Binding of drugs to Plasma Proteins:

- Albumin- major carrier for acidic drugs

- Alpha-1 acid glycoprotein- major carrier for basic drugs (alkaline drugs)

- Sex hormone binding globulin

- Thyroxin binding globulin

If a drug is bound to a protein it is NOT free to act

- The bound drug is not free to act

- Only the unbound drug acts

- Fat soluble drugs are drugs that cross the blood brain barrier AND are drugs that are highly protein bound

- Fat soluble drugs may be alkalin (atropine, amitriptyline) OR acid (haldol, atenolol).

Binding and transfer of drugs

- Protein Binding

- Tissue Binding

- Penetration of the Blood Brain Barrier

- Placental Transfer

- Gentamicin binds to tissue in kidney and vestibular apparatus.

- Lipid soluble agents bind to fat, which acts as a reservoir

- Calcium binding agents, like tetracycline, bind to bone or to dairy products in GI tract

- Heavy metals, e.g., lead, may also bind to bone

- Fetal pH of 7.0 somewhat more acidic than maternal pH of 7.4, and this can cause trapping of basic drugs

- Drugs that cross placental barrier and which administered to mother immediately before birth may therefore have adverse effect on fetus

- Drugs which are administered during pregnancy and which cross the placental barrier may cause anomolies. These are called teratogenic agents

Biotransformation by the liver.

- Converts fat soluble (lipophilic) drugs or agents to water soluble (hydrophilic) metabolites so that they can be excreted by the kidneys

- To convert pharmacologically active agents to inactive metabolites

- Take an active drug and convert it to an active metabolite

- Drugs that end in "azole"

- Grapefruit juice

Metabolize drugs at a slower rate and have a difficult time leaving the plasma concentration resulting in toxicity from other drugs that a patient may be taking.

- Ketoconazole, Itraconazole, HIV protease inhibitors, clarithromycin

- Some calcium channel blockers (diltiazem, nicardipine, verapamil), amiodarone, cimetidine, paroxetine, fluoxetine

Metabolizes drugs at a faster rate and we may have a difficult time maintaining an adequate plasma concentration for therapeutic maintenance for patient.

- Rifampin, tobacco/nicotine, chronic ETOH, many anticonvulsants, barbituates, St. John's Wort, charcoal broiled foods

Hepatitis, cirrhosis, biliary cirrhosis, fatty liver, hepatocarcinoma.

- Also decreases the 1st pass effect which increases the plasma concentration of medications the patient is taking which may lead to toxicity or overdose.

- May need to alter drug dosages in patients with liver disease to prevent overdoses in these patients

Anticonvulsants ARE metabolized by the CYP 450 system

- Need to monitor patient's drug level so that the plasma concentration does not fall below or above the therapeutic level

Responsible for:

- Yielding inactive metabolites of drugs (for excretion)

- Converting an inactive drug into an active metabolite

- Converting an active drug into an active metabolite (Active metabolites may be pharmacologically toxic or beneficial)

- A drug or its active metabolite conjugates with endogenous:

- Glucoronic acid

- Sulfate

- Glutathione

- Amino Acids

- Acetate

- (Morphine-6-glucoronide is a metabolite of morphine. In this case, the metabolite is more potent analgesic than morphine itself)

A protein (an enzyme) found in the liver (also in ovaries, adrenals, intestine, testes, and placenta) that is important in:

- Steroid production

- Catalyzing the metabolites of steroids and free fatty acids

- Detoxifying chemical Substrates

About 1000 P450 enzymes, but only about 50 are active in humans, categorized into 17 families and may subfamilies.

- The number of the enzyme family follows "CYP" CYP 1, CYP 2.

- Within an enzyme family, there are subfamilies. Subfamilies share a letter. CYP 1A or CYP 1B are two different subfamilies of the CYP 1 family.

- Any one enzyme may exist in several forms called ISOFORMS, denoted by the number following CYP family number and its subfamily letter= CYP 2A6= (the isoform 6 in the A subfamily of the CYP 2 family)

- Only about 8-10 ISOFORMS in CYP 1, CYP 2, and CYP 3 are responsible for the majority of drug metabolism reactions in humans

- Very Similar isoforms

- Together they account for more than 50% of all drug metabolism

- CYP 3 A is expressed in intestinal epithelium as well as in the liver and may be responsible for significantly decreasing the bioavailability of agents, much like the first pass effect

Nonspecific esterases (enzymes) and amidases found in the endoplasmic reticulum of the liver, intestine, and other sites. They handle or metabolize esters or amides

- Epoxide hydrolase, a enzyme that DETOXIFIES the toxic metabolites of P450 metabolism, is found close to P450 enzymes in endoplasmic reticulum

- Proteases and peptidases metabolize polypeptide drugs in the TISSUE (May render the drug ineffective)

- To deliver such drugs across the cell membrane requires inhibition of proteases (protease inhibitors) or peptidases so that the drug is not metabolized and is "free to act"

Phase 1 and Phase 2 metabolism begins to mature 2-4 weeks post-natally. Newborns and infants metabolize drug effectively butr more slowly than adults.
- Pre-adolescents may metabolize some dugs more effectively than adolescents, REQUIRING A DOSE REDUCTION when adolscence is reached (phenytoin)

- Older adults may experience decline in liver function at the same time they are being prescribed multiple drugs with high risk of drug interaction

- Increasing age increases rick of polypharmacy (the older you are more chronic conditions)

- Pregnant woman will metabolize drugs faster during the second and third trimester. May need to increase dosage of medication a woman is on during her second and third trimester, but adjust it after the baby is born to prevent toxicity

- Drugs are excreted unchanged or converted to metabolites ONLY unbound drugs are eliminated renally

- Weak alkaline urine facilitates excretion of weak acids

- Weak acidic urine facilitates excretion of weak bases

- If you alter the pH of the urine and make it more alkaline (tomato, grapefruit juice make more alkaline urine) you can get rid of acidic drugs or increase the reabsorption of alkaline drugs.

- If you alther the pH of the urine and make it more acidic you can get rid of alkaline drugs or increase the reabsorption of acidic drugs. (Do not recommend cranberry juice to patients taking sulfa products)

- IMPORTANT you can manipulate the urine pH to hasten the elimination of toxic drugs

- Kidney is the most important organ in excretion

- GI tract eliminates unabsorped drugs or metabolites excreted in bile

- Breast milk excretion is important because of potential passage of drugs to the infant

- Lungs excrete gases, ketones, etc.

Changes in renal function impact drug elimination

- Neonates

- Adults (decreases by about 1% a year as the person ages)

- Only unbound drugs are eliminated through renal excretion

- Urine pH effects excretion

- Breast milk

- Tears

- Saliva

- Sweat

Drugs excreted by these routes are usually FAT-SOLUBLE agents

Plateau at which the rate of drug elimination equals rate of drug administration.

- Usually takes four or five doses of an agent before steady state is achieved

Of all the variables that influence dosing, four are most important.

- Clearance

- Volume distribution

- Elimination half-life

- Bioavailabiliy

- CrCl (estimated) = [(140 - age in years)(IBW-Kg)/Serum Cr] in mg/dL)(72)

- For WOMEN-  multiple the obtained estimated CrCl by 0.85

- If clearance of the drug exceeds liver blood flow, then extrahepatic mechanisms are involved

- Caveat: Sometimes, clearance of the drug even exceed cardiac output. For example, esmolol is cleared at a rate of 11.9 L/minute. This is due not only to hapatic mechanisms but also to the esterases present in the RBC's that rapidly clear the blood

- Hepatic clearance is influenced by the extraction rate of the drug from the plasma, that is by the amount of drug delivered to the liver for clearance. If the extraction rate is high, then enzyme induction and liver disease do not influence hepatic clearce greatly.

- The body is effective in extracting the drug from the plasma

- If the intrinsic ability of the liver to clear drugs is low, then changes (enzyme inhibition) and competitive protein binding (more drug being available because of competitive binding) will influence the rate at which the drug is extracted from the plasma. So a person with liver disease is going to have even more trouble eliminating drugs when the P450 system is inhibited than the normal person. The person with liver disease is going to have even more difficulty with more drug being available because of protein binding competition than the normal person

Renal clearance is influenced by

- Filtration

-Active secretion

- Reabsorption

Example 70 kg male

- Plasma volume = 3 L

- Blood volume = 5.5 L

- ECF Volume = 12 L

- Total body water volume = 45 L

- BUT, the volume distribution of digoxin = 650 L, a value more than 10 times higher than total body water volume. Why? It is sequestered in tissue and fat- and elimination half-life is greatly prolonged

t 1/2 = time it takes for the plasma concentration of the drug or the amount of drug in the body to be reduced by 50%

I changes as a function of clearance and or total volume distribution

As clearance DECREASES (with age), half-life increases. So, LOWER doses may be indicated

Caveat- But the half-life of some drugs (Dilantin) increase with age not because of clearance but because of volume distribution (So, with some drugs, a 14 year old may require a smaller drug do than a 9 or 10 year old)

It takes about four half-lives to reach steady state or at least 94% of steady state.

How long will it take a drug with a half-life of 4 hours to reach steady state? Around 16 hours

Between minimal effective level and toxicity

- MEC = Minimum expected concentration for toxic effects

- MEC = minimum expected concentration for desired therapeutic response

TI = LD 50/ ED 50

OR

Therapeutic Index = Lethal dose 50%/ Effective Dose 50%

Narrow Therapeutic Index = Overdoses are lethal

Wide Therapeutic Index = Overdoses are not lethal

Goal- maintain steady state or target concentration, rate of drug administration is adjusted so that rate of input equals rate of loss

KNOW therapeutic range, Digoxin 0.8 - 2.0 ng/ml

Intermittent dosing: peaks and troughs

Intermittent dosing: Amoxicillin has half-life of 2 hours, but usual dosing is every 8 hours.

- Advantages- May be needed when time required to reach steady state (4 half-lives) is relatively long compared with clinical needs of the patient

- Disadvantages- Drug sensitive person exposed abruptly to what may be a toxic level for that person, and this is even more complicated if the drug has a long half-life. (Digitalization, if gradual without loading dose and using the maintenance dose only, takes 10 days)

- Avoid the one size fits all approach

- Why? Because too much variability can occur in important variables.

- When the Therapeutic index is low, monitor the drug, but avoid drug monitoring pitfalls...

-When to draw specimen when intermittent dosing is used? Especially important when the lethal dose and therapeutic dose are close or the Therapeutic Index is narrow.

- One rule does not apply to all. Concentrations of digoxin exceed toxic range if drawn from 2 hours postadministration, but this peak effect does not cause toxicity. So,,, When is the maintenance dose of digoxin monitored? Before the next planned dose.

A more refined approach is used to determine both peak and trough (maximum and minimum) concentrations

- There are also advantages of taking a sample after the second and before the third dose when beginning a drug. If the concentratios is 90% of expected steady state (4 half-lives) concentration, then halve the dose (drug has already reached 90% of expected steady state after 2 doses)

- Fat soluble drug distribution and degree of protein binding are influenced by age

* Increases in total body fat (Increased sequestering and decreased clearance of fat soluble drugs)

*Decreases in serum albumin (within decreased protein plasma binding and increase in amount of drug that is free to act)

* Clearance reduced in the elderly because of decreasing renal fxn yielding increases in drug half-life

* Reduced hepatic blood flow and related hepatic metabolism (CYP 450 activity reduced- drugs don't metabolize as quickly, but conjugation mechanisms remain intact

* Increased sensitivity to CNS drugs at any given plasma concentration

* Increased sensitivity to side effects, Benadryl- decrease in coordination

* Decreased vascular resonsiveness yields increased risk of orthostatic hypotension when taking anthypertensives

* Elderly benefit as much if not more from antihypertensive tx of systolic HTN (SHEPS) and dyslipidemia

ADME

-Absorption

-Distribution

-Metabolim

-Excretion

- Solid dosage forms- must first be dissoved for the drug to be "liberated"

- Oral ingestion is the most common route, the most convenient, and the most economical

Fat soluble drugs are lipophilic- they love fat and readily merge or penetrate the cell's lipid membrane and pass by PASSIVE diffusioninto the cell

* This process is facilitated by bile salts

* Food in the stomach stimulates the release of bile, so food in the stamach increases the absorption of fat soluble drugs.

* Fat soluble drugs are NON-IONIZED, NON-POLAR agents

* Fat soluble drugs are absorped better the the presence of food.

Oral Contraceptives are surrounded by a sugar coating. Sugar is destroyed by bacteria in the gut or GI Flora. The contraceptive agent is then released or liberated and absorbed.

* Think about what happens when antibiotics are taken with OCP's.

1. Emesis- Causes expulsion of gastric contents (No absorption)

2. Gastric emptying time. As gastric emptying increases, rate of absorption increases. This is influenced by estrogen, which slows down gastric emptying, especially in premenopausal women

3. Gastric enzymes - proteins are destroyed by gastric enzymes (Heparin and insulin are proteins and therby cannot be given orally or they would be destroyed)

4. Binding with substances in the stomach- tetracyclines bind to calcium products and decrease absorption of such (don't eat dairy products close to taking tetracycline or absorption will be greatly decreased)

5. Surface area for absorption (Surface area of upper intestine is greater than the surface area of the stomach. Therefore the rate of absorption is greater from the small intestine)

6. Physical state of the drug

* Solution

*Suspension

* Solid- solid drugs with low water solubility may have slow rate of dissolution and thus absorption may be delayed; enteric coated drugs may resist dissolution

7. Drug pH

* Weak acids are absorbed better in the acidic stomach environment than in more alkaline intestine. BUT intestine has a greater surface area.

* Weak bases are absorbed better in alkaline environment of small intestine than in the acidic environment of the stomach

* A drug is a base or alkaline if it ends in "ine"

Amitriptyline

Nicotine

Scopolamine

Ephedrine

Atropine

* If a drug does not end in "ine" it is an acid

Acetysalicylic Acid

Acetaminophen

Atenolol

CR= Controlled Release

ER = Extended Release

SR = Sustained Release

PA = Prolonged Action

Benefits to using these agents:

* No peaks and troughs

* Decreased incidence of intensity of undesired effects because there are NO peaks

* They maintain a therapeutic effect overnight OR throughout a 12-24 hour period

*Decreased frequecy of administration = possible increased compliance

Disadvantages to using these agents:

* Dumping of agent if broken = toxicity

* Controlled release agents that are the best are ones with short half lives

* Greater interpatient variability in systemic concentration of drug (Different people will have no prolonged effects if half-life is shorter)

Have immediate vascular acess to the vascular bed, these drugs are non-ionic fat soluble drugs and are potent (small amounts are effective)

* Sublingual drugs Bypass the 1st pass effect

PO vs. Parenteral administration of Morphine

* PO dose must be 3 times greater than the IV dose to equal the same effect because of the 1st pass effect

* Morphine loses 2/3 of it's bioavailability through the 1st pass effect

Water Soluble or Hydrophilic

require active transport

absorbed slowly

Fat Soluble or Lipophilic

Require Passive transport

Absorbed faster

* Only fat soluble agents are appropriate for transdermal drugs

Only fat soluble drugs are appropriate for trandermal application

Bypasses the 1st pass effect, abosorbed immediately into the vascular system.

Irregular absorption- fecal matter impedes absorption

50% bypass the first pass effect

Into the space around the spinal cord

*Avoids the blood brain barrier

Into an artery

* For localized effect to particular organ within a particular arterial bed (some liver tumors)

Opthalmic

Nasopharyngeal

Buccal

Vaginal

Bladder

*Usually for local effects

* Newer topical agents for systemic effects

- Synthetic ADH (Desmopression) OR H1N1 Flu mist vaccine