Pharm Basics-Exam 1 Flashcards
Bioavailability = F =
% of the drug that makes it into circulation.
Calculate amount of drug in circulation for a given bioavailability
Drug in circulation = F x dose
Calculate a new dose for a new administration mode
new dose = (old dose x old F) / new F
MEC
Minimum effective concentration
ADME
Administration
Distribution
Metabolism
Excretion
henderson hasselbach
pH = pKa + log (non-protonated / protonated)
partition coefficient
lipid solubility of the non ionized form
[organic drug] / [aqueous drug]
First order kinetics
most drugs follow this clearance
constant fraction of the drug is cleared
rate of elimination directly proportionate to [ ]
zero order kinetics
Phenytoin, ETOH, Aspirin
Saturates- constant amount cleared
independent of [ ]
clearance
volume of blood cleared of drug/unit time
CL = rate of elimination / C
Volume of distribution (Vd)
Vd= dose / C
half life (t1/2)
t1/2 = (0.7 x Vd) / CL
steady state
plateau
takes about 4-5 t1/2’s to get to the plateau
loading dose
loading dose = (Vd x TC) / F
maintenance dose
maintenance dose = (dose rate x dose interval) / F
or
md = (CL x TC) x dose interval / F
or
md =((rate of elim / C) x TC) x dose interval / F
dosing rate
dosing rate = CL x TC
What are some great examples of very rapidly dividing cells that would be damaged with chemotherapy?
Lymphocytes, epithelium, hair follicles, RBCs
Primary resistance
Resistance to drugs after the first treatment due to inherent resistance
Aquired resistance
Resistance developed from multiple treatments
Selective toxicity
Ability of a drug to harm a target while sparing the good guys
- Unique target in pathogen (cell wall)
or - Target must be structurally different in pathogen (ribosomes)
or - Target must be more important to pathogen than to host
5 important aspects to consider when selecting antibiotics
- organisms identity and sensitivity to agent
- site of infection
- safety of the agent
- patient factors (ie pregnancy, gender, age, etc…)
- cost of therapy
Combination broad spectrum antibiotics
Clindamycin and gentamicin
Single broad spectrum antibiotics
Imipenem and cilastatin
3 targets of selective toxicity
Disrupt cell wall
disrupt protein synthesis (ribosomes)
inhibit enzyme unique to bacteria (dihydrofolate reductase)
Sulfonamides
Trimethoprim
suppress bacterial growth by inhibiting folic acid synthesis from PABA.
Works great with trimethoprim, which binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF)
Xenobiotics
Any foreign substance really
Bio transformation
The processing of xenobiotics for elimination
Two functions of biotransformation
Metabolism - phase 1, and elimination - phase 2
Sites of metabolism
LIVER, kidney, intestines, skin, lungs
Phase 1 reaction does what?
Who does the majority of the reactions?
Enzymes add a polar group to the molecule to make it somewhat more hydrophilic, allowing the drug to be conjugated. Drug is likely still active after phase 1.
Cytochrome p450 does the majority of the reactions (CYP)
Phase 2 reaction does what?
What is a possible negative effect of this reaction?
Phase 2 conjugates with endogenous stuff (OH, NH2, COOH, glucuronidation, acetylation, sulfation) making it quite polar and easily excreted. Drug probably inactive after phase 2.
ROS could result from conjugation!
Acetaminophen conjugation?
What about with overdose?
Normally, 95% of the drug is conjugated and excreted with no problems. 5% is converted via CYP450 to NAPQI which accumulates and forms protein adducts in the liver and kill you. GSH takes care of this problem under normal conditions, but with overdose, GSH gets saturated. He dead.
How does one treat an acetaminophen overdose?
N-acetylcysteine (NAC) binds the toxic proteins and creates conjugates that can be excreted.
factors that affect biotransformation
Genetic (race) age, sex, diet, environment, metabolic drug interactions, disease
CYP2D6 polymorphism (phase 1)
ultra metabolizers need more drug to have the same therapeutic effects in the treatment of depression. Codine is also metabolized to morphine much more rapidly. Ethiopians and Saudi Arabians have this polymorphism often.
CYP2C19 polymorphism (phase 1)
poor metabolizers (japanese) don’t metabolize the S form of the racemic mixture of mephenytoin, and get a more profound effect. Ataxia and sedation.
Mephenytoin is a hydantoin, used as an anticonvulsant.
CYP2C9 polymorphism (phase 1)
Much more sensitive to warfarin. This can lead to bleeding and death. Much smaller dose is needed!
Slow acetylater phenotype (phase 2)
isoniazid (treatment of TB) accumulates and can lead to induced peripheral neuritis, bladder cancer and autoimmune diseases
Note: INH is known to reduce cytochrome P450 and in theory promotes the efficacy of contraceptives. Therapy is often combined with rifampin. Rifampin increases the P450 enzyme and also can reduce the efficacy of contraceptives. Alternative means of birth control should be used when taking these medications.
Chloramphenicol and newborns
newborn livers don’t conjugate the oxidative metabolite of chloramphenicol very well, and it accumulates toxically and leads to “gray baby syndrome”
Diet and environment effects on biotransformation
- grapefruit juice
- st johns wart
- cigarette smoke
- lead
- inhibits 3A4 (could cause pregnancy)
- induces 3A4 (depression meds metabolized)
- induces 1A1, 1A2, 2E1
- induces heme-oxygenase that breaks down P450
metabolic drug/drug interactions
Rifampin induces 3A4
Erythromycin metabolite complexes with 3A4 and inactivates it!
Diseases affect metabolism
Cardiac-changes blood flow
liver- main metabolizer
thyroid- metabolism rate
kidney- drug excretion rate
3 mechanisms of antibiotic resistance
Failure of drug to reach target (most common)
Drug is inactivated
Target is altered
How might an antibiotic not reach its target?
Example drugs?
Drug could get metabolized before reaching target. Porins that once let the drug in may mutate.
Efflux pumps can confer multi drug resistance.
Tetracyclines, chloramphenicol, floroquinolones, macrolids, beta-lactam antibiotics
How might an antibiotic be inactivated?
Beta-lactamase is an enzyme that alters the drug and renders it ineffective. A prodrug like anti-beta lactamase can help to fix this issue.
Three principle factors for choosing antibiotics:
Hint: its pretty obvious
Identity of organism
Drug sensitivity of organism
Host factors such as infection site and host defense status
Drug with great efficacy, low toxicity, and narrow spectrum
Why might the first drug of choice not be used?
Allergy, inability of drug to penetrate to site of infection (gentamicin), and unusual susceptibility of pt to toxicity of drug
When should sulfonamides not be used?
Produces kernictorus in newborns, a severe neurologic disorder caused by displacement of bilirubin from plasma membranes
Urine pH and drug elimination: weak acid (aspirin) overdose
alkalize the urine with bicarbonate
Urine pH and drug elimination: weak base overdose
acidify the urine with ammonium chloride
Therapeutic index
Measures drug safety. High values are safer.
TI = LD50 / ED50
Therapeutic Index redefined as Margin of safety
LD1 / ED99 I guess it accounts for the slope better.
Drug Efficacy
Maximal effect a drug can produce
Therapeutic window
Measure of clinical drug safety. Range of min effective dose to min toxic dose.
Spare receptor concept
Occupancy theory states that maximum effect is when all the receptors are occupied. Physiologically, a maximum effect is obtained when only a fraction of the receptors are occupied, so not all receptors are necessary. Receptors vs effectors may be the solution; there could be more receptors that effectors, thereby increasing sensitivity to ligand.
Drug potency
amount of drug needed for given effect
competitive antagonist
competes with the agonist for the binding site on the receptor. reversible, and if the [agonist] is high, 100% of response is still possible. Antagonist changes potency, not efficacy.
receptor agonist
produces the proper response of the receptor. can reach 100% of the effect.
functional antagonist
binds to another receptor entirely, and although is has no change on the binding of the agonist, it antagonizes the EFFECTS of the agonist. this looks a lot like non-competitive antagonism.
non-competitive antagonist
binds to receptor somewhere besides the active site, and changes the binding of the agonist. this changes the efficacy, and may alter the potency as well.
inverse agonist
decrease the action of receptors that have intrinsic activity.
partial agonist
these bind to the receptor site and elicit the some response as the agonist, but differ in intensity. partial agonists do not reach 100% efficacy.
clinical relevance is that they can be used to blunt a physiological response in a diseased population. partial agonists do not generate drug tolerance.
Lipid soluble ligands and intracellular receptors
Receptors are located in the cytosol or nucleus.
Ligands must be lipophilic (steroids and gases).
Upon binding, cytosolic receptors translocate to nucleus.
Binds to specific DNA sequences.
Transcription, translation, and protein synthesis.
3 intracellular receptor parts and how they are regulated
- ligand binding domain
- DNA-binding domain
- transcription activating domain
The receptors are kept inactive by chaperone proteins (hsp90), but upon ligand bonding, it dissociates and allows binding to DNA and transcription.
G protein coupled receptors
First, the extracellular ligand selectively detected by a surface receptor. The receptor in turn triggers activation of the G protein located on the cytoplasmic face of the plasma membrane. The activated G protein then changes the activity of effector element, usually an enzyme or ion channel. This element then changes the concentration of the intracellular second messenger.
Gs protein
Stimulatory
Beta-adrenergic, glucagon, histamine
Increase in adenylate cyclase and cAMP
Gi protein
Inhibitory
Alpha-2 adrenergics, Muscarinics (M2,4)
Decrease adenylate cyclase and cAMP
Gq protein
AchR (muscarinic M1,3,5)
Alpha-1 adrenergics
Histamine
Increase phospholipase C, PIP2, IP3 and DAG, and increase in cytoplasmic Ca2+
Three drugs that do not fit into the receptor ligand model
Antimicrobials
Osmotic drugs
Antacids
Proper approach to empiric therapy
- Make a clinical diagnosis of microbial infection
- Obtain specimens for lab
- Make microbiologic diagnosis
- Determine necessity for empiric therapy
- Institute treatment
3 examples of antibiotic synergism
- Trimethoprim and sulfamethoxole
- Beta lactams and beta lactamase
- Penicillins and aminoglycosides(bind to the bacterial 30S ribosomal subunit)
2 examples of antibiotic antagonism
- Tetracycline and penicillin
- Chloramphenicol and penicillin
Bacteriostatic and bactericidal don’t go well together.
Chemotherapeutic index
CTI = toxicity to cancer / toxicity to normal cells
big # is better
Cell cycle specific drugs
inhibit some aspect of cell division to kill cancer. some drugs affect S-phase and others M-phase.
3 advantages to combination chemotherapy
- maximum cell kill
- broader range of coverage of resistant cell lines
- prevents or slows development of new drug resistance
P-glycoprotein
increased expression in cancer causes multi drug resistance due to drug efflux (active transport)
3 cell types and adverse effects of myelosuppression
myelosuppression = bone marrow suppression
- WBC- increased infection
- RBC- fatigue, headaches, etc…
- platelets- bruising, bleeding
Serotonin receptor antagonists
First line and most effective antiemetic therapy, but rather costly. Tron drugs.
Dolasetron (ANZEMET)
Granisetron (KYTRIL)
Ondanisetron (ZOFRAN)
antidopaminergics
second line antiemetic drugs selectively depress CTZ and to lesser extent, vomiting center
Prochlorperazine
Fluphenazine
Chorpromazine
Bacterial conjugation
Common mechanism for gram negative rods as well as enterococci, and staphylococci
Multiple resistance genes can be transferred in a single event via plasmids. Extrachromosomal DNA is transferred. Donor guy must have code for mechanisms of transfer and the necessary sex equipment. Those two segments are called resistance factor.
Pharmacodynamics
Action of the drug on the body
Pharmacokinetics
The action of the body on the drug.
