Lecture 2 - Pharmacokinetics

What is Latanoprost?

A potent prostaglandin analog used to reduce inflammation, can be taken as an eye drop for glaucoma

What is the toxic effect of overdosing on ocular prostaglandin analogs?

Can cause paradoxical spikes in IOP and severe ocular surface toxicity

What is half life?

The time requred for serum concentration of a drug to decrease by 50%.

At what serum concentration is a drug considered eliminated from the body?

3.5%

How many half lives does it take for a drug to be eliminated?

5 half lives

What is the hepatic firstpass effect?

Drugs given orally must pass through the liver to be processed before reaching their site of action.

How much of a drug taken orally is broken down by the liver?

75-85%

How much of a drug taken orally reaches the site of action?

20-25%

Do topical drugs pass through the liver?

NO, only drugs taken orally

What is cytochrome P450?

The group of enzymes created in the liver that are responsible for most drug metabolism oxidation reactions

What are the physiologic barriers of drug absorption?

Physical (anatomical), chemical, and biological barriers

What type of barrier is the hard palate and mucous membrane of the mouth?

Physical/anatomical

What type of barrier is the pH difference between the stomach and fundal veins?

Chemical

What type of barrier is the blood-brain barrier and blood-placental barrier?

Biological

Why are capillary blood vessels an incomplete biological barrier?

Due to endothelial gaps

How do substances move between capillaries and tissues?

Through passive diffusionW

What is passive diffusion affected by?

Concentration gradients/osmosis

What is the bilipid layer made of?

Phospholipids, glycoproteins, glycolipids, and transmembrane proteins (G proteins)

What is pharmacokinetics?

The movement of drugs in the body; what the body does to the drug

What are the 4 process of pharmacokinetics?

ADME: Absorption, Distribution, Metabolism, Excretion

What factors influence drug concentration at the site of action?

Route of administration, dose, and characteristics of drug molecules (ex: lipid solubility)

What kind of barrier is the orbital socket?

Anatomical (physical)

What is the abbreviation for an oral drug?

per Os, PO

What types of substances are enhaled?

Vapors, gases, smoke

What routes go through mucous membranes?

Intranasal (sniffing), sublingual, rectal suppositories, conjunctiva/cornea, vaginal pessaries

What is a suppository?

A drug taken per-rectal (PR)

What is a pessary?

A drug taken per-vagin (PV)

What does parenteral mean?

Given via injection

What are the types of injection routes?

Intravenous (IV), intramuscular (IM), subcutaneous (SC), intradermal, intraperitoneal (IP), intraosseous, intraarticular

What is the transdermal route of administration?

Through the skin

What is the main factor affecting drug absorption?

Lipid solubility

What is pKa?

The pH at which 50% of drug molecules are ionized

Which molecules are lipid soluble?

Uncharged/unprotonated molecules

How does pKa influence drug absorption?

pKa influences the rate of absorption of a drug through tissues into the bloodstream

If a drug has high ionization, will it be more absorbed or less absorbed?

Less absorbed

What is pH trapping?

When a drug is trapped in one area due to a large difference in pH (high potential difference)

What is ASA?

Acetyl-salycilic acid (aspirin)

What is an example of pH trapping?

ASA diffuses faster through the GI mucosa (pH 2), but once it reaches the basic plasma (pH 7.4) it gets trapped in the plasma and cannot re-enter the GI tract

What is the pH of the stomach?

1.5-3.5

What is the pH of the intestines?

6-7 (more basic)

What are the advantages of oral drug administration?

relatively safe, economical, convenient, practical

What are the disadvantages of oral drug administration?

• Blood levels are difficult to predict

• Varying dose concentrations

• Some drugs are destroyed by stomach acids

• Some drugs irritate the GIT

What are the advantages of parenteral routes?

Absorption is more rapid than with oral administration (depends on blood flow to tissue site)

Order the rates of absorption for IV, IM, and SC routes.

IV > IM > SC

What are the specific advantages of IV injection?

• No absorption is involved (directly in blood)

• Rate of infusion can be controlled

• More accurate prediction of dose is obtained

What are the disadvantages of injection?

• Rapid onset can be dangerous during overdose/recovery from dehydration or shock

• If administered too fast, could compromise heart and respiratory function

• Drugs insoluble in water or dissolved in oil cannot be given via IV

• Sterile techniques necessary to avoid infection

What is bioavailability?

The fraction of an administered dose of drug that reaches the bloodstream

What is the bioavailability of any drug injected into the bloodstream?

100%

What factors affect bioavailability?

• Physical properties of the drug (lipophilic, hydrophobic, solubility)

• Drug formulation (sustained release, troche, pessary)

• Fasting state

• Gastric emptying rate

• Interactions with other drugs

• Age and gender

• Diet

• Genetics, disease state, ethnocultural, socioeconomic

What is a troche?

A tablet meant to be dissolved in the mouth (ex: lozenge)

How does levothyroxin need to be taken?

On an empty stomach

What is the major mechanism of drug transport?

Passive transport

What are the types of passive transport?

Filtration, diffusion, and facilitated diffusion

What mechanism is involved in active drug transport?

ATP-binding cassette (ABC transporter)

What is absorption?

The passage of a drug from the site of administration into circulation

How does aqueous solubility affect absorption?

Drugs given in solid form must dissolve in the aqeuous biophase before they are absorbed

How is absorption affected for poorly water soluble drugs?

For poorly water soluble drugs (aspirin), the rate of dissolution governs the rate of absorption

How does concentration affect absorption?

Passive transport depends on the concentration gradient. A drug given as a concentrated solution is absorbed faster than a dilute solution

How does area affect absorption?

Larger surface area = faster absorption

How does vascularity affect absorption?

Blood circulation removes the drug from the site of absorption and maintains concentration gradient across the membrane. Increased blood flow increases drug absorption.

Which orally administered drugs are readily absorbed from the gastrointestinal tract?

Unionized lipid-soluble drugs (ex: alcohol)

Where are acidic drugs absorbed faster?

In the stomach (because they are unionized)

What is an example of an acidic drug that is absorbed faster in the stomach?

Aspirin

Where are basic drugs absorbed?

In the duodenum (they are largely ionized in the stomach)

What are some basic drugs that absorb faster in the duodenum?

Atropine, morphine

How can basic drugs be altered so they don’t become ionized in the stomach?

Enteric coating

How does the presence of food affect absorption?

• Dilutes the drug and slow absorption

• Can form poorly absorbed complexes

• Can delay gastric emptying

Which antibiotics form a poorly absorbed complex when taken with calcium?

Tetracyclines, doxycycline/minocycline

Which drug must always be taken on an empty stomach?

Thyroxine hormone (Levothyroxine: Synthroid)

What are some ways to overcome absorption barriers from the stomach?

Enteric coated tablets (acid resistant coating) and sustained release preparations

Where is the drug deposited in SC and IM routes?

Near capillaries

Which absorption site is faster, SC or IM?

Intramuscular (IM)

How do SC and IM routes compare to PO?

They are faster and more predictable

What can you do to accelerate absorption with SC and IM routes?

Application of heat and muscular exercise (increase blood flow)

What is the effect of vasoconstrictors on absorption?

Slow down absorption

What is an example of a vasoconstrictor that slows absorption?

Epinephrine (sometimes used in local anaesthetics to keep the drug local)

What are depot preparations?

Preparations that have a long action

What is an example of a depot preparation given by SC or IM routes?

Protamine zinc insulin (longer action to prevent multiple injenctions in one day)

What are the locations of topical appliation?

Skin, cornea, mucous membrane, buccal

What does systemic absorption depend on for topical application?

Lipid solubility

Which drugs significantly penetrate intact skin?

Nitroglycerine, Scopolamine, Estradiol

What is nitroglycerine?

A topical vasodilator used for heart attacks

What is scopolamine?

A patch used for motion sickness

What is estradiol used for?

As a cream to treat menopause in women

Can topical glucocorticosteroids produce systemic effects?

Yes, when applied over extensive areas can produce systemic effects and pituitary-adrenal suppression

Why do we need to taper off steroids instead of stopping all at once?

To allow the adrenal cortex to start functioning again

Which topical route absorbs lipophilic drugs?

Mucous membranes of mouth, rectum, and vagina (ex: estrogen cream intra-vaginally)

How are drugs absorbed into the cornea?

Passive diffusion driven by concentration gradients along cellular and paracellular pathways

Which molecules favor corneal penetration?

Small, fat-loving molecules (lipophilic)W

Which molecules have poor corneal permeability?

Large, hydrophilic proteins or ions

What formulations enhance absorption on the cornea?

Viscous agents (ointments and gels) and surfactants prolong residence time and enhance local uptake

(prevents being washed out by tears)

What is the main route of entry for topical ophthalmic drugs reaching intraocular tissues?

Cornea

What is the overal bioavailability of drugs absorbed by the cornea?

1% to 5%

What type of barrier is formed by the corneal epithelium?

Major lipophilic barrier, allows lipid-soluble drugs to pass earily via transcellular routes while restricting water-soluble molecules

What type of barrier is formed by the corneal stroma?

Largely hydrophilic collagen forma a rate-limiting barrier for highly lipophilic compounds, allows hydrophilic drugs to diffuse more freely

What type of barrier is formed by the corneal endothelium?

Lipophilic barrier (allows lipid-soluble drugs to go through)

What is distribution?

The passage of a drug from the circulation to the tissue and the site of action.

What does the extent of distribution depend on?

Lipid solubility, ionization at physiological pH, extent of binding to plasma and tissue proteins

What does it mean if a drug binds to plasma proteins?

It is kept in the bloodstream for longer (ex: warfarin/anticoagulants)

What diseases can impair distribution of a drug?

Congestive heart failure, cirrhosis, renal failure