General Pharmacology-2 for USMLE1

Pharmacokinetics is the study of what the body does to a drug.

·         Absorption

·         Bioavailability

·         Distribution

·         Metabolism

·         Excretion.

Drug pharmacokinetics determines the onset, duration, and intensity of a drug's effect.

Absortion:

·         Concerns the processes of entry of a drug into the systemic circulation from the site of its administration.

·         The determinants of absorption are those described for drug permeation (Solubility, Concentration gradient, Surface area and vascularity)

• Intravascular administration (e.g. IV) does not involve absorption, and there is no loss of drug.

For drug absorption:

·         Acidic drugs absorb in Acidic media

·         Basic drugs absorb in basic media

Bioavailability:

Is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route

Bioequivalence:

For Bioequivalence to occur between two formulations of the same compound, they must have the same bioavailability and the same rate of absorption.

Bioequivalence is a term used when comparing brand name and generic drugs

With oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. Drugs administered I.V enters directly into the Systemic circulation. But drugs administered PO are 1^st exposed to liver through portal circulation and may be extensively metabolized before reaching the rest of the body (syst. circulation).

For some drugs , their rapid hepatic metabolism decreases bio-availability – the “First-Pass” effect. Example: Propranolol, Lidocaine.

 

·         The processes of distribution of a drug from the systemic circulation to organs and tissues involve its permeation through membrane barriers and are dependant on its

·         Solubility

·         the rate of blood flow to the tissues

·         binding of drug molecules to plasma proteins.

Plasma Protein binding

·         Many drugs bind to plasma proteins, including albumin, with an equilibrium between bound and free molecules

·         recall that only unbound drugs cross bio-membranes

·         Drug + Protein = Drug-Protein complex

·         Competition between drugs for plasma protein binding sites may increase the “free fraction”, possibly enhancing the effects of the drug displaced (NSAID, OHA, Warfarin, Sulfonamide)

• Special barriers to distribution

·         Placental : most small molecular weight drugs cross the placental barrier, although fetal blood levels are usually lower than maternal.

·         Blood-Brain: permeable only to lipid-soluble drugs or those of very low molecular weight.

• Volume of distribution : Is a volume of fluid into which the drug is disseminated. Two types:
• Physical VD (plasma, ECF, interstitial space)
•  Apparent VD: A kinetic parameter of a drug that correlates dose with resultant plasma levels.

·         Vd = D/C =  Total amount of drug in the body 

                                     plasma conc of drug      

·         The higher the volume of distribution, the lower the plasma concentration and vice versa.

·         Vd is low when a high percentage of a drug bound to plasma proteins.

Redistribution

·         In addition to crossing the blood-brain barrier(BBB), lipid-soluble drugs redistribute into fat tissues prior to elimination.

·         In the case of CNS drugs, the duration of action of an initial dose may depend on the redistribution rate than on the half-life.

·         With repeated doses, fat and other tissue depots become saturated ,resulting in longer durations of action than the first dose.

• The general principle of biotransformation is the metabolic conversion of drug molecules to more water-soluble metabolites that are more readily excreted.
• In many cases, metabolism of a drug results in its conversion to compounds that have little or no pharmacologic activity.
• In such cases, biotransformation rate can be a primary factor in determining the duration of drug action.

A few compounds (pro-drugs) have no activity until they undergo metabolic activation.

Phase I : modification of the drug molecule via oxidation, reduction and hydrolytic reactions. Involves cytochrome p450 enzyme system.

Phase II : conjugation with endogenous compounds via the activity of transferases – a prerequisite is the presence of a reactive group (-OH,-NH2, acetate) on the molecule.

Phase I: Hydrolysis

·         Phase I reactions involving addition of a water molecule with subsequent bond breakage.

·         Include esterases and amidases.

Oxidations:

Non-microsomal Oxidations

Microsomal oxidation: Most common, requires CYP

·         Non-microsomal Oxidations

Include monoamine oxidases that metabolize both endogenous amines (e.g. dopamine, seratonin) and exogenous compounds(e.g. tyramine).

Alcohols are metabolized by alcohol dehydrogenase(ADH) to aldehydes, which are then substrates for aldehyde dehydrogenase, which can be inhibited by disulfuram.

Phase II:

Conjugation

·         Conjugated drugs are usually inactive but occasionally activate some drugs (morphine, minoxidil).

·         If metabolite from phase 1 is sufficiently polar/ionized it can be excreted by kidney. But many metablolites are too lipophilic to be retained by kidney tubules.

So subsequent conjugation reaction with endogenous substrate e.g. Glucoronic acid, Sulfuric Acid, Amino Acid, Glutathione, Acetate results in polar/more water soluble compounds that are therapeutically inactive

Types of conjugation

·         Glucuronidation : addition of glucoronide group

·         Inducible

·         Conjugates may undergo enterohepatic cycling.

·         Reduced activity in neonates (Grey Baby Syndrome)

·         Acetylation: addition of acetate group

·         Genotypic variations present

·         Some people are fast acetylators but some are slow.

·         hydralazine, procainamide, isonicotinic acid hydrazide (INH) (treatment for TB and need to take for 6 months)

·         Sulfation : addition of sulphate group

E.g. minoxidil, steroids

Glutathione( GSH)conjugation: depletion of GSH in the liver is associated with acetaminophen (Tylenol) toxicity.