Flashcards in Pharmacology Deck (63):
subtances binding to a receptors recognition site
A factor regulating a physiological process
A change in Emax with no change in EC50. Curve shifts up and down.
Interpretation: for the same concentration of hormone, the effect produced is far less → “decrease in responsiveness” Decrease in efficiency.
A shift in ED50 with no change in Emax. The curve shifts left and right. Reduced sensitivity is a shift to the right or an increase in EC50 without a change in Emax.
-If more effector is required to achieve the same Emax, then you can say that the hormone has decreased sensitivity (or decreased potency) – means that it takes more hormone to achieve the same response
The dose of an effector that causes 50% of Emax
Define partial agonists
Occupy all receptors but not enough to generate Emax
Define full agonists with spare receptors
effector generate a stimulus sufficient to produce Emax but without occupying all receptors.
What are the steps of the drug approval process?
1. Safety - “Is this drug safe?”
o studies are done on small groups of control patients to determine tolerated dose range and what types of side effects might appear
o drugs targeted for serious disease → serious side effects commonly occur, “control” = patients affected with the disease
2. Efficacy - “does it work in patients?”
o done on small groups of patients with disease (100-200 patients)
o study design:
• control: placebo
• experimental: patients treated with new drug
• see if drug has efficacy and at what dose
3. Large group safety and efficacy – “is it safe in large groups?”
o performed in thousands of patients in multiple clinical sites by multiple physicians
o double blind studies – both clinicians and patients don’t know if they are receiving the new drug or a placebo
o with larger groups → greater opportunity to discover adverse side effects and most appropriate dose ranges for most patients
4. Long term surveillance of the drug for safety and efficacy after marketing (post-marketing surveillance)
o requirement for marketing of all drugs that drug-makers continually monitor the use of the drugs for any side effects, toxicity, or contraindications
o problems must be reported to the FDA – issue warning about the drugs
What is neurocrine signaling?
a neuron releases hormones that travel through the blood stream and effect far away cells
What is GCPR?
G protein coupled receptors. Once activated, GPCRs cause a conformational change in the attached G protein complex, which results in the alpha subunit's exchanging GDP for GTP, separating from the other subunits and causing downstream effects
What are examples of regulatory events?
-reversible or irreversible covalent modifications
-changes in physical location of a molecule
-change in the number of molecules by changing rates of synthesis or degradation
What would a decrease in Emax with no change of ED50 illustrate?
decreased responsiveness or decreased efficacy
What would a decrease in ED50 with no change in Emax illustrate?
It would indicate increased potency, or increased sensitivity
What would an increase in ED50 with no change in Emax illustrate?
decreased sensitivity; shows that it takes more hormone to achieve the same Emax
What is the difference between efficacy and effectiveness?
Efficacy is related to Emax and refers to the maximum response achievable by the drug. Effectiveness refers to the ability of the drug to produce a beneficial effect. (Intrinsic activity refers to the efficacy or Emax of a drug compared to the best drug or effector we know for that particular condition)
What is efficacy?
a measure of the magnitude of the response caused by binding of the effector
What is a synergistic effect?
1+1= 4 – two different receptors produce different effects, but they are related! i.e. one transcribes a gene, the other activates the gene which causes the effect
What is cooperativity?
Positive cooperativity is when the binding of an effector to a receptor makes other effectors more likely to bind. (think hemoglobin)
What is sensitization?
-Also called “potentiation,” an effector causes an effect and causes more receptors to be present, the next dose of the effector will have an even greater effect
-A pulse of the effector increases the effectiveness of the subsequent pulse – if the hormone causes rapid modification of an enzyme and less rapidly induces synthesis and accumulation of the enzyme, then a subsequent pulse of the effector may cause more enzyme molecules to be activated, thereby increasing the effector effectiveness
What is heterologous desensitization?
-Heterologous refers to desensitization towards multiple effectors which act via distinct receptors but cause common effects
What is pharmacokinetics?
Effectsof body on the drug
What is the pathway of a drug in the body?
(L) A D M E
-L = liberation (of active part of a drug formulation)
-A = absorption
-D = distribution (i.e. CSF, Plasma)
-M = metabolism (biotransformation) – how drugs are handled
-E = excretion (kidney, liver, lung, skin)
What is Bioavailability (F)?
-fraction or proportion of drug dose that gets into general circulation unchanged – variable = “F”
- it is the AUC (area under the curve) when “plasma concentration of drug” vs. time is plotted
-F = AUC of drug/AUC of drug if given by IV
What is the first pass effect?
-some substances/drugs are metabolized by liver before reaching systemic circulation
-what effect does this have on bioavailability?
What is bioequivalence?
preparations for which equal doses by same route of administration produce identical AUCs. o If two products are said to be “bioequivalent” it means that they would be expected to be, for all intents and purposes, the same
What is MEC?
minimum effective concentration → minimum plasma concentration of the drug that is required in order to see an effect
What is t 1/2?
the time to decrease plasma drug concentration by ½ after absorption and distribution
t1/2=(0.693 x Vd)/Cl
What is volume of distribution Vd?
the (hypothetical) volume needed to contain the drug in the body at the concentration found in plasma after the drug has been distributed throughout the body
Vd=amt of drug in body/plasma drug conc (Cp)
What is clearance?
it is the VOLUME of fluid cleared of drug per unit of time (hypothetical volume value)
Cl=0.693/t1/2 for first order
Cl=kc (amount/time) for zero order
What is the rule of thumb for a drug w/ first order elimination kinetics to reach Css (steady state)?
• Takes 4-5 half-lives to reach steady state
What is the difference between first and zero order elimination?
Rate of elimination is concentration independent.
Changing Half-life – concentration of these drugs in plasma decrease linearly over time
rate of elimination is concentration dependent
Constant half-life – the concentration of the drug in the blood decreases by 50% for every half-life
rare, e.g. ethanol
What is therapeutic index?
TI = TD50 / ED50 or LD50/ED50 TILE
The higher TI, the safer the drug. a higher LD50 or TD50 tells you that you need a much greater dose of the drug to produce lethal or toxic effects; therefore you can use the drug more liberally without worrying about toxicity or death (safer!)
What does a low Vd mean? a high Vd?
Low Vd means drug is mainly in blood. High Vd means drug has been distributed to tissue.
What is the mechanism of toxicity induced by carbon monoxide?
-CO binds with hemoglobin to form carboxyhemoglobin
-CO has higher affinity for hemoglobin than oxygen, prevents binding of oxygen to hemoglobin
-CO interferes with dissociation of O2 from oxyhemoglobin, decreasing O2 deliver
What is the treatment for CO poisoning?
-100% oxygen administered so that oxygen displaces bound CO from hemoglobin (competition)
What is the mechanism of Cyanide poisoning?
-CN binds to ferric iron of cytochrome oxidase and stops ETS in mitochondria
-inhibits cellular respiration, O2 utilization blocked
-death due to respiratory failure
How is CN poisoning treated?
1. sodium nitrate to induce oxidation of limited amount of hemoglobin, methemoglobin competes with cytochrome oxidase for CN
2. sodium thiosulfate, reacts to form thiocyanate so that it can be excreted
Hydroxocobalamin: CN bindes to cobalt to form cyanocobalamin, which is excreted
What is the mechanism of methanol poisoning?
-MeOH metabolized to formic acid, which is toxic and cause blindness and metabolic acidosis
How do you treat methanol poisoning?
-Ethanol-has greater affinity than methanol for alcohol dehydrogenase
-Fomepizole-competitive inhibitor of alcohol dehydrogenase, but enhances toxicity of ethanol if given with EtOH
What is the mechanism of iron poisoning?
-inhibits blood coagulation, leads to erosion and ulceration in intestinal tract
-induces lipid peroxidation in mitochondria and inhibits electron transport
How is iron poisoning treated?
whole bowel irrigation with polyethylene glycol. Or deferoxamine treatment
What is the mechanism of lead poisoning?
-hypochromic microcytic anemia caused by decreased life span of RBC due to inhibition of heme synthesis.
-inhibits ferrochelatase-->decrease synthesis of heme
-inhibits ALA dehydratase-->decreased conversion of ALA to phorphobilinogen in heme production
What is the treatment for lead poisoning?
-severe: calcium disodium EDTA to remove lead from bone
-dimercaprol-remove lead from tissue
-less severe: penicillamine, succimer for children
What is the mechanism for chlorinated aromatic hydrocarbons (CAH) toxicity? e.g. dioxin
-bind to arylhydrocarbon (Ah) receptor-->activation-->bind to DNA-->transcription of genes-->Ah hydroxylase enzyme and ALA synthase induced (toxicity)
What are treatments for CAH toxicity?
-cholestyramine increases fecal excretion and removes bile salts to block enterohepatic recirculation
-serial activated charcoal to remove enterohepatic recirculation agents
-anticonvulsants, supportive therapy
What are the clinical presentations of CAH poisoning?
-CNS stimulation: convulsions
-arrhythmias and fibrillation
-liver and kidney damage
What is the mechanism of paraquat toxicity?
-cyclic reduction-oxidation and induces generation of superoxide radicals
-->lipid peroxidation damaging cell membrane and enzymes
What are treatments for paraquat toxicity?
-serial activated charcoal to remove paraquat from enterohepatic recirculation
-NO oxygen therapy-->increases toxicity
What is the mechanism of toxicity for warfarin and superwarfarin?
-blocks binding of vitamin K to its reductase and prevents postranslational maturation of blood coagulation factors-->uncontrolled bleeding and death
What are the treatments for warfarin and superwarfarin poisoning?
-Vitamin K to overcome warfarin competition
-fresh frozen plasma or factor IX for uncontrolled bleeding
-activated charcoal to remove warfarin from gut
-cholestyramine to bind warfarin and block enterohepatic recur
What do phase I reactions in biotransformation do?
-create or unmask a chemical group required for phase II reaction
-common reactions include: oxidation, hydroxylation, dealkylation, deamination
What enzymes/proteins are required for phase I biotransformation?
-cytochrome P450, NADPH cytochrome P450 reducatase, and membrane lipids
How does CYP inhibition cause drug-drug interactions?
-competitive inhibition: two drugs compete from same active site. Drug with higher affinity occupies site and inhibits metabolism of second drug-->increase in levels of second drug and toxicity
-suicide inactivation: inhibitor drug metabolized by enzyme to reactive form that binds to enzyme irreversibly, inactivating enzyme
What happens in phase II biotransformation of a drug?
-conjugation reactions with endogenous substances such as glucuronate, sulfate, acetate, glycine
What is the most common phase II biotransformation? List an example.
Glucuronidation: adds glucuronic acid moiety, makes drug more water soluble and more easily eliminated. Eg. salicylate, acetaminophen
how does biotransformation differ in neonates/infants compared to adults?
-rate of biotransformation of most drugs lower in neonates and infants
-some drugs metabolized by glucoronate conjugation in adults are metabolized by sulfate conjugation in neonates
How does biotransformation differ in elderly patients compared to adults?
-reduced capacity to metabolize drugs.
-may be safer to use drugs that are conjugated because biotransformation via oxidative rxns declines more
How do hepatic and renal disease, and heart failure affect drug biotransformation?
-hepatic/renal: reduce capacity of liver and kidneys to biotransform/excrete drugs,reduces drug clearance
(heart failure reduces hepatic blood flow).
Discuss the drug interactions between cyclosporin A and erythromycin
-cyclosporin A-immunosupressive, reduces organ rejection-->increase risk of bacterial infections
-erythromycin-given for infections
interaction: erythromycin inactivates CYP, decreases first pass metabolism of cyclosporin A, increases its F and plasma conc.
-->excessive immunosuppression and increase in renal toxicity. Need to decrease conc. of cyclosporin A given
Discuss drug interactions between cyclosporin A and ketoconazole.
-opportunistic fungal infections caused by cyclosporin treatment treated by ketoconazole
-mechanism: ketoconazole binds CYP3A4 and inhibits. Increases F and Cp of cyclosporin A.
-Adjustment: decrease cyclosporin A dose
Discuss the drug interactions between cyclosporin A and rifampin.
-rifampin treats Tb and some bacterial infections due to cyclosporin A treatment
-mechanism: rifampin induces CYP3A4 activity, increases first pass metabolism of cyclosporin A, decreasing F and Cp
-adjustment: increase cyclosporin A dose
Does sulfation make conjugate more or less water soluble than parent drug?
more water soluble