Pharm exam 1 lecture 1 pharmacokinetics and pharmacodynamics

What is pharmacokinetics?

What the body does to a drug

What do the four pharmacokinetic properties determine?

Onset, intensity, and duration of a drug’s actions

What are the 4 pharmacokinetic properties?

ADME - absorption, distribution, metabolism, and elimination

What is absorption?

Permits drug entry into plasma from site of administration

What is distribution?

Drugs may reversibly leave bloodstream and be distributed to interstitial and intracellular fluids

Routes of enteral drug administration

Oral (PO) - swallowed by mouth

Sublingual (SL) - under tongue

Buccal -between gum and cheek

What are parenteral routines of drug administration?

IV, IM subcutaneous, or intradermal

What are other miscellaneous routes of drug administration?

Inhalation (nasal/oral), intrathecal/intraventricular, topical, transdermal, rectal, vaginal, otic, and ophthalmic/ocular

Benefits of oral drug administration

-pts self administer

-toxicity/overdoses easily treated with antidote (activated charcoal)

-wide range of preparations

What are enteric coated drugs?

pills with coating that protects drug from stomach acid

What are extended release pills?

Capsules with coating or ingredient which controls drug release

What are the disadvantages of oral administration?

Complicated pathways of absorption (might be metabolized before they can get absorbed)

Drug may be inactivated by low gastric pH

Pt compliance is important

What are the benefits of SL/buccal administration?

Easily administered

Not affected by emesis

Rapidly absorbed

Bypasses harsh stomach conditions

Bypasses first pass metabolism in liver

What are the disadvantages of sublingual/buccal administration?

-taste

-local irritation/mouth sores

-Affected by smoking, drinking, and eating

-very few drugs are available in this formulation

What are the benefits of parenteral administration?

Highest bioavailability (useful for drugs not orally absorbed)

Bypasses first pass metabolism and harsh GI environment

-easily control dose of drug delivered to the body

What are the disadvantages of parenteral administration ?

Irreversible once administered

Painful, fear of needles

Local tissue damage possible

Risk of contamination and infection

Risk of serious adverse effects is greater

What is the benefit of infusion vs IV bonus administration?

Infused over a period of time to increase duration of circulating drug and lower peak plasma level

Subcutaneous administration absorptions occurs via…

Simple diffusion

Oral inhalation

Rapid drug effect

Delivered directly to site of action

Minimizes systemic adverse effects

Intrathecal and intraventicular route

Introduces drug directly into CNS

Bypasses BBB

Topical route of administration

Applied to skin for local effect

Transdermal route

Applied to skin for a slow and sustained systemic effect

Used for drugs that are lipophilic, poor oral bioavailability, and quickly eliminated

Rectal administration

Absorption is erratic and incomplete

Used in of who are unconscious, vomiting, or unable to tolerate PO

Partially bypasses first pass metabolism and avoids GI environment

What is the rate and extent of absorption determined by.

Where the drug is absorbed

Drugs chemical characteristics

Route of administration (bioavailability)

What factors can increase absorption

-increased blood flow

-increased surface area

-increased contact time

How does P glycoproteins impact absorption?

Decreases drug absorption and contributes to multi drug resistance

What is bioavailability

Rate and extent a drug reaches systemic circulation

What factors influence bioavailability

Solubility

Chemical instability (low pH of GI tract or enzymatic degradation)

Nature of drug formulation

What is first pass hepatic metabolism?

Drugs enter the portal circulation from the GI tract before entering system circulation

Unchanged drug entering systemic circulation will be decreased if it is first metabolized in the liver or gut wall

Limits efficacy of oral drugs.

What is bioequivalence?

Drug formulations that show comparable bioavailability and similar times to achieve peak blood concentration

What is therapeutic equivalence

Pharmaceutically equivalent and bio equivalent

What is drug distribution influenced by?

Cardiac output and blood flow

Capillary permeability

Drug lipophilicity

Tissue volume

Binding of drugs to plasma and tissue proteins

What is volume of distribution?

The fluid volume required to contain the entire drug in the body at the same concentration measured in the plasma

Used for calculating loading dose of a drug

What causes increased half life?

Decrease renal/hepatic blood flow (shock, heart failure, hemorrhage)

Decreased ability to remove drug from plasma (renal dysfunction)

Decreased metabolism (hepatic dysfunction, drug-drug interactions)

What causes decreased half life

Increased hepatic blood flow

Decreased protein binding

Increased metabolism

What is drug metabolism?

Production of polar products, which allow for drug elimination

-hepatic metabolism, biliary elimination, urinary excretion

What is first order kinetics

Metabolic transformation of drugs is catalyzed by enzymes

Rate of drug metabolism and elimination is proportional to free drug concentration

-rate is exponential

-dependent on drug concentration

What is zero order kinetics

Enzymes become saturated by high free drug concentration and metabolic rate remains constant

-rate is constant

-independent of drug concentration

What are phase I and 2 metabolism reactions.

How lipophilic drugs are metabolized to more polar/hydrophilic forms in the liver or gut

Phase 1- P450 system

Phase 2- conjugate rxns

-some drugs enter phase 2 metabolism directly

Explain the process of phase 1 metabolism reactions

Cyp450 system metabolizes endogenous compounds and bio transforms exogenous compounds

What occurs with the induction of the cyp450 system?

Drugs can increase CYP enzyme synthesis, increasing metabolism

Results in increased bio transformation of drugs, decreased plasma concentrations of parent compound, and increased or decreased drug effect

Common inducers of cyp450

Phenobarbital, rifamin, carbamazepine

(THINK: CPR -revive system)

What occurs with the inhibition of CYP450?

Drugs may compete for same enzyme or inhibit reactions —> decreased metabolism

Results in decreased bio transformation of drugs, increased plasma concentration, and increased drug effect (including side effects and toxicity)

Common inhibitors of CYP450

Erythromycin, ketoconazole, ritonavir

(Think; REK the system)

What is glucuronidation?

The most common phase 2 reaction

-uses endogenous substances: glucuronic acid, sulfuric acid, acetic acid, or an ammonia acid

-result is a pola, water soluble compound ready for excretion via the kidney or bile

What is elimination?

The total processes involved in the removal of a drug and it’s metabolites from the body

Metabolism produces polar products, which allows for elimination and excretion

Processes of renal elimination/clearance

Filtration at glomerulus

Secretion at proximal tubule (via active transport)

Re absorption at distal tubule

What happens if a drug is not absorbed after oral administration?

If it is not absorbed after oral admin or it’s is secreted into intestines or bile, it will exit the body via fecal elimination

What is the equation for total body clearance?

CLtotal = CLhepatic + Clrenal + CLpulmonary + CL other

What is steady state concentration?

When the rate of drug elimination equals the rate of drug administration

Reached by continuous or repeated administration via IV infusion or oral regimen

related to infusion rate and clearance

What is dose optimization?

Achieve and maintain drug concentrations in a therapeutic range to elicit a therapeutic response while minimizing toxicity and adverse effects

What is narrow therapeutic window

Drugs where small differences in dose or blood concentration may lead to serious therapeutic failures or averse drug rxns.

Digoxin, warfarin, cyclosporine, lithium

What is a loading dose?

Allows rapid attainment of desired plasma levels when rapid results are needed.

Always followed by a maintenance dose to maintain steady state concentration

LS= vd x (desired CSS)/F (bioavailability)

What is the equation for maintenance dose?

Dosing rate = (target plasma concentration x clearance)/fraction absorbed

What is pharmacodynamics?

The actions of a drug on the body and the influence of drug concentrations on the magnitude of response

What are common enzyme linked receptors?

Epidermal growth factor, platelet derived growth factor, and insulin

Enzyme: tyrosine kinase

What is tachyphlyaixs?

To protect against excess stimulation the receptor may become desensitized resulting in diminished effect

What is EC50?

The concentration of a drug (dose) producing 50% of the maximum effect

Used to determine drug potency

-The lower this value is, the more potent a drug is

What is efficacy?

Magnitude of response a drug causes when it interacts with a receptor

Depends on number of drug receptor complexes and the drugs intrinsic activity

What does intrinsic activity refer to?

The maximal possible effect that can be produced by a drug

What are full agonists?

Drugs that bind to a receptor and produce a maximal biological response that mimics the respond of the endogenous ligand

Intrinsic activity = 1

What are partial agonists?

A drug that has an intrinsic activity 0> action < 1

may act as an antagonist to a full agonist

What are inverse agonists?

Drugs that bind to the same receptor as an agonist but induces a response opposite that of the agonist

Decreases the number of activated receptors to less than the number seen in the absence of drug

-reverse activity of receptors

-exert opposite pharamcologic effects

Intrinsic activity less than 0

What are antagonists

Drugs that bind to a receptor with high affinity by have 0 intrinsic activity

No effect without agonist, decrease agonist effect when present

What is an allosteric antagonist?

Antagonist that binds to a distinct site on a receptor to prevent activation by the agonist.

Non competitive

What is function antagonism?

Antagonists may act at a different receptor to initiate an effect that is functionally opposite the effect of the agonist

-opposite effects of Two drugs in the same biological function

Ex: effects of glucagon and insulin on BGL

What is a quantal response?

An effect that either dose or does not occur in an individual

What is a quantal dose response?

Relationship between a drug dose and the population of people that respond to it

Dose that produces a clinically desired/effective response in half the population

What is therapeutic index?

The ratio of the dose that produces toxicity in half the population to the dose that produces a clinically desired/effective response in half the population

Used as a measurement of drug safety

Which of the following types of drugs will have maximum oral bioavailability

A drug that is largely hydrophobic yet soluble in aqueous solutions

What is true about the blood brain barrier

Lipid soluble drugs readily cross the blood brain barrier

A pt with afib is being treated with warfarin. They start carbamazepine for seizures, what describes the likely outcome of this drug interaction

Concentration of warfarin will decrease, pt may experience blood clots

Which of the following phase 2 metabolic reactions makes phase 1 metabolites readily excretable in urine

Glucuronidation

A drug with a half life of 10 hours is being administered by continuous IV infusion. Which of the following best approximates the time for the drug to reach steady state

40 hours

A 55 y/o patient is being treated with drug x for an irregular hr. If the Vd is 1 L/kg and the Desired steady state plasma concentration is 2.5mg/L, which of the following is the most appropriate IV loading dose for drug X?

175mg

LD= 1 L/kg x 2.5mg/L

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

Full agonist