Pharmacokinetics

Pharmacology

the study of any substances that interact with any living systems through chemical processes

Medical/Clinical Pharmacology

the science of substances used to prevent, diagnose, and treat disease

Toxicology

the study of the harmful effects of chemicals on living systems

Chemical name

refers to specific compound structure and chemical make-up for drugs

Generic/Nonproprietary name

derived from chemical name and shorter, interchangeable with Trade/Brand name for drugs

Trade/Brand name

assigned by pharmaceutical company with marketing in mind for drugs

Brand name vs Generic drugs

Brand name = protected via patents; Generic drugs = off-patent substitutes

Generic drugs

• made by competing companies

• significantly cheaper than brand name

• must be tested to assure bioequivalency

How to test for bioequivalency in generic drugs

• same type and amount of active ingredient

• same administration route

• same pharmacokinetic profile

• same therapeutic effects

Prescription medications

must be ordered by healthcare provider with prescribing authority

OTC medication

(over the counter) that can be purchased by general public

Controlled substances

categories that signify potential for abuse (1-5)

Schedule 1 category (controlled substances)

highest potential for abuse without therapeutic benefit

Schedule 2 category (controlled substances)

high risk for abuse, used for specific therapeutic purpose

Schedule 3 category (controlled substances)

moderate risk for abuse, used for therapeutic purpose

Schedule 4 category (controlled substances)

mild risk for abuse, used for therapeutic purpose

Schedule 5 category (controlled substances)

lowest relative abuse potential

Medical order workflow

1. Symptom recognition

2. Diagnosis

3. Treatment

4. Follow up care

Pharmacokinetics (PK)

what the body does to the drug

Pharmacodynamics (PD)

what the drug does to the body

Properties of Pharmacokinetics

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

ADME determines…

• onset of drug action

• intensity

• duration of drug action

Absorption

how a drug gets into the body from site of administration into the bloodstream

Route of administration (ROA)

where and how a drug is administered affects the rate and efficiency of absorption

ROA examples

• Enteral

• Parenteral

• Other (Nasal, Topical, Transdermal, Intrathecal)

Enteral ROA

uses the GI tract

• Oral (PO)

• Sublingual (SL)

• Buccal

• Rectal

Parenteral ROA

doesn’t use the GI tract

• Intravenous (IV)

• Intramuscular (IM)

• Subcutaneous (SC)

What ROA is safest?

Enteral

What Enteral ROA is most common?

Oral (PO)

Advantages of PO ROA

• easy, safe, pain free, economica;

• Many dosage forms available

PO dosage forms

• tablets, capsules, gelcaps

• solutions, suspensions

• powders, gummies, chewable tablets

Oral Drug formulatioins

• standard oral tablet

• extended release

• enteric-coated

3 key concepts of Oral Absoprtion

1. first-pass metabolism

2. prodrug

3. bioavailability

Standard oral tablet

immediate release; drug reaches stomach and starts to dissolve and be absorbs in GI tract

Extended release tablets

special coatings/ingredients control drug release to allow for slower absorption and prolonged duration

Extended release tablet acronyms

ER, XR, XL, CR, SR, 12hr, 24hr

Enteric coated tablet

chemical envelope protects drug from stomach acid and allows it to reach the intestines for absorption

Limitations of stomach absorption (pH, perfusion, surface area, primary function)

• highly acidic

• protective mucosa and muscle later

• low perfusion

• low surface area

• primary functions = digestion & storage

What is the principal site of GI absorption?

small intestine

Traits of small intestine for absorption (pH, membrane permeability, perfusion, surface area, primary function)

• neutral to alkaline pH

• permeable membrane

• efficient perfusion

• largest surface area (villi)

• primary function = absorption of nutrients & drugs

Factors that affect drug absorption at absorption site

• pH

• blood flow

• surface area

• contact time

Most drugs are…

weak acids or weak bases

Weak acids in acidic environment (stomach)

picks up H+ —> becomes un-ionized = easier to absorb

Weak acids in alkaline environment (intestine)

loses H+ —> becomes ionized = harder to absorb

Weak bases in acidic environment (stomach)

picks up H+ or loses OH- —> becomes ionized = harder to absorb

Weak bases in alkaline environment (intestine)

remains un-ionized = primary environment for absorption

Gastric emptying rate

the rate at which the stomach empties into the small intestine

What can change the gastric emptying rate?

food=slower

What can change the contact time in drug absorption?

diarrhea=increase transmit time, decreasing contact time and absorption

First-pass metabolism

when a drug, especially after oral intake, is significantly broken down by enzymes in the gut wall or liver before it can reach the systemic circulation and its intended target, drastically reducing the drug's bioavailability

Where does blood supply draining the GI tract pass through first?

liver

How does blood supply go through liver to reach systemic circulation?

hepatic portal vein

Routes of administration that avoid first-pass metabolism

• sublingual/buccal

• transdermal

• inhalation

• IM & SC

• rectal/vaginal

Prodrug

pharmacologically inactive substance that is converted in the body to a pharmacologically active drug via the liver and metabolism

What are the advantages of prodrugs?

avoids first-pass metabolism or extensive secretion

Prodrug example

Clopidogrel (Plavix)

Bioavailability (F)

the fraction (%) of the administered drug that reaches the systemic circulation

What drugs have 100% bioavailability?

IV

What drugs almost always have below 100% bioavailability?

Oral drugs (PO)

Which dose is higher, IV or oral?

Oral —> makes up for portion lost due to first-pass metabolism

If 100mg of a drug is administered orally and 60mg is absorbed unchanged, what is the bioavailability?

60mg/100mg=0.6=60%

What results in low bioavailability?

poor absorption in GI tract or partial metabolism in liver

Can some drugs have equivalent bioavailability?

yes but it is rare (1:1 IV:PO)

Primary mechanisms for passage of drugs

• passive diffusion

• facilitated diffusion

• active transport

• endocytosis and exocytosis

Passive diffusion

• no E required

• high to low concentration

• majority of drugs

• no carrier

• not saturable

• low structural specificity

How do water-soluble drugs move across membranes?

aqueous channels or pores via passive diffusion

How do lipid-soluble drugs move across membranes?

across biologic membranes via passive diffusion

Facilitated diffusion

uses specialized transmembrane carrier proteins that go through conformational change

• high to low concentration

• no E requirement

• can be saturated

• can be inhibited

Active transport

uses membrane proteins

• requires E via ATP

• requires specific shape and/or electrical charge to bind

• low to high concentration

Endocytosis

transports large drugs across cell membrane

• engulfs drug to transport in

Exocytosis

transports large drugs across the cell membrane

• secretes substances out

Sublingual administration (SL)

drug placed under the tongue (rapid absorption)

Buccal administration

drug placed between cheek and gums

Rectal administration

drug administered as suppository or enema for patients unable to tolerate oral medications (variable absorption)

Inhalation administration

drug administered as gas or aerosol orally or nasally across large surface areas of mucous membranes of respiratory tract (fast action)

Topical application

drug administered in vehicle/base directly to mucous membrane or skin via creams, lotions, eye drops, nasal spray, etc

Injectable applicaiton

drug administered to site of need via needle

• dose is less than oral drugs due to lack of first-pass metabolism

Subcutaneous (SC) administration

drug administered into loose tissue below the skin via needle (slow & constant absorption dependent on blood flow to area of injection)

Intravenous (IV) administration

drug administered directly into vein via injection (no absorption due to 100% bioavailability and high concentration allowing for rapid response)

Distribution

process by which medication is dispersed throughout the body via the bloodstream

What is distribution dependent upon?

• blood flow

• lipophilicity

• capillary permeability

• drug binding to proteins

• volume of distribution

Blood flow in distribution

rate of drug distribution into a tissue

Types of distribution in blood flow

• rapid distribution

• slow distribution

Rapid distribution of blood flow

drug reaches organs wtih high blood flow most quickly, such as the lungs, kidneys, liver, and brain

Slow distribution of blood flow

tissues with fewer blood vessels, such as adipose tissue (fat), experience the least rapid distribution

What factors can affect blood flow and possibly the delivery of drug through the body?

• constricted vessels (hypertension)

• blocked vessels (coronary artery failure)

• weakened pumping (heart failure)

• decreased blood flow (dehydration)

Capillary permeability in distribution

determined by structure (leaky or tight) and chemical nature (ionized, polarized, or lipid soluble) of drug

Continuous capillary permeability

tight structure (ex. CNS)

Fenestrated capillary permeability

windows/openings to allow for slight leakage (ex. kidneys)

Sinusoid capillary permeability

incomplete basement membrane and intracellular gap allowing leakage (ex. liver)

Blood-brain barrier (BBB)

highly selective and semi-permeable membrane that protects the brain and CSF using tight junctions

Tight junctions and their function

two adjoining cells merge and form a continuous wall; stops passage of 98% of all molecules in the blood

Ways drug can enter the brain

1. lipid soluble drug via passive diffusion (ionized/polar drug cannot pass via this way)

2. Active transport for ionized/polar drug via transport protiens

Examples of drugs that can get through BBB

• acetaminophen (Tylenol) and ibuprofen (Motrin/Advil)

• fluoxetine (Prozac), sertraline (Zoloft)

• diazepam (Valium)

• morphine

First generation antihistamines and side effects

Readily crosses the BBB leading to CNA adverse effects like sedation

Second generaiton antihistamines and side effects

Designed to be less lipid-soluble, minimally crossing the BBB, resulting in reduced sedation

Opiates and the BBB

they readily cross the BBB and result in significant and therapeutic CNS effects, as well as slow down peristalsis in the GI system resulting in constipation

Opiate in BBB and function

actively transported out of CNS with minimal CNS effects at normal doses

Lipophilicity

a drug's tendency to dissolve in fats/lipids

Lipophilic drugs vs biologic membranes

drugs readily move across membranes, dissolving in the lipid membrane and penetrating the entire cell surface