotension when a potent and effectivevasoconstrictor is needed and to limit the absorption of local anesthetics.

Toxicity of EPI and NE: hypertensive crises, arrhythmias, anginal pain, necrosis and sloughing of tissues atinjection site, hyperglycemia. Responses to EPI are more severe then those of NE.

c. dopamine (INOTROPIN, DOPASTAT): at low concentrations, DA binds to vascular D1 receptors(kidney, coronary and mysenteric vessels) resulting in vasodilation as well as increased glomerularfiltration rate (GFR) and renal blood flow (RBF). At high concentrations it also binds to F1 producingincreased force. At even higher concentrations, it binds to E resulting in vasoconstriction. Used to treahypovolemic shock (to maintain renal blood flow), to prevent renal failure, increase cardiac output andblood pressure.d. isoproterenol (ISUPREL): a non-selective F agonist (F1 andF2). Increases heart rate and forceof contraction, stimulates lipolysis (F1), dilates arterioles in skeletal muscle, increases insulinsecretion , relaxes uterine and GI smooth muscle, stimulates liver glycogenolysis. Used primarily as acardiac stimulant where it prevents heart block by shortening conduction time. Its use as a bronchiadilator has largely been supplanted by F2 selective agonists. It can cause tachycardia, cardiac

insufficiency, arrhythmias and hyperglycemia.

2. ESELECTIVE AGONISTS: used primarily to control blood pressure and vascular perfusion (e.g. nasadecongestion)

a. E1-selective agonist: phenylephrine (NEO-SYNEPHRINE) - may also cause NE release. Usedto treat hypertensive emergencies, as a nasal decongestant and as a mydriatic agent.b. centrally acting E2-selective agonist: clonidine (CATAPRES): primary use is to treat systemichypertension. Peripherally, it causes transient vasoconstriction due to activation of vascular Ereceptors. But centrally, it inhibits NE release and reduces SNS tone thus producing long-lived drops inblood pressure. This latter effect predominates. It can cause dry mouth, sedation, bradycardia, sexua

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dysfunctionc. peripheral E2 agonist: oxymetazoline (AFRIN): nasal decongestant. Large dose canproduce CNS effects.

3. F SELECTIVE AGONISTS: Selectivity of a drug for F orF or even Freceptors in general is NOTabsolute and selectivity is generally lost at high concentrations. Used primarily as cardiac stimulants or totreat asthma.

a.F1-selective agonist: dobutamine (DOBUTREX). This drug has F1 effects but also interacts with

E1 and F2 receptors. Increases force with little effect on heart rate. Improves inotropic activity followingheart surgery, congestive heart failure or myocardial infarction (MI). Can cause tachycardia, increasedblood pressure, ectopic ventricular beats and exacerbates MI.b. F2-selective agonist-albuterol (PROVENTIL, VENTOLIN) orally effective; not a substrate foCOMT (it is not a catecholamine). Long-lived bronchodilation; aerosols (inhalers) can limit F1 effectsCan cause skeletal muscle tremor and systemic administration can increase heart rate.

4. INDIRECT- ACTING ADRENERGIC AGONISTS: cause release of NE (and often DA in the CNS)

a. ephedrine: found in plants. Causes NE release but also has activity at F AR (it is DUALACTING) and thus mimics EPI in its effects. Used primarily as a decongestant and as a pressor agent.b. amphetamine: CNS stimulant used for treatment of ADHD, narcolepsy, weight control.

Abused because of the euphoriant effect associated with elevated catecholamine levels in the brain.c. methylphenidate (RITALIN): CNS stimulant used for treatment of ADHD, narcolepsy, weightcontrold. cocaine: a local anesthetic that still has medical uses. Peripherally it produces SNS-like effectsby inhibiting NE re-uptake (predominant effects are on cardiovascular function). Centrally, it actsmuch like amphetamine, but its effects are shorter lived and more intense. It also inhibits DA re-uptakein the pleasure centers of the brain, contributing to abuse potential.e. methamphetamine: Methamphetamine is closely related chemically to amphetamine, but has agreater effect in the CNS. It has some limited therapeutic uses, primarily in the treatment ofobesity.f. ecstasy: MDMA (3-4 methylenedioxymethamphetamine) is a synthetic drug chemically similar tomethamphetamine and the hallucinogen mescaline. MDMA exerts its primary effects on serotonergic

neurons which are important in regulating mood, aggression, sexual activity, sleep, and sensitivity topain.

SYMPATHOLYTIC DRUGS - SNS ANTAGONISTS:

1. E ADRENERGIC ANTAGONISTS (BLOCKERS): E receptors mediate many of the important responsesto EPI and NE. Particularly important are E1-mediated vasoconstriction and E2-mediated suppression of SNStone, inhibition of NE release from nerve terminals and vasoconstriction in some vascular beds. Their use islimited almost exclusively to the treatment of cardiovascular disorders although some are now being used totreat benign prostate hyperplasia

a. phenoxybenzamine (DIBENZALINE): somewhat E1-selective, binding covalently and irreversibly(i.e. non-competitively) to receptors. Blocks and reverses the effects of NE/EPI, decreases PVR andincreases cardiac output due to reflex SNS stimulation. Used to treat severe hypertension, particularlythat associated with pheochromocytomas (epinephrine-secreting tumor of the adrenal gland). Cancause postural hypotension and reflex tachycardia.b. prazosin (MINIPRESS): competitive E1-selective antagonist, causing arterial and venous dilationand a drop in blood pressure. Causes arterial and venous dilation and is used to treat hypertensionCan cause postural hypotension and syncope (fainting) with administration of the first dose and reflextachycardia.

2. F ADRENERGIC ANTAGONISTS (BLOCKERS): used to manage cardiovascular disorders, primarily Fantagonists, blocking effects of catecholamines on heart action. Consequences of F blockade include a

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reduction in heart rate, decreased force of contraction and a reduction in conduction velocity through theatrioventricular (AV) node. Fantagonists are use to treat hypertension (decreases force and rate resulting indecreased cardiac output and blood pressure), angina, cardiac arrhythmias. Fantagonists have little effect onnormal heart rate of an individual at rest, but has marked effects when SNS tone is high. Also with little effecon heart rate or blood pressure in people with normal cardiac function and blood pressure.

a. propranolol (INDERAL): non-selective F antagonist. Propranolol decreases force, rate and cardiacoutput (F1). It also decreases renin secretion (F1), cause vasoconstriction and reduced glycolysis inskeletal muscle and bronchial constriction (F2). Used to treat hypertension, angina and cardiac

arrhythmias. Can cause bradycardia, rebound cardiac excitation, AV heart block and CHF, masksdiabetic hypoglycemic tachycardia and bronchial constriction in asthmatics.b. metoprolol (LOPRESSOR): F1-selective antagonist that decreases force, rate and cardiacoutput and renin secretion. Used to treat hypertension, angina and cardiac arrhythmias. Cancause bradycardia, rebound cardiac excitation, AV heart block and CHF, masks diabetichypoglycemic tachycardiac. labetalol (NORMODYNE): A F1 and E1 antagonist with some sympathomimetic F2 activity. Eblockade blocks SNS reflex increases in heart rate. F2 agonist effects may contribute tovasodilation. Used to treat hypertension due to its multiple sites of action.

Study Questions:

1. What are the four catecholamines? What characteristics do all catecholamines possess?2. The net result of using an adrenergic agonist depends on what 3 factors?3. Where are EEFandFreceptors located and what responses occur when each is activated?4. What type(s) of adrenergic receptors does EPI activate? What are the therapeutic uses and adverse

effects associated with the use of EPI? Answer these questions with regards to NE, DA and ISO(REMEMBER: If you know what receptors are activated by each catecholamine youll know whatresponses they produce andthe adverse responses they cause)

5. Describe the responses to selective and non-selective F agonists. Based on their effects, for whapurposes might they be used therapeutically?

6. Describe the responses to selective and non-selective E adrenergic agonists. What are they used fotherapeutically? What are their side effects?

7. How do indirect-acting adrenergic agonists produce their responses?

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INTRODUCTION TO CNS PHARMACOLOGY

Nearly all CNS drugs act directly or indirectly on specific receptors that modulate synaptic transmissionDrugs used therapeutically that affect CNS function include: 1) anesthetics, 2) analgesics, 3) anti-pyretics, 4)anti-Parkinsons and Alzheimers drugs, 5) anticonvulsants, 6) sedatives/hypnotics, 7) treatments for ADHD, 8)anti-psychotics and anti-depressants and more. While the mechanisms of action of most CNS drugs are nowell understood, these drugs have been extremely useful in defining CNS physiology. Using agonists andantagonists and observing the consequences of their use have provided insights into the disease mechanism

and the role neurotransmitters play in the disease process. For example, many antipsychotic drugs aredopamine receptor antagonists. Since these drugs relieve the symptoms of schizophrenia, this suggestschanges in dopamine levels in the brain contribute to the appearance of schizophrenia.

Macroanatomy and functionality of the CNS:

1. cerebral cortex: sensory information is processed in the cerebral cortex is including somatosensory(touch), visual, auditory, olfactory and motor. The cerebral cortex can also be subdivided on an anatomicabasis, including frontal, temporal, parietal and occipital lobes.

2. limbic system: regulates complex emotional and motivational function. The extrapyramidal motosystem helps control the function of the voluntary (pyramidal) motor systems. This region is damaged inParkinsons disease and in Huntingtons disease. The hippocampus controls the formation of recen

memory and is the site of damage in amnesia and in Alzheimers disease.3. diencephalon: houses the thalamus which regulates eating and drinking and relays information between

incoming sensory pathways and the cortex. The hypothalamus regulates body temperature, watebalance, blood pressure, sex and circadian cycles, sleep, etc

4. midbrain/brain stem: composed of the mesencephalin, the pons and the medulla oblongata. Theseregions of the brain contain the reticular activating system which controls sleep, wakefulness, levels ofarousal, and sensory filtering by linking sensory input to the interpretive centers of the brain. Monoamines(NE, DA, 5-HT) are important here. Coordination of reflex acts like swallowing and vomiting are alsolocated here.

5. cerebellum: regulates balance in anti-gravity or postural muscles and during movement.

The Basics of Nerve function: A common

misconception is that all neurotransmitters and allnerves produce excitatory responses. However,there are inhibitory neurotransmitters thatsuppress the activity of post-synaptic nerves. Infigure 1, the depolarization associated with anaction potential results in Ca2+-mediated releaseof neurotransmitter at the synapse (3), theinteraction of the neurotransmitter with receptorson the membrane of the second (post synaptic)neuron (4) and a local change in ion compositionand potential difference. This post-synaptic

potential (PSP) can be a) depolarizing

(excitatory PSP = EPSP) and if large enough cangenerate an action potential in the secondneuron or b) hyperpolarizing (inhibitory PSP=IPSP) and reduce the likelihood of actionpotential generation.

Drugs affecting CNS function can affectthe same 5 steps in neurochemical transmissionthat were discussed with regard to the autonomicnervous system 1) synthesis, 2) storage, 3) release, 4) action and 5) inactivation.

NEUROTRANSMITTER SIGNALING/ACTION RESPONSE NOTES

Post-synapticcell

(neuronorneuroeffector)

Pre-synapticcell

YY

YYYY

YYY

synapse

ACh

ACoA

choline

AChE

AC

hE

Post-

synaptic

recepto

rs

Acetate

+choline

1

2

43

5

Fig 1: Steps inneural transmission

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Table 1: CNS neurotransmitter pharmacology

Study Questions:

1. How do most/all CNS drugs produce their effects?2. In general terms, define the function of the

a. cerebral cortexb. the limbic systemc. the diencephalonsd. the midbrain/brainsteme. cerebellum

3. Define excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs, respectively)4. What are the major neurotransmitters in the CNS? Are they excitatory or inhibitory?

AChRM - GPCRRN - ligand-gated ion channel

excitatorymay be involved in cognitivedisorders like Alzheimers.

GABA (GABAA) increase Cl- permeability inhibitory

major inhibitory neurotransmitter inthe CNS. Target for barbiturates,benzodiazepines and generalanesthetics

glycine increase Cl- permeability inhibitoryglutamate ligand-gated ion channels and GPCR excitatory

monoamines

NE GPCR excitatoryinhibitory

target for TCADs like amitriptylline

in treating affective disorders;target in treatment of ADHD (?)

DA GPCRgenerallyinhibitory

target for antipsychotics likechlorpromazine; also important inParkinsons disease andregulation of pituitary function

5HT(serotonin)

GPCR and ligand-gated ion channelsinhibitoryexcitatory

target for SSRIs like fluoxetine.regulation of behaviors (sleep,pain perception. depression,sexual activity, aggressiveness.

peptides: substance P, opioids, neurotensin, cholecystokinin, vasoactive intestinal peptide, thyrotropin releasinghormone

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PAIN AND THE TREATMENT OF PAIN

Pain is a reaction of the body to harmful stimuli and thus serves a protective function. However, painassociated with cancer or chronic disease such as rheumatoid arthritis does not serve a useful function andcan have harmful effects on the body; the stress response to pains can increase SNS activity, producech