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Principals of Pharmacology
Terms in this set (20)
What is phamacodynemics?
pharmacodynemics studies the effects a drug has on the living organisms and focuses on both the wanted and unwanted effects: mechanisms of action, dose-response relationship, therapeutic (intended) and unwanted (toxic) effects
What has to be studied when asking about the mechanism of action of a drug?
What are the targets of the drug? Targets of drugs are ligand-gated receptors and targets that are not gated by the ligand, for example ion channels, enzymes, transporters, DNA
What are examples for receptor types?
receptors in the plasma membrane: ion channels, enzymes, GPCR, gp130-coupled receptors
intracellular receptors: transcription factors, soluble guanylate cyclase
What are two examples for ion channels with opposite function?
The nicotinic acetylcholine receptor is a sodium channel that is gated by acetylcholine. Sodium influx results in the depolarization of the cell.
The GABA A receptor is a chlorid channel that is gated by GABA and its opening results in the hyperpolarization of the cell.
What are two examples for tyrosine kinase receptors?
Tyrosine kinase receptors are enzyme receptors that phosphorylate other proteins at tyrosine residues. Two examples are the Insulin receptor and growth hormone receptors.
Describe the mechanism of GPCR. What are target enzymes of GPCR?
GPCR consist of seven transmembrane helices that are coupled to a G-potein with three subunits (alpha, beta and gamma). In the inactivated state, the alpha subunit binds GDP. Upon the activation of the receptor, the receptor acts as GEF, which means guanin nucleotide exchange factor. This leads to the exchange of GDP by GTP, which activates the G-protein. The mobile subunit alpha moves and binds to its target enzyme. One target enzyme is the adenylcyclase (AC), which produces cAMP. AC can be inhibited by Gi-coupled receptors or stimulated by Gs-coupled receptors. Another target of GPCR is phospholipase C, which causes the activation of calcium-dependent pathways. The beta and gamma subunits of GPCR have signaling functions.
What is an agonist? What is an antagonist?
an agonistig drug activates (or decreases) receptor activity. An antagonistig drug prevents an agonist from acting on the receptor.
How can the action of an agonist be described? What two features of the agonist are important?
The effect of the agonist on the receptor at different concentrations on a logarithmic scale is observed, so the concentration-response relationship is observed.
Thereby, two important features are determined, the efficacy (Wirkstärke) describes the maximal activation of a receptor (1 or 100%) that can be achieved by the drug. The intrinsic activity (ISA) is the maximal effect of a compund in % of the maximal activation.
Another important feature is the potency (Potenz) that describes the affinity of a compound to its receptor. The EC50 falue shows what concentration is needed to achieve 50% effect. The smaller EC50 is the higher is the affinity of the compound to its receptor and the better it is for the treatment, because less concentration of the drug leads to minimized off target effects.
What types of agonists exist? What intrinsic activity has an antagonist?
Full-agonists reach a full activation of the receptors, so the ISA is 100%. Partial agonists have an ISA over 0%, but under 1 or 100%.
Partial agonists, for examples opioids, have a ceiling effect, which means that the impact of the drug on the body plateaus. This is an advantage, if the maximal activation would be dangerous. Partial agonists have an agonistic action when apllied on its own, but an antagonistig action when apllied together with a full agonist that have a lower affinity, so a partial agonist is also a partial antagonist.
Inverse agonists reduce basal activity of a receptor, which is only possible if the receptor has a basal activity without binsing of an ligand. The ISA of an inverse agonist is less 0.
Antagonists have an ISA of 0.
How can antagonists be characterized?
Antagonists are characterized in the presence of agonists using concentration-response curves. A concentration-response curve for an agonist is generated and then another concentration-response cuve is generated by adding increasing concentrations of the antagonist resulting in different curves. Subsequently the EC50 falues for the antagonist is calculated.
What are types of antagonists?
Competitive antagonists compete for the same binding site with an agonist and are characterized by an increasing EC50 value, while the ISA stays the same. The concentration-response curve shifts to the right. Competitive antagonists are reversible.
Non-competitive antagonists can prevent the action without any effect on the binding of the agonist to the receptor. They are characterized by a decrease of the ISA, while the EC50 value stays the same. There is no shift of the concentration-response curve. Non-competitive antagonists are reversibel or irreversibel.
How can the safety of a drug be considered?
To consider the safety of a drug, its therapeutic (intended) and its unwanted (toxic) effects have to be quantified. Therefore, the dose is calculated that is needed to achieve 50% of each effect. For the therapeutic effect the ED50 value is calculated. For the toxic effect the TD50 value is calculated. For the lethal effect the LD50 value is calculated. Subsequently, the distance between the two concentration-response curves is calculated by dividing the LD50 or TD50 value by the ED50 value. The larger the ratio the saver is the drug, so the larger the distance of the curves the saver is the drug.
How does the organism do to a drug?
The organism liberates, absorps, distributes, metabolizes and excretes a drug
On what does liberation of a drug by an organism depend?
Liberation of a drug in an organism depends on galenic. How fast the liberation has to occur depends on what you want to treat. You need a fast liberation for example for pain reliever, you need a delayed liberation for example to protect the drug from degradation in the stomach. Or you need a retarded liberation for example to prevent high plasma levels.
On what does absorption of a drug by an organism depend?
Absorption can only occur, when the drug is given oraly. It depends on the drug alone and can not be influenced. After liberation, the drug is absorped by the epithelial layer of the intestinal, which is easier if the drug is lipophilic. Before that, the drug can interact with microbes, food or other drugs, which can prevent its absorption. The portal vein transports the drug to the liver. The drug can only enter the bloodstream if it is not detoxified by the enzymes of the liver.
How can the oral bioavailability of a drug be measured?
The oral bioavailability can be measured by comparing the trajectory of plasma concentrations after oral application with a concentration curve produced after injection. This is important to test the savety and the efficacy of a drug. Therefore, plasma concentrations are measured at different time points after oral application. From these points the area under the curve (AUC) can be calculated that shows the amount of drug in the blood. The cmax is the maximal drug concentration after an oral aplication and the tmax is the time point where cmax is reached. The oral bioavailability in percent is calculated by dividing AUC per os by AUC after injection and multipliing it by 100.
What factors do distribution of a drug influence? What parameter is used to measure distribution?
The distribution of a drug is influenced by its lipophilia, the blood flow to the tissue that can differ on different time points (for example during sports the blood flows to the muscles), blood tissue barriers (the BBB for example) and plasma protein binding (for example lipophilic binding to albumin).
Volume of distribution is a theoretical parameter. To calculate this theoretical parameter the injected dose is divided by the plasma concentration after injection.
How does the metabolism of a drug work?
Metabolism occurs mainly in the liver and has often two phases: functionalization of lipophilic compounds by adding a group and subsequent conjugation to make the compound more water soluble for the excretion by the kidney. In phase I reactions cytochrom P-(P450-) dependent oxidoreductases play an important role: for example CYP3A4, which metabolizes 40-50% of all drugs and CYP2D6 + CYP2C9, which metabolize 20% of all drugs, each. In phase II reaction different transferases play an important role.
Metabolism can also occur through other pathways, like oxidation or hydrolases.
How does excretion of a drug work?
The major organ that excretes compounds is the kidney, so renal excretion is the major process. This can be done by filtration or active secretion. If the function of the kidney is impaired, the dosis of a drug needs to be adapted.
Other ways of excretion are hepatic excretion by the biliary (Galle) system ending up in the intestin and pulmonary (Lunge) excretion by breathing.
What does elimination of a drug mean?
Elimination can occur by metabolism or excretion. It shows how often a drug has to be apllied and if it accumulates.
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