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Chapter 4

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Zachariah Campbell

PSYC62: Ch. 4 Notes: Properties of Drugs: - pharmacokinetics: how drugs move throughout the body - This process involves factors concerning how a drug is administered and how it is absorbed into the bloodstream, permeates different body parts, and is eliminated from the body - Many therapeutic drugs fail in clinical testing because they are inadequate in reaching the areas of the body necessary for the drug’s actions, making the treatment useless - pharmacodyamics: how drugs cause biological changes in the body Pharmacokinetic Properties and Drug Passage Through the Body: Stage 1: Absorption: - absorption: Entry of a drug into the circulatory system (To do so, a drug must pass through different membranes such as the mucus membranes in the mouth or the walls of the intestines: fig 4.1 & table 4.1) - Most therapeutic drugs are orally administered because it is easier than giving ourselves an injection - After swallowing a pill or drinking a liquid, a drug passes through the stomach and into the intestines, where the drug may absorb through stomach or intestinal walls along the way (most drug absorption occurs in the small intestine) - therefore, developers must find ways to protect the drug from digestive acids in the stomach - Encasing a drug within a tablet or capsule will manage this - But stomach acids must dissolve enough of the tablet or capsule to free drug molecules for absorption in the intestines - This delicate balance often reduces the amount of drug that actually reaches the bloodstream - The duration of time needed for a drug to pass through the digestive system affects the delay for drug effects - Although these delays also depend on unique chemical properties of the drug and the substance it is delivered in, most drugs take at least several minutes to reach the bloodstream; for intestinal absorption, it might take between 15 minutes and one hour - The analgesic—that is, pain-relieving—drug acetaminophen (Tylenol) requires about 30 minutes to provide headache relief for most people - Users also inhale many substances, including medications such as albuterol for treating asthma or addictive substances such as tobacco - Through the inhalation route, drugs enter the circulatory system primarily through the lungs and to some degree through membranes in the nose, mouth, and throat - Therapeutically for asthma and other lung disorders, inhalation brings a drug directly to the area needing treatment (ex. albuterol treats asthma by relaxing air passages in the lungs) - Similar to oral administration, not all of an inhaled substance absorbs through tissue to reach the bloodstream, but inhaled substances absorb more quickly than orally administered drugs (ex. when tobacco is smoked, nicotine reaches the user’s brain within 7 s) - Many administration methods require an injection - Intravenous injection involves drug delivery into a vein through a hypodermic needle - This route provides for rapid drug effects and avoids absorption limitations - Intravenous injections may be used in emergency medicine if physicians need a rapid drug effect or if a patient is too unresponsive to take a medication herself (ex. an intravenous injection of naloxone to a patient experiencing a heroin overdose) - Users of abused drugs may also prefer intravenous injections because of their speed of onset and full absorption of the drug - Noncompliance to a medication provides another reason for delivering drugs by injection (ex. A patient with schizophrenia may refuse to swallow an antipsychotic medication out of suspicions about the motives of the medical care staff) - this is also why many drug developers pursue antipsychotic drugs that are deliverable sublingually (a pill dissolves on or under the tongue) or intranasally (nasal spray) Stage 2: Distribution: - distribution: Passage of a drug through the circulatory system - After absorption of the drug into the bloodstream, the drug may need to cross certain membranes in order to reach the site of drug action - bioavailability: Ability of a drug to reach a site of action - For psychoactive drugs, bioavailability depends on the drug reaching the CNS; to enter the brain, drugs must possess sufficient properties to permeate the blood–brain barrier (ex. lipid soluble and small) - poor bioavailability often ends clinical trial testing to experimental drugs (ex. the experimental antipsychotic drug SR-142801(Osanetant) exhibited antipsychotic-like effects during preclinical testing but after approval by the FDA for clinical trial testing, Osanetant proved only modestly better than haloperidol (fig 4.3) - This study revealed that Osanetant’s efficacy, albeit modest, was positively correlated with blood plasma levels, indicating that Osanetant was sufficiently absorbed into the bloodstream - However, higher doses of Osanetant failed to provide any greater improvement for schizophrenia, suggesting that the drug did not permeate the blood–brain barrier sufficiently to provide stronger antipsychotic effects (Osanetant had poor bioavailability) which subsequently halted its further testing - The placental barrier is also important to consider for drug effects, virtually all drugs taken by the mother can permeate the placental barrier and enter the placenta which may allow harmful effects on a fetus - nonspecific binding: the binding of the drug to sites that are not the intended target for drug effects - This may occur in the form of protein binding: the drug binds to proteins in the bloodstream, causing the drugs to not cross the blood–brain barrier - Another form of nonspecific binding is depot binding: which is the binding of drugs to receptors or other parts of the body that the drug does not affect Stage 3: Metabolism: - drug metabolism: Process of converting a drug into one or more metabolites: Products resulting of enzymatic transformation of a drug - This conversion most often takes place in the liver, but metabolism of a drug may also occur in other areas such as the stomach - Most drugs are broken down by members of the CYP-1, CYP-2, and CYP-3 cytochrome P450 enzymes (These enzymes can play an important role in a person’s response to a drug) - ex. in poor metabolizers, the appropriate enzymes for a drug may either be too few or, because of gene polymorphisms, have a diminished ability to metabolize drugs, therefore they tend to have greater treatment sensitivity for certain drugs because the drug remains for a longer duration in unmetabolized form in the body - Others may be ultrarapid metabolizers who can exhibit opposite characteristics compared to poor metabolizers, such as greater levels of an enzyme or a greater ability of enzymes to metabolize drugs - Unlike poor metabolizers, ultrarapid metabolizers tend to have weaker treatment sensitivity for certain drugs because the drug remains for a shorter duration in unmetabolized form in the body - personalized medicine: a method of prescribing drugs most appropriate for a patient’s unique biological makeup (through use of a blood test for these enzymatic activities) - first-pass metabolism: Metabolism of a drug begins to occur before the drug reaches the site of action (usually occurs with orally administered drugs, ex. about 90% of buspirone (BuSpar), a treatment for anxiety, converts to metabolites in the stomach before absorption occurs, substantially reducing the amount of drug available for biological effects - A drug’s metabolites may help to explain its effects: - First, metabolites may act in the body (could be harmful, or they may interact with another drug a patient is taking) - Second, the metabolites of a drug may offer pharmacological effects of their own (active metabolite) - ex. enzymes convert the antipsychotic drug quetiapine (Seroquel) to the metabolite N-desalkylquetiapine, which functions as an antidepressant drug - Alternatively, an active metabolite that is converted from an inert compound is called a prodrug - Third, metabolites reveal the substances a person used (ex. most drug-screening tests detect metabolites of controlled substances) Step 4: Elimination: - elimination: Process for how a drug leaves the body (through urine, feces, sweat, saliva, and breath; depending on the drug) ex. alcohol through breath, which is why police use breathalyzer tests - elimination rate: Amount of drug eliminated from the body over time (Physicians rely on drug elimination rates when prescribing how frequently a patient should take a medication) - The elimination rate for most drugs occurs in a half-life (Duration of time necessary for the body to eliminate half of a drug, usually based on measuring the drug concentration in blood) - A drug eliminated in half-lives is referred to as having first-order kinetics (the amount of drug eliminated differs for every half-life) - However, not all drugs follow first-order kinetics for elimination; for other drugs, the elimination rate varies by dose or drug levels in blood (ex. the body eliminates approximately 10 to 14 ml of 100% alcohol per hr - drugs that are not eliminated in set half-lives are described as having zero-order kinetics - Physicians use elimination rate info. when prescribing how frequently patients should take a medication, so they can have patients take the next dose of medication at a time when the effects from the previous treatment begin to subside & drug effects will reach a steady state (sustained level of drug in the body) - ex. take drug A 3 times a day: The drug’s half-life might be about 6–8 hours, so approximately half of the - drug is still in the body 6–8 hours later, the next administration of the drug would boost the drug concentrations back to therapeutically effective levels Pharmacodynamics: Describing the Actions of Drugs: - pharmacodynamics: Mechanisms of action for a drug (for psychoactive drugs this usually occurs at the synapse with neurotransmission) - First, certain substances can interfere with the propagation of action potentials (ex. a toxin called tetrodotoxin, found in the puffer fish, prevents action potentials from occurring by blocking Na+ channels, which causes a cessation in neurotransmission) - Through these actions, puffer fish paralyze any prey they successfully inject - For nervous system research, neuroscientists administer tetrodotoxin to different brain structures in animals to temporarily disable a structure’s functioning in order to learn about a structure’s effects on the functioning of other structures in the brain as well as the importance a structure has for behavior - Second, many substances can alter the synthesis of NTs (like dopamine) - ex: “L-DOPA,” also serves as a drug for the treatment of Parkinson’s disease (a movement disorder produced by the destruction of dopamine neurons in the nigrostriatal pathway) - By increasing the number of L-DOPA molecules within dopamine neurons, L-DOPA administration leads to an increased production of dopamine - In doing so, L-DOPA counteracts dopamine loss in Parkinson’s disease - Unfortunately, these drug effects fail to prevent further dopamine neuron loss in this progressive degenerative disease & eventually, the neural loss reaches a point when no medication provides sufficient relief of Parkinson’s symptoms - Third: Drugs also may interfere with neurotransmitter storage in vesicles - ex. The psychostimulant drug amphetamine interferes with dopamine storage by entering dopamine vesicles and expelling dopamine, then dopamine leaks out from the axon terminal and enters the synaptic cleft where dopamine binds to dopamine receptors, causing an increase in dopamine transmission - Fourth: Drugs may also interfere with the binding of a neurotransmitter to a receptor (Fig 4.7) - ex. haloperidol (antipsychotic) acts through a basic receptor mechanism called receptor antagonism - As a receptor antagonist, haloperidol binds to the D2 receptor and prevents dopamine from binding to and activating the D2 receptor - Through this action, haloperidol prevents dopamine neurotransmission through the D2 receptors - Fifth: Drugs can alter the activity of enzymes that break down neurotransmitters - ex. Fig. 4.7 shows a drug bound to both the MAO & COMT - For MAO, an antidepressant drug called moclobemide binds to and prevents MAO from breaking down dopamine (MAO inhibitors such as moclobemide may reduce depressive symptoms by enhancing neurotransmission of dopamine, as well as the neurotransmitters serotonin and norepinephrine) - Fig 4.7: also shows a drug called entacapone (COMT inhibitor) acting on the enzyme COMT to increase dopamine levels (COMT inhibitors serve as another treatment option for Parkinson’s disease) - Sixth: Many drugs also interfere with the reuptake of neurotransmitters. - Figure 4.7 shows the psychostimulant drug cocaine bound to the dopamine transporter - Cocaine blocks the dopamine transporter preventing dopamine from entering the axon terminal, resulting in increased dopamine levels in the synaptic cleft and the continuation of dopamine neurotransmission Radioligand Binding for Measuring Receptor Affinity: - Radioligand binding: a technique for studying the affinity and efficacy that drugs have for receptors - ligand: a chemical substance that binds to a receptor (both drugs and neurotransmitters) - radioligand: produced by adding a radioactive element to a ligand - Researchers conduct most radioligand experiments using dissected brain tissue that was mixed together with a chemical solution called a buffer, forming a homogenized solution of brain tissue and buffer - Another approach uses a large collection of cells grown in culture, referred to as cell lines - After preparing the brain tissue using either method, researchers apply the radioligand to the tissue solution, then the solution is passed through a filter which allowa the buffer solution to pass through but not brain tissue to pass through - After filtering, the filter contains brain tissue along with any of the radioligand bound to receptors in the brain tissue - Researchers then use radioactivity counters on the filters - If the drug successfully binds to receptors in the brain tissue, then the researchers will find high radioactivity counts in the filters - However, if the radioligand bound to few if any receptors in the tissue, then the radioligand would have passed through the filter with the rest of the solution & researchers would detect low radioactivity counts from the filter (measured in molality) - Molality: number of moles (mol) per volume of solution - mole: number of grams of a substance divided by the molecular weight of the substance - Bm a x (maximum binding potential): amount of drug that fully binds to population of receptors. - In figure 1, the Bm a x value of the radioligand is 10 –3 M (or 0.001 M) - Kd value (dissociation constant): the amount of drug that occupies 50 percent of receptors - Drugs with low Kd values can achieve 50 percent receptor occupancy at lower drug concentrations than drugs with higher Kd values (for interpreting these data, the lower the Kd value, the greater a drug’s receptor affinity) - An alternative approach for assessing receptor affinities produces an inhibition constant, or Ki value: The approach uses similar radioligand experimental procedures, except That Ki values are derived by assessing the competition between two different drugs - Only one of the drugs serves as the radioligand; the other drug is not radioactive - For this procedure, a researcher places both the radioligand and the nonradioactive drug into the same brain tissue solution - In this way, the researcher assesses the affinity of the nonradioactive drug by how well it binds to these receptors in the presence of the radioligand - The compound with the higher receptor affinity outcompetes the compound with the lower receptor affinity - In this case, fewer radioactivity counts indicate that the nonradioactive compound had a greater receptor affinity than the radioligand - Box 4.1 figure 2 shows an example of a K i experiment. Like figure 1, this graph provides the concentration of a drug—in this case, the nonradioactive drug—on the x-axis. In this figure, however, the y-axis refers to the percentage of receptors bound by the radioligand - According to the figure, greater receptor occupancy by the radioligand occurred with the lowest concentration of the nonradioactive drug, whereas lower receptor occupancy by the radioligand occurred with the highest concentration of the nonradioactive drug - The K i value represents the concentration of the nonradioactive compound that caused the radioactive compound to provide 50 percent receptor occupancy Psychoactive Drugs and Receptors: - most psychoactive drugs act on receptors for neurotransmitters - The actions of a drug at a receptor depend on how well a drug binds to the receptor and the effects a drug has on the receptor - Binding affinity: a drug’s strength of binding to a receptor - receptor efficacy: a drug’s ability to alter the activity of receptor - Researchers measure a drug’s binding affinity using techniques described above; these tec
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