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What is an acid and what is a base and what does that mean for absorption?

An acid is a proton donor.
HA = H+ + A-
The protonated form is uncharged and better absorbed

A base is a proton acceptor.
B + H+ = HB+
The protonated form is charged and not well absorbed


What is ion trapping?

At steady state – an acidic drug would accumulate on the more basic side of a membrane and a basic drug on the more acidic side – this is known as ‘ion trapping’.
An example of this is the mothers plasma is 7.4 and so a basic drug the reaction favours the formation of non-ionized drug (proton is easily given off by the drug in the more basic medium) or the B in the HB equation. So this non-ionized molecule will easily cross over to the fetal circulation or breast milk, which is more acidic. In the fetal circulation or breast milk the protonated ionized fraction (the HB+) will predominate and will accumulate because it cannot cross the cell membrane easily.


What is the clinical significance of ion trapping?

Fetus: Basic drugs taken by the mother can accumulate in the fetal circulation and the breast milk and can have harmful effects in the fetus and in the breast-milk fed baby.
Poisoning: Acidification or alkalinization of urine can accelerate the excretion of basic or acidic drugs that have reached toxic concentrations in the body. E.g.
To increase excretion of acidic drugs such as phenobarbital and salicylates, intravenous sodium bicarbonate is given
To increase excretion of basic drugs such as amphetamine, ammonium chloride or ascorbic acid may be given


What is the "first pass effect" or "first pass metabolism" and its clinical significance?

Some drugs are ineffective when given orally – examples: nitroglycerine, nor-adrenaline, insulin
If the drug is completely destroyed before it can be absorbed (e.g. insulin) then it has to be given by the parenteral route. Parenteral route is any other than the oral route (e.g. i.v., i.m., sc., inhalation, rectal etc.). When you give a drug sublingually (like a nitroglycerine tablet) it will be absorbed into the capillaries in the mouth, enter the superior cava and enter the heart and general circulation and distributed to the boy. It thus bypasses the liver and first-pass metabolism.
metabolizing enzymes in the liver and intestin means very little or no drug would reach the general circulation.


What is bioavailability and how would it relate to this first pass effect?

Bioavailability – is the fraction of an orally given drug that reaches the circulation.
Bioavailability = (AUC oral/AUC iv) x 100
(area under curve)
the graph is plasma concentration of drug on y axis and time on x axis.


There are some drugs that bind to things in the bloodstream called?

some drugs bind to plasma proteins!
One example of this is warfarin, Warfarin for example most of it is bound and not free but some drug interactions can caused displacement of binding and more free warfarin causing toxicity.
Drugs compete for binding sites, which are saturable
Displacement of a drug from plasma protein binding generally causes no change in its overall effect or adverse effects (except for drugs which have a very small volume of distribution, i.e., nowhere to go)


What happens if most of the drug is extracellular and there is a plasma protein binding displacing drug in competition with this one?
What if it was intravascular in majority?

Most drug is extravascular, so a change in free plasma drug concentration caused
by displacement from plasma protein binding would be minimal
Most drug is intravascular, so a change in free plasma drug concentration caused
by displacement from plasma protein binding would have significant effects


What is distribution?

After absorption a drug is distributed to various body compartments
Distribution is the REVERSIBLE movement of a drug between body compartments.


What factors affect distribution?

Factors that affect distribution from the general circulation to other tissue compartments are:
Capillary permeability
Blood flow
Plasma protein binding


What is the capillary permeability like in the spleen and the liver?

In liver and spleen, the capillaries are very leaky.
Drugs leave the capillaries regardless of whether they are poorly lipid soluble, charged, or polar.
In other tissues, selective capillary permeability varies somewhere between the above two extremes.


how does the blood brain barrier affect distribution? what are the clinical implications of this?

Blood-Brain Barrier
Brain capillaries have tight junctions.
Glucose and amino acids have specific carrier-mediated transport systems
Only lipophilic drugs (like alcohol!!) diffuse across brain capillaries (unless they are actively transported across).
The degree to which drugs penetrate the brain should be known to treat diseases of the nervous system properly.
E.g. the amines dopamine and serotonin penetrate brain tissue to a very limited degree but their corresponding acid precursors, L-dopa (to treat Parkinson’s disease) and 5-hydroxytryptophan, respectively, enter with relative ease.
The blood-brain barrier does not work properly in areas of infection or injury.

Tumors of the brain develop new blood vessels and capillaries that have no tight junctions. Substances such as radioactive iodine-labeled albumin penetrate normal brain tissue very slowly, but they enter tumor tissue, and help in diagnosis.


How does blood flow affect distribution?

Drugs reach the majority of tissues via the general circulation.
The rate at which drugs distribute from the bloodstream into the various tissues, depends on the relative blood flow to the various tissues.
Brain, liver, kidneys > skeletal muscle > fat


What are the body fluid compartments like in terms of volume? What is the adult blood volume about?

Total Body Water (60% of body weight) ~ 42 L
2/3 of TBW in intracellular fluid space ~ 28 L
1/3 of TBW in extracellular fluid space ~ 12 L
1/3 of extracellular fluid is intravascular (i.e., plasma)
Adult blood volume: ~ 5L
When we administer a drug, it distributes into many compartments (lipophilic drugs even distribute out of fluids and concentrate in fat), but we normally measure the drug concentration in the blood.


How do you measure the volume distribution of a drug?

Volume of distribution (Vd) = dose administered/plasma concentration
We normally take plasma samples of a drug to calculate Vd.
Example: Dose administered = 500 mg
If the concentration in the plasma is less (e.g. due to high concentration of a lipid soluble drug in fat stores) the Vd will be very high
Plasma concn. = 1 mg / litre
Vd = 500 / 1 = 500 litres
A high Vd indicates that most of the drug is in the extravascular compartment (e.g. amiodarone)


What if the Vd is low?

If the plasma concentration of a drug is high (e.g. due to high plasma protein binding) its Vd will be low
Plasma concn. 50 mg / litre
Vd = 500 / 50 = 10 litres
A low Vd indicates that most of the drug is in the vascular compartment (e.g bound to plasma proteins, a drug such as warfarin)


What is biotransformation (drug metabolism) of drugs?

Chemical modification of drugs by enzymes, to make them more polar (less lipid soluble), and therefore readily excretable by the kidneys
Drug metabolizing enzymes are present in
The liver
Gastrointestinal wall


What are prodrugs?

Certain drugs do not reach their site of action because of pharmacokinetic obstacles. E.g. A drug can be destroyed by digestive enzymes. Their precursors, known as prodrugs, may be useful in such cases.

Prodrugs are inactive. After metabolism they are converted into an active form
Proton-pump inhibitors – omeprazole, lansoprazole are prodrugs. (Used to reduce stomach acid secretion)
Olsalazine is a prodrug. It is metabolized to the active drug mesalamine (for the treatment of inflammatory bowel disease)


What are the two phases of two-phase biotransformation?

Phase I (functionalization) reactions:
Oxidation, Reduction, and hydrolytic reactions (makes the drug more polar, but not necessarily inactive)

Phase II (conjugation) reactions:
Conjugation to polar groups: glucuronidation, sulfation, acetylation (most of these result in drug inactivation)


What are phase I enzymes?

Microsomal cytochrome P450 monooxygenase family of enzymes which transfer electrons from NADPH to an oxygen molecule and thus oxidize drugs (mostly hydroxylations, and dealkylations).
These enzymes act on structurally unrelated drugs (i.e., not very substrate specific)
They are located in the endoplasmic reticulum of the cell
Require NADPH and O2
Metabolize the widest range of drugs
In most cases these reactions inactivate a drug


What is the nomenclature of cytochrome P450 enzymes?

CYP is first, then CYP1, 2, or 3 is the family. Then CYP1A or CYP1B is the sub-family. Then CYP1A1 or A2 or B1 or B2 is the isogorm (gene number)


Why are CYP enzymes important?

They are responsible for most cases of drug-drug interactions (DDIs)
They undergo mutations and can result in higher or lower than expected plasma concentrations with the standard doses of substrate drugs.

Over 90% of drug oxidation can be attributed to 6 main CYPs.
CYP3A4 is the primary enzyme for metabolism of about half of all drugs and is inhibited or induced by many drugs. This can cause DDIs


With factors affecting drug biotransformation, what is enzyme induction and inhibition?

Enzyme Induction and Inhibition: Drugs (including herbals) and other substances (food items) can stimulate or inhibit the expression of some metabolizing enzymes, especially the cytochrome P450 enzymes.

Induction or inhibition of phase I enzymes (especially Cyt P450 enzymes) can cause drug-drug interactions (DDIs) when two or more drugs that are metabolized by the same enzyme are given


what is meant by induction of enzyme and drug interactions

Cause expression of more CYP enzymes and faster elimination of substrate drugs
Lower than expected drug levels can cause treatment failure
Rifampin (antibiotic)
St. John’s Wort (Herbal antidepressant)


What is meant by inhibitors ?

Inhibit the activity of CYP enzymes and reduce elimination of substrate drugs
Higher than expected drug levels can cause drug toxicity
Grapefruit juice
Cimetidine (stomach acid inhibitor)
Erythromycin (antibiotic)
Itraconazole (antifungal)


What is meant by polymorphism?

genetic variations in the population
Mutations are found in some drug metabolizing enzymes in some people.
The most common P450 polymorphism in Caucasians is of CYP2D6 expression. Approximately 7% to 10% of the Caucasian population and 2% to 5% of Africans lack expression of this enzyme
Codeine is almost ineffective as an analgesic in these patients. It must be metabolized by CYP2D6 to morphine for analgesic effect


What are the phase II reactions?

These are conjugation reactions
In phase II reactions a chemical group such as glucuronic acid, sulfate, glutathione, an amino acid or acetate is added to the drug
The conjugated drug is highly polar and in most cases inactive
The conjugated drug is rapidly excreted
Enzymes for phase II reactions are mostly located in the cell cytosol


What is P-glycoprotein?

P-glycoprotein is an efflux pump. Uses energy (ATP)
It removes compounds from inside to the outside
P-glycoprotein has a broad substrate specificity for drugs - digoxin, quinidine, and others
It is located at many sites (luminal surfaces) –
colon, small intestines
kidney tubules
liver – bile canaliculi
cancer tissue
Mostly on the cell membrane.
Cancer tissue will throw out the drugs so they don’t work.
P-glycoprotein expression is increased (induced) by some drugs - St. John’s Wort, rifampin
It is inhibited by some drugs - verapamil, quinidine, macrolide antibiotics, antifungals etc.

P-glycoprotein in the blood-brain barrier protects the central nervous system (CNS) from a variety of structurally diverse compounds through its efflux mechanisms


What is the clinical significance of P-glycoprotein?

P-glycoprotein plays a role is drug resistance to cancer chemotherapeutic agents. It is over expressed in tumor cells (e.g. in acute myelogenous leukemia) after exposure to anticancer agents, and it pumps out the anticancer drugs
Drugs such as calcium channel blockers, phenothiazines and cyclosporin A inhibit P-glycoprotein and may be useful to reverse resistance


What is enterohepatic recirculation?

A compound is conjugated in the liver, excreted in the bile, deconjugated in the intestine (by intestinal bacterial enzymes) and is reabsorbed into the circulation
This phenomenon prolongs the duration of action (half-life) of a drug


What is the therapeutic significance of enterohepatic recylcing?

Therapeutic significance:
Bile acids are conjugated in the liver to taurine and glycine and excreted in the intestine where they are deconjugated. 95% of bile salts are reabsorbed and are used in cholesterol synthesis.

If we give a bile acid binding resin such as cholestyramine, we interrupt the enterohepatic recycling of bile salts and reduce cholesterol synthesis and plasma levels

The liver needs cholesterol and so if cholesterol isn’t reabsorbed then the liver tries to get it from other sources.