General Pharmacology Principles Flashcards
What does ADME stand for and give a breif description of each letter.
A- absorption- from the site of administration to systemic ciruculation (defined as major vessels adn well perfused organs)
Most often from GI tract (orally administered drugs must pass through the liver before reaching systemic circulation)
D- distribution- of the drug from systemic ciruclation to tissues (target and non-target) and back again
Drug not bound to plasma proteins (free drug) is disstributed into tissues - where it is either bound to tissues or back to circulation
Blood and lymph-pigott
M- metabolism -elimination of the drug from the body via metabolism
Hepatic metabolism
E- excretion -elimination of the drug from the body via excretion
Renal or biliary exretion of drug or its metabolites. Excreted drugs can be passively reabsorbed by kidneys following enterohepatic circulation (bile)
- these movements are dynamic, occuring simaltaneously
- net effect determines PDC at any time during the dosing interval (following adminstration of a fixed dose)
Boothe pg 2 ,5
Define Pharmacokinetics
1 : the study of the bodily absorption, distribution, metabolism, and excretion of drugs
2 : the characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism, and excretion
Merriam-Webster Dictionary
Describe the Plasma Drug Concentration Vs Time Curve
- movement of drug through the body are characterized by plotting drug concentrations measured after adminstration of a known dose against timeon semilogarithmic paper.
- Fig 1-3 (A and B)
Boothe pg 3,4,6,7
Discuss oral absorption
- Orally adminnistered drugs reach systemic circulation after absorption from the SI
- rate and extent of drug absorption from GIT depends on many factors (which often passive diffusion):
- GI pH (which favors absorption of weak acids)
- Surface area (which favors absorption in the SI >stomach)
- Motility (which favors mixing drugs thus increasing concentration of diffusable drug)
- Permeability and thickness of mucusal epithelium
- intesitnal blood flow (which maintains the concentration gradient across teh mucosal epithelium- most improtant for drugs with rapid transfer)
Bioavailability
Boothe
Define bioavailability and discuss
- The percentage of an administered dose that reaches systemic circulation = bioavailability
- Determined by measuring the area under a PDC vs time curve (AUC) after non-IV adminstration and comparing this number with the AUC after IV adminstration of the same dose.
- if the AUC is the same for both then bioavailability is 100%
- Bioavailability is used to predict efficacy of different routes of administration (or different forumlations)
- Factors which effect absorption also effect bioavailability
- Bioavailability is also decreased if the drug is metabolized by: intestinal cells, microbes or liver
- Hepatic metabolism can have a profound effect on bioavailability and PDC (first pass metabolism)- so you can have great absorption and poor bioavailabitlity (so administer the drug by a route other than PO to account for high first pass metabolism)
Boothe
Explain first-pass metabolism
- Occurs as drug absorbed from the GIT (stomach to lower colon) enters the portal vein and flows to liver, drug is then characterized by high extractin are remomved rapidly from the blood before entering systemic circulation
- plasma concentrations of the drug may not reach therapeutic concentrations unless dose is increased to account for first pass metabolism.
- Hepatic metabolism can have a profound effect on bioavailability and PDC (first pass metabolism)- so you can have great absorption and poor bioavailabitlity (so administer the drug by a route other than PO to account for high first pass metabolism)
- The amount removed by the liver vareis with species and age and disease status
Boothe
Define and discuss drug distribution
- Distribution from the central (blood) compartment to peripheral tissues, major factords which determine distribution include:
- Lipid solubility (ability to penetrate cell membrane)
- Plasma or tissue bound (degree to which it is)
- Regional (organ) blood flow
Vd= volume of distribution= the amount of tissue to which a drug is distrubuted. It directly influences PDC
Boothe
Define bioequivalence and mean absorption time (MAT)
-“a drug whose rate of absorption is slower maybe completely absorbed, but the PDC may not reach smae magitude or peak as another preparation or route because the absorption occurs very slowly (absorption rate constant Ka)”
MAT- likely to be the parameter reported for assessing drug absorption from the site of adminsitration
Boothe
Define Volume of Distrubution and what give example of what causes it to increase or decrease?
Vd= volume of distribution= the amount of tissue to which a drug is distrubuted. It directly influences PDC
- Maximal PDC is determined after distribution equilibrium and before excretion
- Reported in L/kg
- Increased by: disease associated with fluid retention or obesity
- Decreased by: dehydration or weight loss
Boothe
Discuss protein binding in relation to drug distribution?
- Plasma protein binding renders a drug more water soluable, thus facilitating its movement in circulation, however it cannot be distrubuted from the plasma into tissues (or tissues back to plasma).
- Protein bound drugs are:
- not pharacologically active
- cannot be renally excreted
- re more slow to metabolize by the liver
- Displacement from plasma proteins also increased Vd because the drug is more likely to enter tissues when freed
- Weakly acidic drugs thend to bind to albumin whereas weakly basic drugs tent to bind to alpha1-glycoproteins
- Displacement of drug from protein binding sites become significant only if the drug is greater than 80% protein bound.
- Hightly protein bound drugs do not distribute into tissues, but remain in systemic circulation (the Vd of the unbound portion of drug can be very high)
Boothe
Discuss drug distribution with respect to water vs lipid soluable drugs
- Water-soluable drugs tend to be distrubuted to ECF with Vd 0.1-0.3L/kg
- Lipid-soluable drugs tend to be distrubuted to ECF and ICF, b/c they cross cell membranes with large Vd >0.6L/kg
- Regardless of soluability, drugs not bound to plasma proteins are able to pass unimpeded through fenestrated capillaries into ECF
Boothe
The capillaries of which oragans are not fenestrated, thus requring drug to pass through the capillary endothelium in order to penetrate the target tissue?
- brain
- CSF
- Eye
- testis
- prostate
-lipid-soluabe drugs are more likely to penetrate the endothelial barrier
Boothe
Drug excretion is a combination of what factors?
Elimation by hepatic metabolism
Renal excretion
or both
Boothe
Discuss phase I metabolism
- chemically changes drug so that it is (usually) more water soluable and more susceptably to phase II metabolism
- recations include: oxidation/hydrolysis/reduction
- Performed by enzymes referred to as cytochrome P450 enzymes
- Phase I metabolites are usually inactive, but can be equally, more or less active or toxic than parent coupound
Boothe
What are cytochrome P450 enzymes?
- Enzymes responsible for the majority of phase 1 metabolism
- large superfamily
- found other places than the liver (lungs, skin, kidney)
Boothe
Discuss phase II metabolism
- AKA conjucation, occurs when large water-soluable molecule is chemically added to parent or metabolite
- Glucuronidation most common reaction (sulfonaton and acetylation less common)
- with rare exceptions phase II metabolites are inactive
- most metabolites are eliminated through the urine
Boothe
Summary of hepatic metabolism and elimination (Fig 1-8)
fig 1-8 boothe
Discuss renal elimination of drugs
- renal elimination is most improtant/common route of drug elimination (>biliary)
- rate of renal excretion:
- active tubular secretion in proximal tubule is a rapid process and no limited by protein binding (depends on RBF, drug pKa)
- Glomerular filtration is passive process, protein bound drugs cannot be filtered (depends on RBF, protein binding, MW)
- Un-ionized drugs that are sufficiently lipid soluable maybe passively resorbed (depends on drug concentration, MW, lipid soluability, drug pKa, urine pH). Reabsorption slows renal excretion.
-kidney also capable of metabolizing
Boothe
Discuss biliary exretion of drugs
- very slow and clinically less improtant
- characteristics which determine biliary excretion”
- chemical structure
- polarity
- MW *major determinant
- more contact with GI and flora and more likely to cause adverse GI SE
- enterohepatic circulation
Boothe
Describe enterohepatic circulation
- enterohepatic circulation can prolong the elimination half-life of a drug
- After oral or parenteral administration, drug is conjucated in the liver and eliminated in the bile. -Drug travels the duodenum to the lower SI/colon. -Bacterial degredation results in deconjugation of the drug which can then be re-absorbed.
Boothe
How are drugs concentrated in the urinary system?
- Urinaryy pH can be therapeutically altered to change excretion rate of drug (weakly acidic drugs are more likely to be reabsorbed in acidic urine, but are trapped and excreted in alkaline urine)
- Also drugs that are renally excreted can concentrate up to 300-fold in the urinary bladder (not kidney) compared to the plasma concentrations (ex-amoxicillin)
- Also can use other drugs (ex probenecid) to compete with drugs during the active transport phase of excretion to inhibit their excretion (ex imipenem) to prolong theraputic PDC
Discuss drug elimination
- rate of drug elimination (kel - is the slope frome the PDC vs time curve) describes the fraction of drug in the body irreversibly eliminated per unit time (time -1)
Boothe
How does age (pediactric) affect ADME?
Table 2-14 Boothe
Theraputic Window Chart
Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients.
Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC). The levels of drug should always be between MEC and MTC in order to provide risk free therapeutic effects. If any drug crosses MTC then it will surely elicit toxic effects and if drug is unable to surpass MEC then it will cause therapeutic failure. MEC is also called as minimum inhibitory concentration (MIC).
Medimoon
Theraputic index chart
Therapeutic index (TI) describes a relationship between the doses of a drug that causes lethal or toxic effects with the dose that causes therapeutic effects. It is also called as therapeutic ratio.
Mathematically you can calculate TI by following way;
Therapeutic Index: LD50/ED50
or
Therapeutic Index: TD50/ED50
Where
LD50 is the minimum amount of drug that causes adverse effects in 50% of the population. LD50 could also be replaced with Toxic dose (TD50)
ED50 is the quantity of a drug that can produce desired therapeutic effects in 50% of the population. Such types of studies are usually conducted in animal models
Ideally any drug that requires more amount to produce toxic or adverse effects in 50% of population will have wider therapeutic index and vice versa. Drugs having wider therapeutic index are safer in comparison to those having low therapeutic index because minor modification in the dose of such drugs (aspirin, acetaminophen) will not produce toxic effects.
Medimoon
Hypothetical dose response curve (chart) and example dose response cureves (charts)
