Pharmacodynamics

Pharmacodynamics

what the drug does to the body

Mechanism of Action (MOA)

describes how a drug works in the body via drug-receptor interaction

Receptor

component of cell that binds with a drug and initiates the chain of events leading to the drug's effect on the body

What part of the cell is most central to the study of pharmacology in regards to mechanism of action of drugs?

receptors

What are receptors important for in terms of physiological processes?

• development

• metabolism

• immune response

What does dysfunction of receptors lead to?

disease

Adrenergic receptor types

• alpha-1

• alpha-2

• beta-1

• beta-2

• beta-3

Alpha-1 adrenergic receptor function

• contracts vascular smooth muscle

• relaxes intestinal smooth muscle

Alpha-2 adrenergic receptor function

• decreases GI motility

• deceases insulin secretion

Beta-1 adrenergic receptor function

• increases HR

• increases contractibility

• increases kidney function

Beta-2 adrenergic receptor function

• bronchodilation

• vasdilation

• reduces GI motility

Beta-3 adrenergic receptor function

• decreases heart contractibility

• reduces bladder contraction

Most drug receptors are…

proteins

The polypeptide structure of receptors provides…

diversity and specificity of shape and electrical charge

How are drug receptors commonly named?

based off of substance it interacts best with and stimulates/activates

Fundamentals of drug action

D+R —> DR Complex —> Effect

Effects of drug action

• increased drug concentration

• increased number of drug-receptor complexes

• increased drug effect

Full agonist

drug that activates or stimulates receptors to produce a response with affinity and efficacy

Partial agonist

drug binds to and activates receptor but has only partial efficacy compared to full agonist

Antagonist

drugs that block, prevent, or counteract a response with affinity but no efficacy

What are the two types of antagonists?

• competitive

• noncompetitive

Competitive antagonist

• reversible

• competes with agonist for binding to receptor

• can be overcome with increase agonist concentration

• most common

• decreased potency

• same efficacy

Noncompetitive antagonist

• irreversible

• decreases apparent Emax

• allosteric

• decreased efficacy

Allosteric drug

binds to another site on receptor and indirectly changes agonist binding

Full agonist examples

Albuterol: relaxes bronchial smooth muscle by acting on beta 2 receptors

Heroin: opioid drug made from morphine that binds to opioid receptors

Partial agonist example

Buprenorphine: produces effect weaker than full opioid agonists to avoid extreme withdrawal

Antagonist example

Narcan: opioid that competes with and displaces opioids at opioid receptor sites

Factors that affect degree of drug binding and resultant drug response

• recognition of drug at receptor

• concentration of drug at site of the receptor

• amount of drug needed to produce effect

• density of receptors on the cell surface

Threshold

minimum number of drug-receptor complexes required for a response to occur

Saturation

point when all receptors are bound/occupied by drug and no further drug-receptor complexes can be formed, along with the response not increasing

Affinity

strength of binding between drug and receptor

Affinity is dictated by a drug moleecule’s…

• size

• shape

• bonding

• stereochemistry

Drug size limit, ideal, and max

low limit: 100 mol weight

ideal: greater than 100 mol weight, less than 1000 mol weight

max: 1000 mol weight

What happens if drug size is too small?

sufficient binding with receptor cannot occur

What happens if drug size is too big?

unable to diffuse between body compartments, so direct administration at site of action is necessary

Drug shape is _____ to its receptor

complementary

More than half of all useful drugs are _____ molecules that exist as _______

chiral, enantiomers

What is different about enantiomers when each interacts with a receptor?

One is pharmacologically active with therapeutic benefits, and another is inactive or harmful

What are both Prilosec and Nexium?

proton pump inhibitors

Which is better and why? Prilosec vs Nexium

Nexium: biological activity for increased absorption and lower half life

Which is better and why (SSRIs)? escitalopram (Lexapro) vs citalopram (Celexa)

escitalopram (Lexapro): better tolerated, less side effects

Which is better and why (antihistamines)? levocetirizine (Xyzal) vs cetirizine (Zyrtec)

levocetirizine (Xyzal): more potent, less sedating

Which is better and why (beta antagonists)? levalbuterol (Xopenex) vs albuterol (Ventolin/ProAir)

levalbuterol (Xopenex): fewer systemic side effects

Which is better and why (ADHD)? dexmethylphenidate (Focalin) vs methylphenidate (Ritalin)

dexmethylphenidate (Focalin): more potent, longer duration of therapy

Covalent bonds

• strong bon

• -less selectivity

• commonly irreversible

Noncovalent bonds

• most common (hydrogen, VDW, ionic)

• require better fit of drug to receptor site since they’re weaker

• commonly reversible

K1 (drug receptor binding)

association rate constant (how fast drug binds to receptor)

K2 (drug receptor binding)

dissociation rate constant (how quickly the complex separates)

Selectivity

preference of a drug for one receptor type over another

Selectivity may equate to ____ side effects

less

As concentration of drugs increase, they may combine with receptors with ___ affinity specificity

lower/loss of

Selectivity examples

• alpha-adrenergic receptors: drug contracts blood vessels and prostate as primary, but can also treat BPN and HTN as non-selective antagonist

• beta-adrenergic receptors: some antagonists are selective for beta-1 receptors in heart, but with larger doses they can effect beta-2 receptors in lungs

Efficacy

the ability of a drug to activate the receptor and produce a biologic response

K3

intracellular events that occur following receptor binding/intrinsic activity (efficacy)

Can drugs have high affinity or selectivity with a low efficacy?

yes

____ is more clinically useful than ____ in drug-receptor process

efficacy, potency

Emax

maximal efficacy of a drug, assuming all receptors are occupied by drug with no increase in response with higher drug concentration

Potency

amount of drug required to produce a specific effect

more potent drug =

less needed

less potent drug =

more needed

A drug with a high affinity would have:

A. K1 > K2

B. K1 < K2

C. K1 = K2

A. K1 > K2

True or false: A drug can have different selectivity for multiple receptors

true

Isoproterenol produces maximal contraction of cardiac muscle in a manner similar to epinephrine. Which of the following best describes isoproterenol?

B. partial agonist

C. competitive antagonist

D. irreversible antagonist

A. full agonist

In the presence of naloxone, a higher concentration of morphine is required to elicit full pain relief. Naloxone by itself has no effect. Which of the following is correct?

A. Naloxone is a competitive antagonist

B. Morphine is a full agonist and naloxone is a partial agonist

C. Naloxone is a noncompetitive antagonist

A. Naloxone is a competitive antagonist

In addition to receptors, what else can drugs interact with and what are the potential outcomes?

• enzymes

  • inhibit normal reactions

  • interfere with metabolite production

• ion channels

  • block permeation

• transporters

  • inhibit or block transport

Full course of drug action

1. drug dose

2. route of administration

3. rate and extent of absorption

4. distribution rate to site of action

5. rate of elimination

6. effective concentration

7. concentration-effect relationship

Dosage level outcomes

• right dosage: maximize efficacy but limit toxicity

• too low: subtherapeutic = ineffective

• too high: supratherapeutic = adverse side effects and toxicity

Dose-response curve

displays peak response from drug and potency

What is dose-response curve used for?

compares drug potencies

Parts of lines on dose-response curve

1. response develops slowly

2. linear phase over wide dosage range

3. plateaus at highest drug doses

EC50

(half maximal effective concentration) concentration of drug producing 50% of the maximum response

What is EC50 used for?

sets recommended doses

Threshold dose

dose at which effects start to occur

Ceiling effect

dose at which max effect occurs (more drug will not change effect)

Therapeutic index (TI) and equations

measurement of drug safety based on therapeutic window and desired effect (LD50 or TD50 / ED50)

LD50

(median lethal dose) dose that kills 50% of subjects

TD50

(median toxic dose) does that has toxicity in 50% of subjects

ED50

(median effective dose) dose producing a therapeutic effect in 50% of subjects

What does a large therapeutic index indicate? Examples?

increased margin of safety = wide therapeutic window (ex. nicotine or penicillin)

What does a narrow therapeutic index indicate? Examples?

narrow therapeutic window, small difference in concentration between desired therapeutic effect and unwanted side effects (ex. warfarin, levothyroxine, lithium)

The higher the TI, the ____ the drug

safer

Duration of action

length of time a drug remains effective in the body, providing a therapeutic effect after administration

For most drugs, what determines the duration of action?

dosage and rate of elimination

What is elimination of a drug expressed as?

clearance (CL)

3 major routes of elimination

• hepatic metabolism

• urinary elimination

• biliary elimination

Clearance (CL)

the amount of plasma from which the drug can be totally removed per unit of time

Elimination rate constant

(ke) fraction of drug eliminated per unit time (slope of decline in plasma drug concentration)

If tetracycline has a clearance of 130mL/min, what does that mean?

drug would be completely removed from 130ml of plasma each minute

The bigger. the value of ke, the ___ the elimination of the drug

faster

Half-life (t 1/2)

measure of how long it takes for half of a drug to be eliminated from the bloodstream

What does this mean? “Dose is 100 mg, t 1/2 = 6 hrs”

6 hours after the dose is administered, 50 mg of drug is left

What are the half lives 1-5 if t ½ = 4 hours?

1. hr 4, 50% of drug left

2. hr 8, 25% of drug left

3. hr 12, 12.5 of drug left

4. hr 16, 6.25% of drug left

5. hr 20, 3.125% of drug left

General clinical principle concerning half-life

elimination occurs after about 5 half-lives

Relationship between half-life and rate constant

inverse

• large ke = small t ½ —> more rapid elimination

• small ke = large t ½ —> less rapid elimination

half-life and rate constant impact ________

frequency of drug administration to maintain drug levels in the body

Steady state of drug

plasma concentration will increase to a steady value so the amount of drug administered during dosing interval exactly replaces the amount of drug excreted (rate in = rate out)

greater frequency of fixed dose & longer half-life = ______ plasma fluctuation

smaller

Single fixed dose

a single dose of drug given orally results in a single peak in plasma concentration followed by a continuous decline in drug level

Repeated fixed dose

repeated oral administration of a drug results in oscillations in plasma concentration that are influenced by both the rate of drug absorption and the rate of drug elimination

____ fixed dose is important when administering drugs with a narrow therapeutic window

repeated