Pharmacokinetics

Where are most drugs administered and moved to?

* into one body compartment
* to the site of action where they produce effects

Drugs must ______ various barriers that separate compartments ie. cell membranes

permeate

The absorption, distribution, metabolism, and excretion of a drug involves

transport across cell mebrnes, which is affected by several drug characteristics

Passive transport includes

* paracellular transport
* passion diffusion

What is passive diffusion

of a drug thru cell membranes is generally limited to unbound(free) drug

* large lipophilic drugs typically pass thru membranes
* thru cell mebranes dominates transport for most drugs

What is paracellular

passage of molecules thru intercellular gas

* transfer in the capillary endotherlium is limited only by blood flow
* some. capillaries have “tight” intercellular junctions, limiting flow

Carrier-mediated transport includes

* facilitated transport
* active transport

What are a 4 drug characteristics that involve transport across cell membranes

* molecular size & structural feature
* degree of ionization
* relative lipid solubility of ionized/non-ionized forms
* affinity and binding to serum and tissue protein

Passive transport consists of what kind of lipid

amphipathic

Are cell membranes permeable to water

yes

* bulk flow of water can carry small water soluble substances(100-200 Da)

Passive flux across the membrane is driven by

* drug concentration gradient across membrane
* solubility of drug
* greater the coefficient, the faster the diffusion
* The surface area of membrane
* Membrane thickness

Many drugs are ____ acids or bases present in solution as un-ionized and ionized species

weak

Un-ionized species ____ lipid soluble; ____ readily diffuse cell membranes

more, more

Ionized species are __ lipid soluble; __ able to cross thru cell membranes \n directly;

less, less

Transmembrane distribution of a weak electrolyte is influenced by ________ and _________

* its pKa (ionizable constant)
* the pH gradient across the cell membrane

pKa

= pH at which 50% of drug is ionized and 50% is unionized

* pKa usually between pH 3 and pH 11

Drug accumulation of side of cell membrane where ionization is highest or lowest

* highest
* called ‘ion trapping’
* basic drugs accumulate in acidic forms and vice versa

Important to memorize about passive transport

* basic drugs accumulate in acidic fluids
* acidic drugs accumulate in basic fluid

Why is carrier-mediated transport important (for) (3)

* molecules too large for passive diffusion
* molecules not soluble in lipids for passive diffusion
* carriers are saturable, selective, and inhabitable

What does a active transporter do

move molecules against their concentration and electrical

* requires energy in the form of ATP

What do faciliated transporters do?

Move large/lipid insoluble molecules down their electrochemical gradients

* no energy input acquired

Acronym for pharmacokinetics

* what the body does to the drug

M- metabolism

A - absorption

D- distribution

E- excretion

Where can drugs first be absorbed into the systemic circulation?

site of administrations to get to target sites

Which route does not required absorption

* Intravenous, intrathecal, and other minor routes

Before enter circulation for solid or semi-solid dosage form what does absorption first require of an active drug

dissolution

What affects rate of absorption from site of adminstation?

* physiochemical drug factors
* physiologic factors
* drug formation

What are the physiological factors of absorption?

* large concentration gradient between site of drug administration and surrounding tissue drives the uptake of drug into the circulation

What are the drug formation of absorption?

* physical and chemical ingredients of a medication
* Includes both the active drug, and any inactive chemicals that comprise a pharmaceutical product ready for administration to the patient

Modifications of the active pharmaceutical ingredient and/or final \n formulation can be employed to....

* Slow or delay the release of the API for absorption \n • More convenient as the drug is less frequently administered \n • Usually for drugs with short elimination half-lives \n • Modifications aimed at prolonging the dissolution phase of absorption \n • “Dose-dumping or erratic absorption is a potential concern

What is bioavailability

a fraction of administered dose that reaches the systematic circulation unchanged

Bioavailability can be reduced or affected by

* Precipitation of drug at injection site
* unable to be absorbed by the G.I. tract
* physiochemical property of drug
* reverse transport protein (P-glycoprotein)
* “First Pass” elimination effect following oral administration of drugs
* Primarily due to liver metabolizing enzymes inactivating drug
* Enzymes in G.I. tract wall can also metabolize drug
* Drug can also be excreted in bile

What is the most common method of drug administration

Enteral: Oral

What is enteral

going through the GI tract

What are the advantages of oral administration (5)

* most convenient for self-administration
* most economical route
* usualy safer than injection
* minimal risk of infection
* can induce vomiting to potentially remove drug

What are the disadvantages of oral administration (6)

* Absorption may be erratic
* enteric coating protects some drugs against gastric juices/acids
* patient compliance problems
* not for unconscious patients
* emesis and GI irritation possible
* “first pass elimination

What is first pass effect

in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation.

What are other eternal minor adminstration routes

* Oral transmucossal
* Rectal

What are the 2 kinds of oral transmucosal

* Sublingual
* Buccal

What is sublingual oral transmucosal? (4)

* under the tongue
* absorption from the oral mucosa
* can potentially by-pass “first pass effect” by venous drainage to superior vena cava
* usually higly lipophilic drugs, eg. nitroglycerin for angina pectoris

What is buccal oral transmucosal

* between the cheek and gum
* absorbed from mucosa, eg. fentanyl lollipop

Explain rectal admission

\
* Estimated that roughly 50% of drugs administered by the rectum will by-pass “the first pass effect”
* potential for irritation
* less nausea
* used in patients with GI motility disorders, and near end-of-life car

What is parenteral

* injectable drugs are most comon form
* drug availability is usually more rapid, and predictable over oral
* by passes “first pass effect”

What is subcutaneous injection

* SC or SQ
* injection is administered in the tissues lying below the skin

What are the advantages of subcutaneous injection

* suitable for solid pellets eg. contraceptives
* suitable fro insoluable suspensions
* easier to administer than IV

What are the disadvantages of subcutaneous injection

* absorption is slower than IM route

- can be erratic depending on blood flow to the site

* not suitable for large volumes
* pain and/necrosis with the irritating injectable drug solution
* technical skills needed for some injections
* generally, the drug is irretrievable once injected

What is intramuscular injection

* more painful than SQ - bigger needle, deeper
* administered into the muscle (gluteus maximus, vastus laterals of the thigh, deltoid of upper arm, etc)

What are the advantages of intramuscular injection

* absorption is typically rapid for drugs in aqueous solutions; oily suspensions will form depot
* safe, easier than IV

What are the disadvantages of intramuscular injection

* local pain and swelling with irritating solutions

What is intervenous injection (IV)

administered into an accessible vein (bolus vs slow infusion)

* ex. cephalic vein, jugular vein, others

What are the advantages of intervenous injection (IV) (5)

* route of choice for emergency administration of drugs
* large volumes can be given by this route
* Bioavailability is complete; dose delivery is controlled
* Route with most rapid onset of action
* irritating solutions given by this route

What are the disadvantages of inteerbenous injection

* most inject many solutions slowly
* not for oily suspensions
* adverse reactions can occur due to higher blood levels achieved rapidly compared to other routes

What are topical

drugs applied topically to the eye, skin, and mucus membranes

* cream etc

What are the advantages of topical?

* drug delivered locally; can achieve very high concentration

What are the disadvantages on topical (2)

* may be absorbed systematically
* may not remain at desired site

What is transdermal

Drugs applied to the skin and absorbed into the systemic circulation

What are the advantages of transdermal

* absorption enhanced by abraded, denuded or burned skin
* controlled release, eg. nicotine and fentanyl patches

- prolonged duration of action

* by passes “first pass elimination” effects

What are the disadvantages of transdermal

theraputic blood levels are slow to achieve; delay onset of action

Interstitial Fluid

fluid within the organs, inbetween

What are the 3 distributions in the body is affected by

1. Physiochemical properties of the drugs
2. Anatomy and physiology of patient: Tissue Perfusion
3. Non-target binding of drug

What can a drug do once in the systemic circulation (3)

* remain in vascular (blood) space
* distribute to enter interstitial fluid
* further distribute to enter intracellular fluid

What are the physiochemical properties of the drug

* lipid solubility
* size (molecular weight)
* degree of ionization

Initially, the vessel-rich tissues (liver, kidney, brain, heart) receive

the greatest cardiac output and thus the distribution of drug

Distribution of drug to less well-perfused tissues (muscle, fat, skin, most viscera) is faster or slower

is slower but accounts for most of the extravascular drug

What is plasma protein binding (4)

* Many drugs circulate in the blood bound to plasma \n proteins; can show low → high affinity for proteins \n • Cannot diffuse from vascular space to tissues
* Binding involves a saturable, non-linear process
* Albumin (\~ 4 g/dL) is a major carrier for drugs \n that act as weak acids eg. NSAIDs
* α1-acid glycoproteins bind drugs that are weak bases

What is tissue binding

* Many drugs accumulate in tissues at levels higher \n than blood or interstitial fluid; can prolong drug action \n • bind cellular proteins, phospholipids, etc that are not the target sites

What is the volume of distribution (Vd)

describes the extent to which a drug partitions between blood and tissue compartments

How are drugs eliminated from the body

process of *excretion* or concerted to metabolites by *biotransformation*

What is clearance?

* it gives and indication of efficiency of drug from blood and therefore the body

What do excretory organs elminate

polar (water soluble) compounds more efficiently thsn non-polar (lipid soluble)compound

What is the most important excretory organ

* kidney

What percent of cardiac output do the kidney's receive

roughly 20%

What does active drug selection in proximal convoluted tubule add to the urine

drugs

_ is saturable, selective and inhibitable by other drugs

Active drugs secretion

What is metabolism or biotransformation?

change in the chemical structure of an absorbed drug within an living organism, usually by enzyme-catalyzed biochemical reactions

What is the main metabolizing organ

Liver

Why is drug metabolism important?

* we don’t want drugs to keeping doing its thing forever
* enzymes play a pivotal role in matabolism by making drugs more excretable and terminating their action(inactive)

Where are drugs metabolized

* livers the major site
* also occurs in other organs (lungs, GI tract, skin, kidneys, brain, plasma, etc)

Biotransformation reactions are catluzed by cellular enzymes that are located in hepatocytes…..

* **mainly smooth ER and cytoplasm**


* mitochonidra
* nuclear/cell mebrain
* lysosome

How are drugs metabolized?

2 phases


1. Phase I reactions (oxidation/reduction/hydrolysis reactions)
2. Phase II reactions (conjugation reactions)

What is occurs in Phase I

drugs are converted to more polar(hydrophilic) metabolites → either excreted or →undergo phase II reactions

What are characteristics of phase I reactions

involves 1 or more cytochrome P-450 (CYP)

(called P-450 that bc they are heme-containing proteins that absorb light at 450nm)

Approx how many CYP450’s are know to be important for metabolism of drugs

12

* mainly the CYP2C, CYP2C, CYP3A subfamilies

What are the types of phase I reactions

Oxidation - most common - addition of oxygen or removal of hydrogen (loss of e-) from drug

Reduction and hydrolysis - less common

What percent of oxicdative reactions involve CYP450

95%

What occurs during Phase II

reactions in which a substance from a diet is attached to a group from phase I → more polar, excretable product

What are the characteristics of phase II

* couple drugs with substates from diet to propuce conjugates(more polar, inacitve, readily excretable)
* conjugates required the drug to have an oxygen, nitrogen, or sulfur atoms as acceptors doe hydrophilic conjugate moiety
* eg. **Glucuronic acid, sulphate, glutathione, acetyl groups most commonly,** but also methyl, glycine, cysteine , or methionine

What are types of Phase II reactions?

1. **Glucuronic and acid conduction (UDP glucuronosyl transferase):**
2. **Sulphate conjugation (sulfotransferases):** phenols and alcohols conjugated to sulphates (SO4)
3. **Acytlation (N-acetyltransferases):** occurs in drugs with -NH2 group conjugated to COCH3
4. **Glutathione conjugation (glutathione S-transferase):** epoxides, arena oxides conjugated to glutathione (GSH)

What do the dynamic interactions among drug ADME determine

plasma concentration of drug and target site concentration

What are the 4 key parameters govern drug disposition (PK) and dosage regimen

* Bioavailability (%F)
* Volume of distribution (Vd)
* Clearance
* Elimination half-life(t1/2)

Elimination of drug processes are usually

first-order processes

* half-life can be used to describe the rate of drug elimination (how frequently should I take that drug)

What is elimination half-life?

time requirednfor blood drug concentration to decrease by 50%

For clinical purposes, drug is considered essentially eliminated from blood after how many half-lives?

4-5

Therapeutic requirements often exceed …?

the duration of action following a single dose

Elimination half like (1/2) provides clinicians with

info about regarding frequency of drug administration needed to maintain blood drug levels in the therapeutic range

Elimination half life is a “___ ____” being dependant on other independent parameters

hybrid constant

Elimination half life equation

Dosing regimes consist of:

* Dose(amount of drug given)
* Rotue of administration
* Frequency of administration eg. q12hrs
* Duration pf therapy ed. 3 days

What is dosage?

amount of drugs given per body weight

What is are loading doses?

can be used to acheive trarget therapeutic drug levels quickly

What are maintenance doses?

are given to maintain drug levels in the target therapeutic range