Flashcards in Foundations: Pharmacology Deck (115):
How would you describe a selective drug?
One that only interacted with its intended molecular target over its therapeutic range
Define selective toxicity.
Describes a drug aimed at killing something (parasites, tumor) without harming the host
How long does it take to design a new drug?
How much does it cost to design a new drug?
When writing a prescription, should the generic or brand name of a drug be used?
The generic name (allows pharmacist to choose most economical form of drug)
When writing scientific publications, should the generic or brand name of a drug be used?
The generic name
What is the generic name for Coumadin?
What is the generic name for Lamisil?
What is the generic name for Lasix?
What is the generic name for Glucophage?
If the drug concentration and % biological effect are plotted on a linear scale, what relationship is expressed?
A hyperbolic dose relationship
If the drug concentration and % biological effect are plotted on a semilog scale, what relationship is expressed?
A sigmoidal dose relationship
What is the effective concentration/dose?
That which elicits the biological response in 50% of individuals (ED50)
What is the toxic dose?
That which elicits toxicity in 50% of individuals (TD50)
What is the lethal dose, and how is it determined?
That which causes death in 50% of individuals
What is the therapeutic index, and how is it calculated?
The range where a drug will be effective but not toxic
TI = TD50/ED50
Does a large therapeutic index mean a safer or more dangerous drug?
A larger TI means a safer drug
What is an example of a drug with a small TI?
Warfarin... higher doses produce anticoagulation leading to hemorrhage
What is an example of a drug with a large TI?
The amount of drug needed to produce an effect that is 50% of the maximum (EC50)
The maximum response that can be achieved by a drug (ECmax).
It's the inherent ability of the drug to couple receptor activation to production of a biological effect.
Which is more important, potency or efficacy?
How does an agonist activate receptors?
By mimicking natural ligands
How does a partial agonist differ from an agonist?
The partial agonist binds to the receptor to elicit a lesser response (decreased efficacy)
When a drug binds to a receptor but elicits no response. The drug has full affinity but no efficacy.
How does competitive antagonism change the dose-response relationship?
The agonist must be present in higher concentrations to produce the same efficacy. The potency of the agonist shifts.
Is competitive antagonism reversible?
Yes. Binding the agonist and the antagonist is reversible.
How does irreversible antagonism change the dose-response relationship?
The antagonist binds irreversibly to the same receptor as the agonist, and no amount of agonist can overcome the antagonist's effects. The efficacy of the agonist decreases.
What is an example of a competitive/reversible antagonist?
What is an example of an irreversible antagonist?
How does a non-competitive/allosteric antagonist change the dose-response relationship?
The antagonist binds to the receptor near the agonist's binding site to cause a conformational change in the receptor. The efficacy of the agonist is decreased.
Define physiologic antagonism.
When two molecules have opposite effects that are mediated through different mechanisms.
What is an example of physiologic antagonism?
The antagonism of histamine-induced vasodilation by epinephrine-induced vasoconstriction
Define chemical antagonism.
The antagonist removes the drug being antagonized to inhibit its ability to reach the target.
What is an example of chemical antagonism?
Dimercaprol is a chelator (binds up the compound to render it ineffective) of lead and other toxic methods
What the drug does to the body.
What is the fundamental principle of pharmacodynamics?
Drugs are not able to generate responses de novo. They either block or stimulate a response that is already present.
What are the immediate targets for most drugs (molecular level effects)?
What type of receptor is the most prevalent target for drugs?
Rhodopsin-like G-protein coupled receptors (GPCR)
Describe the structure of the GPCR.
Made of 7 transmembrane helices that are linked to G-proteins (3 subunits)
What happens to the GPCR after being active for awhile?
Desensitization - it will shut down even if the ligand is still around
What are some examples of GPCR?
Regulators of mood and behavior
Control of automatic functions (BP, HR, digestion)
How does the GPCR interact with the G-proteins?
When the GPCR is occupied, it undergoes a conformational change and interacts with the G-protein
How does the G-protein initiate a signal to be sent?
The alpha subunit dissociates and activates adenylyl cyclase
What type of receptor is the second most prevalent target for drugs?
Where are nuclear receptors located?
Inside the cell
What process does nuclear receptors regulate?
Describe Type 1 Nuclear Receptor Steroid signaling.
The steroid receptor is bound to a Hsp90 protein in the cytoplasm. When a steroid crosses the cell membrane to bind to the receptor, it releases the Hsp90 and moves into the nucleus to bind to the gene regulatory sequence to activate transcription.
Describe Type 2 Nuclear Receptor Non-steroid signaling using the thyroid hormone receptor.
The thyroid hormone receptor is in the nucleus sitting on the DNA. When hormone binds, it activates the receptor to activate transcription.
What is the role of the Tyrosine Kinase receptors?
Regulate growth and cell differentiation
What are some tyrosine kinase receptor agonists?
What are some examples of receptor operated channels (ligand gated ion channels)?
Describe the nicotinic acetylcholine receptor.
When acetylcholine binds to the nicotinic receptor, the receptor undergoes a conformational change to allow Na+ to influx and initiate an AP in the neuromuscular junction
Describe the GABA receptor.
When GABA binds to the receptor, the receptor undergoes a conformational change to allow Cl- ions into the cell to decrease Vm and make it harder to generate an AP
**major molecular target for drugs in the brain
How can drugs affect voltage operated/gated channels?
Drugs can change voltage dependence or cause the channel to be blocked
What is an example of a voltage operated/gated channel?
The voltage gated Na+ channel in neurons and in cardiac and skeletal muscle
What is an example of an antiporter?
The Na+/Ca++ exchange
What is an example of an energy dependent channel?
The Na+/K+ ATPase pump
What drug affects the Na+/K+ ATPase pump?
What differentiates the action of competitive and noncompetitive enzyme inhibitors?
Competitive inhibitors interfere with the active site
Noncompetitive inhibitors binds to a different site to change the shape of the enzyme
How does Metformin work on a molecular level?
Binds to Complex 1 in mitochondria
How does Metformin work on a cellular level?
Acts on AMP Kinase, which is involved in neoglucogenesis
How does Metformin work on a tissue level?
Decreases the amount of sugar made by the liver
How does Metformin work on a systemic level?
Lowers plasma glucose
Prevents cardio complications associated with diabetes
People tend to lose weight
What the body does to the drug.
What is the most common route of drug administration?
What is the major site of entry into systemic circulation?
What are some advantages of oral drug administration?
Variety of forms
What are some disadvantages of oral drug administration?
Can be inefficient
May be only partially absorbed
What are some advantages of sublingual drug administration?
Rapid access to circulation
Drug stability due to neutral pH in mouth
What are some disadvantages of sublingual drug administration?
Can only accommodate small doses
What is an example of a sublingual drug?
Nitroglycerin, used to relieve acute attack of angina
What are some advantages of rectal drug administration?
Half of rectal drainage bypasses first-pass
Avoids GI enzyme breakdown
Good for those unable to take drugs orally
What are some disadvantages of rectal drug administration?
Erratic and often incomplete absorption
What form of drug administration provides the most dose control?
What are some advantages to intravenous drug administration?
Max control over dose of drug
What are some disadvantages to intravenous drug administration?
Can't remove it if the patient has a toxic reaction
Requires trained personnel
What is an advantage to intramuscular drug administration?
Drug can be delivered fast or slow
What is a disadvantage to intramuscular drug administration?
Requires trained personnel
What are some advantages to subcutaneous drug administration?
Patient can give drug to self
Slow but complete absorption
What are some disadvantages to subcutaneous drug administration?
Tissue damage can result at site of administration
Can only inject a limited dose
What is an advantage to inhaled drugs?
Convenient/effective route, especially if the lungs are the target
What is an example of an inhaled drug?
Glucocorticosteroids, to treat asthma
What are some advantages to intranasal drug administration?
Great for drugs that would be eliminated by first-pass if taken orally
Can deliver potent drugs to elicit systemic effects
Easy to administer
What are some examples of topically administered drugs?
What are some advantages to transdermal drug administration?
What is the main disadvantage of transdermal drug administration?
Only very small drug molecules can penetrate the skin
What are the 4 basic pharmacokinetic processes?
How does size affect absorption?
The smaller the molecule, the better it is absorbed (doesn't matter if molecule is uncharged)
How does the pH of the environment affect absorption?
The pH determines the fraction of drug available in non-ionized form, which is the only form that can get across the membrane
In what environment is an acidic drug best absorbed?
An acidic pH (lower #)
In what environment is a basic drug best absorbed?
A basic pH (higher #)
What is the Partition Coefficient?
The solubility of a drug molecule in a lipid solvent in comparison to its solubility in water
Will a drug with a greater partition coefficient have a greater or weaker solubility in lipid?
Greater lipid solubility
Will move rapidly across the membrane
What is an example of a drug with a particularly high partition coefficient?
Thiopental (580) used to quickly induce anesthesia
What is an example of a drug with a particularly low partition coefficient?
Phenobarbitol (3) used for treatment of chronic epilepsy
If you wanted rapid gastric emptying, would you recommend the drug to be taken with or without food?
Without food, with only a glass of water
If you wanted delayed gastric emptying, would you recommend a drug be taken with or without food?
Is plasma protein (albumin) binding of a drug beneficial or detrimental to distribution?
Can be either
Drug will not be accessible for metabolism or for function
What 3 factors affect the distribution of a drug?
Size of the drug
Plasma protein binding
Permeability of the cell membrane
What organ is a major site for metabolism?
Describe first order elimination kinetics.
Drug has not saturated the body's capacity to eliminate it.
Loss of drug from body is proportional to the drug concentration in the plasma.
After how many half lives is a drug gone?
Describe zero order elimination kinetics.
The drug has saturated the body's ability to eliminate it with a very low concentration.
The loss of drug from body is constant over time. The concentration of the drug does not matter.
What is an example of a drug that displays zero order elimination kinetics?
What elimination process do normal doses of Aspirin exhibit?
Between first and zero order.
Once first order is saturated, elimination switches to zero order.
How do Phase 1 reactions affect drug metabolism?
Oxidation and hydrolysis provide functional groups to increase the polarity of a drug
What enzyme usually induces oxidation, and where is it found?
Cytochrome P-450 (CYP) in microsomes of the liver
How do Phase 2 reactions affect drug metabolism?
Attach large chemical groups to increase water solubility and excretion from body
How is most drug excretion accomplished?
Renal excretion (urine)
How can you measure renal function directly?
24 hour creatinine clearance
Describe entero hepatic circulation.
A drug secreted in bile is hydrolyzed in the lower intestine to release the original drug. The drug is reabsorbed into the blood stream with a prolonged half life.
What type of drugs are mainly excreted via the lungs?
General anesthetics in gaseous or vapor form
What other substance can be excreted via the lungs in minor amounts?
Ethanol (basis for the breathalyzer test)