CHAPTER 5 PHARMACODYNAMICS

Pharmacodynamics – study of the biochemical and physiologic effects of drugs and the molecular mechanisms by which those effects are produced

- study of what drugs do to the body and how they do it

I. DOSE RESPONSE RELATIONSHIPS- relationship between the size of an administered dose and the intensity of the response produced- determine the minimum amount of drug we can use, the maximum response a drug can elicit, and how

much we need to increase the dosage to produce the desired increase in response

A. BASIC FEATURES OF THE DOSE RESPONSE RELATIONSHIP - as dosage is increased, the response becomes progressively larger- because drug responses are graded, therapeutic effects can be adjusted to fit the needs of each

patient (raise or lower the dosage until a response of the desired intensity)- if drug responses were all-or-nothing instead of graded, drugs could produce only one intensity of

response- if response were too strong or too weak for a particular patient, there would be nothing we

could do to adjust its intensity to better suit the patient

1. Phase I – occurs at low doses- the curve is flat during this phase because doses are too low to elicit a measurable response

2. Phase II – an increase in dose elicits a corresponding increase in the response- during this phase the dose response relationship is graded

3. Phase III – as the dose is raised higher, we eventually reach a point where an increase in dose is unable to elicit a further increase in response and the curve flattens out

B. MAXIMAL EFFICACY AND RELATIVE POTENCY

1. Maximal Efficacy – largest effect that a drug can produce- indicated by the height of the dose-response curve- a drug with very high maximal efficacy is not always more desirable than a drug with lower

efficacy

2. Relative Potency – potency refers to the amount of drug we must give to elicit an effect- a potent drug is one that produces its effects at low doses- potency is rarely an important characteristic of a drug- can be important if a drug is so lacking in potency that doses become inconveniently large

(which is rare)- potency of a drug implies nothing about its maximal efficacy – potency and efficacy are

completely independent qualities- refers only to the dosage needed to produce effects – never to the maximal effects a drug can

produce

endogenous – produced by the body naturally- relating to or produced by metabolic synthesis in the body

II. DRUG RECEPTOR INTERACTIONS

A. INTRODUCTION TO DRUG RECEPTORS - only way drugs can produce their effects is by interacting with other chemicals

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- receptors are the special “chemicals” in the body that drugs interact with to produce effects

receptors – any functional macromolecule in a cell to which a drug binds to produce its effects- generally reserved for what is arguably the most important group of macromolecules

through which drugs act: the body’s own receptors for hormones, neurotransmitters, and other regulatory molecules

- general equation for the interaction between drugs and their receptors D + R ↔ D-R COMPLEX → RESPONSE (D = drug and R = receptor)

- binding of a drug to its receptor is usually reversible- receptors are activated (turned “ON”) by interaction with other molecules, regulated by

endogenous compounds and then mimics or blocks the actions of endogenous regulatory molecules- the drug will either increase or decrease the rate of the physiologic activity normally controlled

by the receptor

Receptor Binding Effects : - drugs can mimic the action of endogenous NE and thereby increase cardiac output

OR- drugs can block the action of endogenous NE and thereby prevent stimulation of the heart by

an autonomic neurons

Properties of Receptors and Drug-Receptor Interactions:- receptors through which drugs act are normal points of control of physiologic processes- under physiologic conditions, receptor function is regulated by molecules supplied by the body- all that drugs can do at receptors is mimic or block the action of the body’s own regulatory

molecules- because drug action is limited to mimicking or blocking the body’s own regulatory molecules,

drugs cannot give cells new functions – rather, drugs can only alter the rate of pre-existing processes (cannot make the body do anything that it is not already capable of doing)

B. THEORIES OF DRUG RECEPTOR INTERACTION - help explain dose-response relationships and the ability of drugs to mimic or block the actions of

endogenous regulatory molecules

1. Simple Occupancy Theory - assumes that all drugs acting at a particular receptor are identical with respect to the ability to bind to the receptor and the ability to influence receptor function once binding has taken place

- the intensity of the response to a drug is proportional to the number of receptors occupied by that drug

- a maximal response will occur when ALL available receptors have been occupied- there is nothing in this theory to explain why one drug should be more potent than another, nor

can this theory explain how one drug can have higher maximal efficacy than another

2. Modified Occupancy Theory- intensity of the response to a drug is still related to the number of receptors occupied- intensity is also related to the ability of the drug to activate receptors once binding has

occurred

Independent Qualities of drugs:a. affinity – the strength of the attraction between a drug and its receptor

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- drugs with high affinity can bind to receptor when present in low concentrations, therefore, are effective in low doses - very potent

- drugs with low affinity must be present in high concentrations to bind to their receptors- not very potent

- ex. of carbon monoxide

b. intrinsic activity – the ability of a drug to activate the receptor following binding and is reflected in its maximal efficacy

- drugs with high intrinsic activity cause intense receptor activation and have high maximal efficacy (able to cause intense responses)

- drugs with low intrinsic activity cause only slight activation and have low maximal efficacy

- two drugs can occupy the same number of receptors but produce effects of different intensity; the drug with the greater intrinsic activity will produce the more intense response

E. AGONISTS, ANTAGONISTS, AND PARTIAL AGONISTS

1. Agonists – drugs that mimic the body’s own regulatory molecules- molecules that activate receptors- neurotransmitters, hormones, and all other endogenous regulators of receptor functions- as agonists, drugs simply bind to receptors and mimic the actions of the body’s own regulatory

molecules- in terms of modified occupancy theory, these drugs have both affinity and high intrinsic

activityaffinity allows the agonist to bind to receptorsintrinsic activity allows the bound agonist to “activate” or “turn on” receptor

function- agonists do not necessarily make physiologic processes go faster; receptor activation can also

slow down a particular process

2. Antagonists – drugs that block the actions of endogenous regulators- produce their effects by preventing receptor activation by endogenous regulatory molecules

and drugs (agonists)- employed most commonly in the treatment of overdose- have virtually no effects on their own on receptor function- in terms of modified occupancy theory, these drugs have affinity for a receptor but with no

intrinsic activity- response is determined by how much agonist is present (if there is no agonist present,

administration of an antagonist will have no observable effect)

Classes:a. Noncompetitive (Insurmountable) Antagonists – bind irreversibly to receptors and

inhibition of these agents cannot be overcome – no matter how much agonist may be available

-irreversibility does not mean effects last forever; effects wear off as the receptors to which they are bound are replaced (life cycle)

- effect of binding is equivalent to reducing the total number of receptors available for activation by an agonist

- intensity of response is proportional to the total number of receptors occupied- reduce the maximal response that an agonist can elicit

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- if sufficient antagonist is present, agonist effects will be blocked completely- rarely used therapeutically

b. Competitive (Surmountable) Antagonists – bind reversibly to receptors and the inhibition they cause is surmountable

- produce receptor blockade by competing with agonists for receptor binding- if competitive antagonist and an agonist have equal affinity for a particular

receptor, the receptor will be occupied by whichever agent is present in the highest concentration

3. Partial Agonists – also mimic the actions of endogenous regulatory molecules, but they produce responses of intermediate intensity (moderate intrinsic activity)

- maximal effect that a partial agonist can produce is lower than that of a full agonist- can act as antagonists as well as agonists

F. REGULATION OF RECEPTOR SENSITIVITY - in response to continuous activation or continuous inhibition, the number of receptors on the cell

surface can change, as can their sensitivity to agonist molecules (drugs and endogenous ligands)

desensitized / refractory / down regulation - when the receptors of a cell are continually exposed to an agonist, the cell usually becomes less responsive

- responsible mechanisms include destruction of receptors by the cell and modification of receptors such that they respond less fully

hypersensitive / supersensitive – when the receptors of a cell are continually exposed to antagonists, the cell usually becomes more responsive

- responsible mechanisms include synthesis of more receptors

IV. INTERPATIENT VARIABILITY IN DRUG RESPONSES- in order to promote the therapeutic objective, you must be alert to interpatient variation in drug

responses- it is not possible to predict exactly how an individual patient will respond to medication- each patient must be evaluated to determine his or her actual response to treatment

A. ED 50

- an abbreviation for average effective dose- the dose that is required to produce a defined therapeutic response in 50% of the population- can be considered a “standard” dose and is frequently the dose selected for initial treatment- after evaluating the response to the “standard” dose, adjustments can be made for subsequent doses

B. CLINICAL IMPLICATIONS OF INTERPATIENT VARIABILITY 1. The initial dose of a drug is necessarily an approximation. Subsequent doses must be “fine tuned”

based on the patient’s response.- administer the medication as prescribed and evaluate the response- dosage adjustments can then be made as needed- if the physician’s order calls for a dose that differs from the recommended dose by a large

amount, that order should be challenged

2. When given an average effective dose (ED50) some patients will be undertreated, whereas others will have received more drug than they need.- when therapy is initiated with a dose equivalent to the ED50 it is especially important to

evaluate the patient’s response- patients who fail to respond may need an increase in dosage

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- signs of toxicity will need a dosage reduction

3. Since drug responses are not completely predictable, you must look at the patient (and not the reference books) to determine if too much or too little medication has been administered- doses should be adjusted based on the patient’s response and not just on the basis of what

some reference says is supposed to work- an average dose may be effective for some patients, ineffective for others, and toxic for still

others

4. Because of variability in responses, nurses, patients, and other concerned individuals must evaluate actual responses and be prepared to inform the prescribing physician about these responses so that proper adjustments in dosage can be made

V. THERAPEUTIC INDEX- a measure of a drug’s safety- determined using laboratory animals- ratio of a drug’s LD50 to its ED50

LD50 – average lethal dose- dose that is lethal to 50% of the animals treated

- large therapeutic index indicates that a drug is relatively safeLD50 is much larger than the therapeutic dose

- small therapeutic index indicates that a drug is relatively unsafeLD50 is not much larger than the therapeutic dose

- if a drug is to be truly safe, the highest dose required to produce therapeutic effects must be substantially lower than the lowest dose capable of causing death

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