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Pharmacology Quiz One: Chapter 1-3
Terms in this set (84)
What the body does to the drug
what the drug does to the body
movement of drug into the blood stream
- passive diffusion- Fick's Law
movement of drug into the tissues and organs
1. Tissue perfusion
2. Plasma protein binding
3. Molecular size
4. Lipid solubility
biotransformation of the drug
- enzyme - catalyzed conversion of drugs to metabolites some metabolites are active.
- role to inactivate and detoxify drugs,
- prodrug inactive compounds metabolized to active compounds
- first pass bioavailability - conversion to inactive metabolites during their first pass through the gut.
removal of the drug
The rate of absorption is proportional to the drug concentration gradient across the barrier and the surface area available for absorption at that site.
occurs by passage through aqueous pores in cell membranes, restricted to drugs with LMW.
Henderson Hasselbach Equation
- only non-ionized form of drugs are soluble in lipid membranes
- the protonated form of a weak acid is non-ionized, whereas the protonated form of a weak base is ionized.
- the ratio of the protonated form to the nonprotonated form of these drugs can be calculated using the equation.
- the pKa is the negative log of the ionization constant particular for each or basic drug
-at a pKa equal to the pH equal amounts of the pro and non pro forms are present
- if the pH is less than the pKa, the protonated form predominates and visa versa.
Weak acids are more readily absorbed in the
stomach ( stomach has a pH of 1) than weak bases.
Weak bases are absorbed more readily in the
intestines than from the stomach, however weak acids are also more readily absorbed in the intestine then in the stomach strictly because there is more surface area in the intestine.
- the process where drugs accumulate on the side of the membrane where the pH most favors its ionization, this restricts diffusion out of a cell and results in a large Vd.
- pH dependent ionization: acids tend to ionize in base and visa versa
-pH partitioning, acidic drugs will accumulate on the alkaline side and basic drugs will accumulate on the acidic side
protein of the cell membrane that pumps foreign substances out of the cell.
Drug Biotransformation can be divided into two phases
Phase I Biotransformation:
1. oxidative - most common, microsomal cytochrome P450 (CYP) monooxygenase system, CYP3A catalyzes more then half, enzyme inducers, enzyme inhibitors cause drug interactions, watch for MAOI inhibitors.
3. reductive reactions- less common, i.e. nitroglycerin
Phase II Biotransformation
- Conjugation reactions - use endogenous substances in the liver to form water soluble metabolites that are usually inactive
- glucoronide formation - most common, uses glucoronosyltransferases.
- acetylation, uses n-acetyltransferase enzymes
-sulfation - sulfotransferases.
1. slow acetylators - cause drug accumulation due to lower rates of biotransformation, drugs that may cause toxicity in these populations are sulfonamide abx, procainamide and hydralazine.
2. fast acetylators cause rapid drug metabolism.
3. Variations in CYP2D6 and CYP2C19 - 10 % of the pop are poor metabolizers, higher ADR rates esp psych pts, reduced pain relief from codeine
4. Atypical cholinterase - inability to metabolize succinylcholine
- primarily in the urine also the bile, sweat, saliva, tears, feces, breast milk and exhaled air
- glomerular filtration - free drug enters renal tubule as a dissolves solute, if it is largely bound to plasma proteins it will have a low glomerular filtration because it is too large.
- active tubular secretion - transport mechanism in the proximal tubules which can be competitively inhibited; NOT affected by protein binding.
- passive tubular reabsorption - ionized weak acids and bases are not reabsorbed across renal tubular cells and are better excreted in the urine than are non-ionized drugs that undergo passive reabsorption ( change pH), extent depends on lipid solubility.
One Compartment Model
drug undergoes absorption into the blood at a rate constant Ka and elimination at a constant Ke
drugs are absorbed into the central compartment distributed to the peripheral compartment ( tissues) and eliminated from the central compartment.
Drug concentration equals
drug plasma concentration curve
-drug plasma concentration over time
- area under the curve is the total amount of the drug during the time course.
the fraction of the administered dose of a drug that reaches the systemic circulation in active form. ( IV drugs have 100% bioavailability)
Volume of distribution
the volume of fluid in which a drug would need to be dissolved to have the same concentration as it does in plasma, obese patient's have a larger Vd and they need higher doses.
- Ascites, burns and pregnancy will require you to adjust the volume of distribution
-calculation- IV dose divided by the plasma drug concentration immediately after the distribution phase
the volume of body fluid from which a drug is removed per unit of time
- renal clearance is the renal excretion rate divided by the plasma drug concentration
- drugs eliminated by glomerular filtration will have a renal clearance close to the creatinine clearance
- renal drug clearance that is higher is indicates tubular secretion
- renal drug clearance that is lower suggests highly PPB or passive reabsorption in the renal tubules.
First order kinetics
- rate of drug elimination is proportional to the plasma drug concentration multiplied by the drug clearance.
- plasma concentration can be determined by the dose of a drug and its clearance, therefore it is possible to adjust drug doses to achieve a desired effect.
Elimination half life
time required to reduce the plasma drug concentration by 50%
- can also be expressed in terms of the drug's clearance and volume of distribution, indicating that the drug's half life will change when either of these factors are altered.
Zero order kinetics
the rate of drug elimination is constant, the drug's elimination half life is proportional to the plasma drug concentration; the clearance is inversely proportional to the drug concentration
Steady State Equilibrium
the rate of drug administration equals the rate of drug elimination
- takes about five half lives
-dose per unit of time divided by the clearance
a single or divided dose given to rapidly establish a therapeutic plasma drug concentration.
- multiplying the volume of distribution by the desired plasma drug concentration.
The Big Three ( to consider when prescribing a drug )
Is it effective?
Is it safe?
Is it selective?
Additional things to consider when prescribing
1. reversible actions
3. ease of administration
4. freedom from interactions
5. low cost
Syrup is ________ based
Elixir is _______ based
When you prescribe drugs that can cause toxicity you must ...
follow up with the patient.
what the body does to the drug
what the drug does to the body
Tablets and capsules
can be immediate or long acting, for oral use although some are used vaginally, must dissolve in GI fluids, may have enteric coating to prevent dissolution in the stomach
Solutions and suspensions
can be made for oral, topical or parenteral form
used for potent drugs that are lipid soluble, must rotates site, tell the patient to remove the patch when done.
used for inhalation to prevent systemic side effects, considered topical use
ointment, cream, lotion or suppository
drug is incorporated into a vehicle that enables contact for a sufficient amount of time, used to prevent systemic side effects or if oral use is not possible
-drug is absorbed through the GI tract,
- sublingual, oral and rectal routes,
-goes through first pass metabolism ( except sublingual and very little in rectal)
- most convenient and economical route
- drug absorption varies
- patient must be awake and alert
-administered by needle
- intravenous route: bypasses the absorption stage, has greatest reliability and control over the dose, most dangerous.
- intramuscular and subcutaneous route: can be solutions or suspensions last longer, drugs are absorbed more rapidly IM then SC because of increased blood supply to the muscle.
drug is injected into the spinal cord, used to administer drugs that do not cross the blood brain barrier
used during L and D
bypasses first pass metabolism, can release drug for 1-7 days ( date the patch)
- the study of the detailed mechanism of action by which drugs produce their pharmacological effects
( WHAT THE DRUG DOES TO THE BODY!)
- starts at the binding of the drug to it's target receptor enzyme, contd thru a signal transduction pathway ( receptor activates 2nd messenger molecules and ends with the ultimate description of intracellular processes altered by the impact of the drug.
Drugs produce their effects by...
interacting with specific cell molecules called receptors.
( by far most ligands bind to protein molecules, although some agents act directly on DNA or membrane lipids.)
The largest family of receptors for pharmaceutical agents is ...
- G- protein coupled receptors!
G- protein coupled receptors
- largest family of receptors for pharm agents
- consist of four extracellular, seven transmembrane, and four intracellular domains.
- extracellular domains and to some extent transmembrane regions determine ligand binding and selectivity.
a ligand that binds to the same active, catalytic site as the endogenous substrate.
Non competitive inhibitors
Ligands that bind to a different site on the enzyme and alter the shape of the molecule, thereby reducing its catalytic activity are called non competitive inhibitors.
Drugs can bind at the SAME site as an endogenous ligand called ...
Drugs can bind at a DIFFERENT site as an endogenous ligand called ...
-target neuro transporter proteins
( also inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an increase in neurotransmission)
steroid hormone receptors
- intracellular proteins that translocate to the nucleus on the ligand.
- in the nucleus the steroid receptor receptor complex ALTERS THE TRANSCRIPTION RATE OF SPECIFIC GENES
( DNA is also a receptor site for ligands that bind directly to nucleic acids, most notably the antineoplastic agents)
Drug receptors are classified according to their
1. Drug specificity
2. Tissue location
3. Primary amino acid sequences
- receptor like proteins predicted from the human genome for which an endogenous ligand is not identified
( most research takes place on these receptors)
In MOST cases receptor binding is through
( type of bonds )
weak bonds ( hydrogen, ionic or hydrophobic)
- these weak bonds are reversible and enable the drug to dissociate when tissue concentration of the drug declines.
strong covalent bonds are formed with receptors in ...
antineoplastic drugs that bind to DNA and with drugs that irreversibly inhibit the enzyme cholinterase.
- also seen in aspirin ( ASA)
Receptor affinity is the primary determinent of
drug potency, measure of the drug receptor complex
stereo isomers will form a three point attachment
The number of receptors occupied by the drug depends on the ...
drug concentration and the drug receptor association (k2) and dissociation rate constant ( k2)
Kd is the drug concentration ...
required to saturate 50% of the receptors and the lower the Kd the greater the affinity.
Four Primary Receptor Families
1. Cell membrane embedded enzymes- ligand binding domain (LBD) is on the cells surface and the enzymes catalytic site is inside; response is quick i.e. insulin
2. Ligand gated ion channel- regulate flow of ions in and out of a channel, each channel is specific for a particular ion, ligand binding domain ( LBD ) is on the cell surface, when a drug binds the channel opens, there is no second messenger, concentration gradient determines flow, responses are extremely fast i.e. acetylcholine.
3. Protein coupled receptor systems- drug agonists binds to receptor which activates G protein which activate the receptor, the LBD can be on the surface or in an accessible pocket from the cell surface, response develops rapidly i.e. norepinephrine, epinephrine, acetylcholine, histamine, opioids and serotonin.
4 Nuclear receptors (transcription factors) - LBD is located INSIDE the cell they are located on the DNA in the cell nucleus, once activated bind to specific DNA sequences upstream of genes and initiate transcription, delayed response, must be lipid soluble to pass membrane ( cortisol). Two types: Type I nuclear receptors- steroidal, Type II - non steroidal ligands.
Efficacy ( intrinsic activity)
the ability of a drug to initiate a cellular effect.
drugs that have BOTH receptor affinity AND efficacy
drugs that have affinity BUT lack efficacy
Three types of agonists:
1. Full agonist
2. Partial agonist
3. Inverse agonist
can produce the maximal response obtainable in the tissue and therefore have maximal efficacy.
can produce only a submaximal dose. In the presence of a full agonist, a partial agonist will act as an antagonist
also called negative antagonist are involved in a special type of drug-receptor interaction. Decreases the rate of signal trasnduction.
bind to the same site as the agonist on the receptor but are reversibly bound.
Non competitive antagonists
block the agonist site irreversibly usually by forming a covalent bond.
The continuous or repeated exposure to agonists can ...
desensitize receptors ( desensitization or tachyphylaxis)
Continuous or repeated exposure to antagonists initially can increase the response of the receptor called
( with chronic exposure to antagonists the number of receptors on the membrane surface increases via up-regulation.
when the same dose of a drug given repeatedly loses its effect or when greater doses are needed to achieve a previously obtained effect.
-pharmokinetic - due to increased elimination by up regulation of metabolizing enzymes
-pharmoakodynamic - Due to receptor down regulation at the receptor level i.e. morphine
Disease can alter the number and function of receptors as in ...
Dose response relationship
the relationship between the concentration of a drug at the receptor site and the magnitude of the response.
Can be described in terms of a graded ( continuos response) or a quantal ( all or none response)
Graded dose response
described in terms of a percentage of the maximal response and is plotted against the log dose of the drug.
Median effective dose
the dose that produces 50 % of the maximal dose, the potency of a drug varies inversely with ED50 of a drug so that with an ED 50 of 4 mg is ten times more potent than a drug whose ED 50 is 40 mg
A partial agonist will never have
(also referred to as therapeutic window or safety window or sometimes as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.
i.e. digoxin, coumadin
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