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N165- Introduction to Pharmacology- Phamacokinetics
Terms in this set (47)
The study of drug movement throughout the body
means related to intestines
so enteric coating on a capsule means its supposed to dissolve in the small intestine
parenteral means by mouth enteral means straight to intestines - for feeding and meds ---ENTERAL FEEDING MEANS TUBE OR MOUTH - ANYTHING WHERE IT GOES THROUGH THE INTESTINES - IV IS NOT ENTERAL
4 Basic Processes
(Elimination is Metabolism + Excretion)
Drugs have to cross biological membranes in order to:
1. Be absorbed from the site of administration into the blood
2. Move from the blood to the site of action
3. Be metabolized
4. Leave the body by excretion
Cell membrane (small amount of info)
1. Phospholipid bilayer
2. embedded with proteins
3. embedded with cholesterol
4. sugars on the outside
Three methods for a drug to pass through the membrane
1. Through channels/pores
2. Via transporter systems
3. Direct penetration
Method 1: Channels and Pores
- Very few drugs move through channels and powers
- This is because channels/pores are very small
-Channels/pores are specific for particular molecules (Na+, K+)
Method 2: Transporters
-Proteins that move molecules form one side of the cell membrane to the other
- Transport specific biological molecules; are selective and will only transport certain drugs
- Can also transport drugs to sites of action or sites of metabolism and excretion
-They can also transport drugs and drug metabolites. Transporters can therefore impact all facets of pharmacology and drug action.
-Different organs and tissues will have different types of transporters
- P-Glycoproteins pump drugs OUT of cells (efflux pump)
- ATP-dependent process
-Can be a source of drug-drug-interactions if a drug inhibits it and therefore increases absorption at site - SO A DRUG CAN INHIBIT THE REMOVAL OF ANOTHER DRUG
Examples: in liver, to bile. In kidney, to urine. In placenta, back to maternal bloodstream. In intestine, to intestinal lumen. In brain, transports to blood. In cancer cells, pumps antineoplastic drugs out of cell (problematic)
Method 3: Direct Cell Membrane Penetration
- Most drugs cross membranes by direct penetration
-Requires lipid solubility (lipophilicity)
No membrane penetration or very poor membrane penetration
1. Polar molecules - uneven distribution of charge, but no net charge
2. Ions - net electrical charge (positive or negative)
- Quaternary ammonium compounds - positive charge
- Weak acids or bases when ionized (ie charged)
- Weak acids - charged (ionized) at higher pH
- Weak bases - charged (ionized) at lower pH
Example: Unionized aspirin can cross membranes, but when ionized it cannot. In the stomach where the pH is acidic, so ASA (aspirin) is unionized and can cross membrane. Once in the plasma ASA becomes ionized and is "trapped". Unionized ASA continues to move across until concentrations of unionized ASA become equal.
Defined as: The movement of a drug from the site of its administration into the bloodstream.
Factors affecting Absorption
1. Drug dissolution
- drug has to dissolve before it can be absorbed; rate of
dissolution helps determine rate of absorption
2. Absorptive surface area
- microvilli of small intestine provides greater surface area than
3. Blood flow at absorptive site
- higher absorption when blood flow is higher
4. Membrane penetration of the drug
- lipophilic drugs are absorbed more quickly than polar drugs
The extent to which the administered drug becomes available in the general circulation
Barriers to absorption
1. Epithelial tight junctions in the GI tract (enteral)
- Epithelium has tight junctions, so drugs must pass through the cells. Transporters can aid movement from lumen to blood but can also work to reduce absorption by returning drug back into the gut lumen (as is the case with P-Glycoproteins).
2. Capillary Wall (IM/SC, enteral)
- Due to gaps between capillary endothelial cells, polar, ionized and lipid-soluble drugs can all pass between these gaps, in and out of bloodstream.
- But only lipid-soluble drugs can also pass directly through the cells of the capillary wall
Enteral: PO Advantages and Disadvantages
Advantages: Convenient, relatively low risk and inexpensive
Disadvantages: Variable absorption, limited bioavailability, NPO patients, dysphagia (difficulty swallowing), decreased level of consciousness
Parenteral: IV Advantages and Disadvantages
Advantages: rapid onset, dilute, controlled blood levels of drug, can be used for irritants
Disadvantages: discomfort, costly inconvenient, irreversible, infection risk, embolism risk, tissue injury risk, fluid overload risk ----- Nonparenteral is oral meds (pills, capsules, syrups, etc.), topical meds (ointments, patches like nitro), suppositories (vaginal and rectal), etc. Pareneteral is anything injected into the body: intradermal, subcutaneous, intramuscular, intracardiac, and intravennous, etc.
Parenteral: SC/SubQ Advantages and Disadvantages
Advantages: can be used for poorly soluble drugs
Disadvantages: discomfort, inconvenient, risk of injury
Parenteral: IM (intramuscular)Advantages and Disadvantages
Advantages: can be used for poorly soluble drugs and depot drugs (preparation from which the drug is absorbed slowly over an extended period of time)
Disadvantages: painful, inconvenient, risk of tissue injury, risk of nerve damage
Defined as: Movement of a drug (following absorption) from the blood stream to other body tissues. How does the drug get where it needs to go?
Factors affecting Distribution
3 main factors affect distribution:
1. Blood flow to tissues
-Not usually a major factor, but
- Certain tissues, such as external ear
2. Ability of drug to exit the vasculature
-Plasma protein binding
-Tissue permeability: brain, placenta
3. Ability of drug to enter cells - if the drug's site of action is
- Degree of ionization
- Transporter proteins
Exit from vasculature
Exit from the vasculature via capillaries typically meets no resistance except for specialized capillary beds like the Blood Brain Barrier (BBB) where tight junction between the endothelial cells limit drug access. Lipid soluble drugs or drugs with specific transport systems can cross the BBB.
Blood-Brain Barrier Distribution: Exit from vasculature
- Tight junctions in brain capillaries -> Prevent drugs from passing btwn cells to exit vasculature -> Drugs must pass directly through cells of capillary wall.
- Lipid-soluble/lipophilic drugs
-Drugs that can use an existing transport system present in brain.
-Brain also has P-glycoproteins
-BBB makes delivery of drugs to brain more challenging.
Placenta Distribution: Exit from vasculature
- To enter the fetal circulation, drugs must cross membranes of the maternal AND fetal vascular systems
- Placenta has P-glycoproteins
-However, placenta does not constitute an absolute barrier to passage of drugs.
-EtOH and other lipid-soluble/lipophilic drugs cross through
membranes and enter fetal circulation
- Ions, polar molecules, protein-bound drugs largely prevented
from reaching the fetal circulation
Plasma protein binding Distribution: Exit from vasculature
-Many drugs reversibly bind to albumin.
-Only free (UNbound) drugs can leave the vasculature - albumin is
too large to leave. Only free (UNbound) drug can exert
-May be affected by comorbidities.
-Catabolic states / cachexia
-Some drugs are highly-protein bound, with bound fractions
exceeding 90%. Example: warfarin
-Competition for albumin binding: Source of drug interactions
- Defined as: Transformation of a drug's chemical structure by enzymatic reaction. Also known as biotransformation.
- Product of metabolism is a metabolite of the parent drug
-Most often occurs in liver but can also occur in small intestine, lung, kidney, skin, placenta, plasma
-One major effect of metabolism: drug becomes more polar/water soluble-> increased excretion, particularly via renal route.
-from lipophilic to hydrophilic---
DRUGS HAVE TO:be absorbed from the site of administration into the blood
move from the blood to the site of action
leave the body by excretion
Metabolism: Hepatic Drug-Metabolizing Enzymes
1. Phase I Reactions
-Usually make the drug more polar by introducing (or
uncovering) a functional group (-OH, -NH2, -SH)
- MAIN ENZYME FAMILY: CYP (CYP3A4, CYP2D6)
2. Phase II Reactions
- Combine an endogenous substrate (glucuronic acid, acetic
acid, amino acid) with the drug's functional group to form a
more polar conjugate
- MAIN ENZYME FAMILY UGT
- Not all drugs undergo both Phase I and Phase II, and some drugs undergo neither reaction and are eliminated unchanged.
Chemical product of metabolism
-usually inactive, has no clinical effect
-metabolites are sometimes toxic and can be dangerous if they
- but MAY be active; has a clinical effect and 2 possibilities:
1. Parent drug and metabolite are active
2. Parent drug is inactive, metabolite is active
#2 means parent is a prodrug
Procaine: local anesthetic; PABA is inactive.
Codeine is markedly less effective in pain relief than morphine.
Prazepam has no clinical effect but is activated to desmethyldiazepam, an anxiolytic.
Acetominophen is can be transformed to a toxic intermediate in the liver.
- Pharmacologically inactive in their administered form.
- Converted to their active form by metabolism, once they are
-Conversion to prodrug often, but not always, occurs in the liver.
CYP fun facts
1. CYP interactions are a MAJOR cause of drug-drug interactions.
2. Some drugs may inhibit CYP enzymes that metabolize a second drug. Any drug that requires a particular CYP enzyme is called a "substrate" for that enzyme.
-Inhibition usually involves 2 drugs that require the same CYP
enzyme for their metabolism. They may compete for binding
sites, and one drug may be the "winner".
3. Other drugs may induce CYP enzymes that metabolize a second drug.
- Induction = the drug stimulates the production of more of that
enzyme, increasing the enzyme's metabolizing capacity.
4. A drug-food interaction that is well-known concerns grapefruit juice, which is an inhibitor of CYP3A4. Patient teaching point!
Metabolism: First-Pass Effect
Defined as: Removal of a substantial amount of an enterally administered drug dose prior to the drug reaching the systemic circulation
Has a major effect on bioavailability
Special Considerations in Drug Metabolism
1. Age- Both infants and older adults have decreased ability to metabolize drugs
2. Nutritional Status- Hepatic metabolizing enzymes require certain co-factors to function. Malnutrition can cause these co-factors to be deficient.
3. Comorbidities- Some drugs may require dose reduction in severe liver disease
Defined as: the removal of drugs and their metabolites from the body
Metabolism + Excretion = Elimination
Kidney is the major organ of excretion for most drugs
Metabolized drug can exit the body through urine, bile feces, sweat, saliva, breast milk, or expired air (mainly inspired anesthet
Factors that modify renal drug excretion
1. pH-dependent ionization
Drugs that are ionized at urinary pH will stay in the urine (not be reabsorbed) and be eliminated more quickly.
2. Competition for active tubular transport
If 2 drugs use the same transporter to move from plasma to the renal tubules, less of them will be transported to the tubules at any given moment, delaying excretion of both
Infant kidneys reach full capacity a few months after birth
Older adults may have decreased glomerular filtration rates, decreasing drug excretion
Renal Routes of Drug Excretion
Urinary excretion is net result of 3 processes:
1. Glomerular filtration: drugs not bound to protein move from blood to urine.
2. Passive reabsorption: Lipid-soluble drugs move back into the blood. Polar and ionized drugs stay in the urine.
3. Active transport (requires ATP):
- Drugs are pumped from blood to urine via system that also pumps organic acids and bases from blood to urine.
- P-glycoproteins are also present in the tubules and may pump drugs into the urine.
Hepatic Routes of Excretion
Metabolites may leave the liver via:
1. Blood, which will take them to the kidneys for elimination.
2. Bile, which will take them into the gut and out of the body via feces. This is known as hepato-biliary excretion. (Some drugs excreted into bile will recirculate repeatedly via enterohepatic circulation before their eventual excretion).
Time Course of Drug Responses
1. Plasma drug levels
2. Drug half-life
3. Steady-state drug levels
Time Course of Drug Responses: Plasma Drug Levels
- Plasma drug levels are the end result of pharmacokinetic processes: absorption, metabolism, elimination.
*remember that although distribution is not mentioned, the
plasma is not the site of action- cells, tissues are the sites of
action. The drug must get to where it needs to be, in sufficient
concentration, in order to have the desired therapeutic effect.
However, for most drugs there is a direct correlation between
plasma concentration and the therapeutic/toxic effects*
Plasma Drug Levels: Minimum Effective Concentration
The plasma drug level below which therapeutic effects will NOT occur
Plasma Drug Levels: Toxic Concentration
Plasma drug level at or above which toxic effects will occur
Plasma Drug Levels: Therapeutic Range or Window
The range of drug levels between the Minimum Effective Concentration and the Toxic Concentration
- the "safe" range
-can vary from person to person
-ideally, would like this range to be wide
-drugs with narrow therapeutic ranges require VERY careful dosing
Time Course of Drug Responses: Drug Half-Life
Defined as: Time for serum drug concentration to decrease by 50%.
Each half-life decreases the concentration of drug in the blood by half.
Half-life is usually measured in hours, but some drugs have half-lives of minutes or even seconds, while others have half-lives of days.
shorthand for half-life is t1/2
Considerations in half-lives
If metabolism and/or excretion is compromised, the t1/2 can be markedly changed. t1/2 can also be changed by drugs competing for the same metabolism or excretion systems.
Time Course of Drug Responses: Steady-state drug levels
- Steady state: when the amount of drug administered (in a given
time period) = the amount of drug eliminated in the same
-Can be thought of as reaching a plateau in average drug levels.
-At steady state, the average plasma concentration of the drug during any dosing interval are similar. Peak and trough concentrations are also similar.
-The time to reach steady-state concentrations is dependent on
the half-life of the drug under consideration. (typically 4-5 half-lives regardless of the dose)
-for a single drug, the time to reach steady state is independent of dose
- so what varies between different drugs is the amount of time (hours, days, etc.) for steady-state to be achieved (b/c they have different half lives)
Time after administration until the drug begins to have a clinical effect
time after administration at which the drug is having its maximal effect
length of time the drug has a clinical effect
-important, along with half-life, for determining dosing interval
- also important for tapering or withdrawal considerations
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