Pharm T8-15 Flashcards
8.1 What is permeation in the context of drug movement?
Permeation refers to the movement of drug molecules into and within the biological environment.
What is aqueous diffusion?
Aqueous diffusion is the movement of molecules through the watery extracellular and intracellular spaces.
It is a passive process governed by Fick’s law and occurs through small water-filled pores in most capillary membranes, allowing molecules up to the size of small proteins to move between the blood and extravascular space.
Where is aqueous diffusion not possible?
Aqueous diffusion is not possible through the blood-brain barrier (BBB), blood-testis barrier (BTB), and other organs that lack pores.
What is lipid diffusion?
Lipid diffusion is the passive movement of molecules through membranes and other lipid environments, governed by Fick’s law.
How are drugs that cannot readily diffuse across membranes transported?
Drugs that cannot readily diffuse across membranes are transported by special carriers, such as transporter molecules that are important for moving drugs or acting as targets.
What are some types of transporters involved in drug movement?
Types of transporters include:
Ion transporters (e.g., Na+/K+ ATPase)
Neurotransmitter transporters (e.g., serotonin, norepinephrine)
Metabolite transporters (e.g., glucose, amino acids)
Foreign molecule transporters (xenobiotics like anticancer drugs)
Why are selective inhibitors for transporters clinically important?
Selective inhibitors for transporters can have clinical value by regulating the movement of drugs or blocking unwanted drug effects.
What is endocytosis?
Endocytosis is the process where molecules bind to specialized components (receptors) on the cell membrane, which is followed by internalization through the infolding of the membrane, allowing large or lipid-insoluble chemicals to enter the cell.
What types of molecules are typically transported through endocytosis?
Endocytosis typically allows very large or lipid-insoluble chemicals, such as large proteins, vitamin B12, and iron (combined with intrinsic factor and transferrin), to enter cells.
What is exocytosis?
Exocytosis is the reverse of endocytosis, where cells expel material, commonly neurotransmitters, through vesicle release.
What is Fick’s law of diffusion?
Fick’s law of diffusion predicts the rate of movement of molecules across a barrier, based on parameters such as the concentration gradient (C1-C2), the permeability coefficient for the drug, and the thickness of the barrier membrane.
How do surface area and membrane thickness affect drug absorption according to Fick’s law?
Drug absorption is faster from organs with large surface areas (e.g., the small intestine) and thin membrane barriers (e.g., the lungs) compared to organs with smaller surface areas (e.g., the stomach) or thicker membrane barriers (e.g., the skin).
What affects the aqueous solubility of a drug?
Aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of the molecule.
Water molecules, behaving as dipoles, are attracted to charged drug molecules, forming an aqueous shell around them.
How is lipid solubility related to charge?
Lipid solubility of a molecule is inversely proportional to its charge; the more charged a molecule is, the less lipid-soluble it becomes.
Why are many drugs considered weak acids or weak bases?
Many drugs are weak acids or weak bases, and their degree of ionization (charged or uncharged) depends on the pH of the surrounding medium, which can be predicted using the Henderson-Hasselbalch equation if the pKa of the drug and the pH of the medium are known.
What happens to weak bases when they are protonated?
Weak bases become ionized, more polar, and more water-soluble when protonated.
What happens to weak acids when they are protonated?
Weak acids are not ionized when protonated, making them less water-soluble.
Why is the Henderson-Hasselbalch equation clinically important?
The Henderson-Hasselbalch equation is important for estimating or altering the partitioning of drugs between compartments with different pH levels, which affects drug absorption, excretion, and distribution.
How does pH affect the excretion of weak acid drugs?
Excretion of weak acid drugs, such as aspirin, is faster in alkaline urine because ionization increases, reducing the drug’s reabsorption in the renal tubules.
How does pH affect the excretion of weak base drugs?
Excretion of weak base drugs, such as amphetamine, is faster in acidic urine because increased ionization reduces reabsorption from the renal tubules.
What affects the aqueous solubility of a drug?
Aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of the molecule.
Water molecules, behaving as dipoles, are attracted to charged drug molecules, forming an aqueous shell around them.
How is lipid solubility related to charge?
Lipid solubility of a molecule is inversely proportional to its charge; the more charged a molecule is, the less lipid-soluble it becomes.
Why are many drugs considered weak acids or weak bases?
Many drugs are weak acids or weak bases, and their degree of ionization (charged or uncharged) depends on the pH of the surrounding medium, which can be predicted using the Henderson-Hasselbalch equation if the pKa of the drug and the pH of the medium are known.
What happens to weak bases when they are protonated?
Weak bases become ionized, more polar, and more water-soluble when protonated.
What happens to weak acids when they are protonated?
Weak acids are not ionized when protonated, making them less water-soluble.
Why is the Henderson-Hasselbalch equation clinically important?
The Henderson-Hasselbalch equation is important for estimating or altering the partitioning of drugs between compartments with different pH levels, which affects drug absorption, excretion, and distribution.
How does pH affect the excretion of weak acid drugs?
Excretion of weak acid drugs, such as aspirin, is faster in alkaline urine because ionization increases, reducing the drug’s reabsorption in the renal tubules.
How does pH affect the excretion of weak base drugs?
Excretion of weak base drugs, such as amphetamine, is faster in acidic urine because increased ionization reduces reabsorption from the renal tubules.
What is the structure-activity relationship (SAR)?
SAR is the relationship between the chemical (3D) structure of a molecule and its biological activity. It involves modifying the chemical structure of a drug to alter its biological effect or potency.
How is SAR analysis used in drug modification?
SAR analysis is used to determine which chemical groups in a drug evoke a specific biological effect.
Techniques of chemical synthesis are employed to insert new chemical groups into the drug and test these modifications for their biological effects.
What structural components are required for maximum sympathomimetic activity?
For maximum sympathomimetic activity, a drug must have:
An amine group two carbons away from an aromatic group.
A hydroxyl group at the chiral beta position in the R-configuration.
Hydroxyl groups in the meta and para positions of the aromatic ring to form a catechol, essential for receptor binding.
How does the type of amine group affect sympathomimetic drug activity?
Primary or secondary amine: Direct-acting drug.
Tertiary amine: Poor direct action.
Amine with bulky substituents: Greater beta-adrenergic receptor activity.
Amine with non-bulky substituents: Greater alpha-adrenergic receptor activity.
What are examples of direct-acting sympathomimetics?
Examples of direct-acting adrenergic receptor agonists include salbutamol, phenylephrine, isoproterenol, and dobutamine.
An example of a dopaminergic agonist is fenoldopam.
What are examples of indirect-acting sympathomimetics?
Indirect-acting sympathomimetics include drugs that block norepinephrine and dopamine transporters, such as amphetamines (MDMA), ephedrine, and cocaine.
8.3 What are the major manifestations of heart failure?
The major manifestations of heart failure are dyspnea (difficulty breathing) and fatigue, resulting from inadequate cardiac output (CO) to meet the body’s needs.
What are the three major groups of drugs used to treat heart failure?
- Positive ionotropic drugs: Digoxin (cardiac glycosides), dobutamine (beta-agonist), inamrinone (PDE inhibitors).
- Vasodilators: Nitroprusside, nitrates, hydralazine, loop diuretics, ACE inhibitors, Nesiritide, inamrinone (PDE inhibitors).
- Miscellaneous drugs for chronic failure: Beta-blockers, spironolactone, ACE inhibitors, loop diuretics, Nesiritide.
What are the causes of heart failure?
Causes of heart failure include:
Loss of functional myocardium (e.g., post-myocardial infarction).
Chronic hypertension, valvular diseases, coronary artery disease, and cardiomyopathic diseases.
What are the types of heart failure?
Systolic failure: Reduced cardiac contractile force and ejection fraction (1/3 of cases).
Diastolic failure: Stiffening or other changes preventing ventricular filling (1/3 of cases), with a normal ejection fraction.
Combination of systolic and diastolic failure: 1/3 of cases.
What are the key therapeutic strategies for treating heart failure?
- Diuretics: Remove salt and water.
- ACE inhibitors: Reduce afterload and salt/water retention.
- Beta-blockers: Reduce excessive sympathetic stimulation.
- Vasodilators: Reduce preload and afterload.
- Positive ionotropic drugs (e.g., digoxin): Augment cardiac contractility, especially in systolic failure.
What is the recommended treatment for acute heart failure?
Loop diuretics.
Beta-agonists or phosphodiesterase (PDE) inhibitors (for severe failure).
Vasodilators to optimize filling pressures and blood pressure.
Nesiritide (a recombinant natriuretic peptide with vasodilating and diuretic properties).
What is the best treatment for chronic heart failure?
Diuretics (loop diuretics + spironolactone).
ACE inhibitors.
Beta-blockers (if tolerated).
Digitalis (if systolic failure is prominent).
What is the role of diuretics in heart failure treatment?
Diuretics are the first-line therapy in both systolic and diastolic heart failure. Furosemide is used for acute failure and severe edema, while hydrochlorothiazide is used for mild chronic failure.
Spironolactone and eplerenone (aldosterone antagonists) have long-term benefits and reduce mortality in chronic heart failure.
What are the benefits of angiotensin antagonists in heart failure?
Angiotensin antagonists (ACE inhibitors and ARBs) reduce morbidity and mortality in chronic heart failure.
They decrease aldosterone secretion, salt and water retention, and vascular resistance.
ARBs like losartan offer similar benefits to ACE inhibitors (e.g., captopril), although less clinical experience exists with ARBs.
When are beta1-adrenoreceptor agonists like dobutamine and dopamine used in heart failure?
Dobutamine and dopamine are used in acute heart failure where systolic function is severely depressed.
They are not used in chronic heart failure due to tolerance development, lack of oral efficacy, and arrhythmogenic risks.
Which beta-blockers are used in chronic heart failure?
Beta-blockers like carvedilol, labetalol, and metoprolol are used in chronic heart failure to reduce disease progression. Nebivolol, a newer beta-blocker, has additional vasodilator effects.
Why are phosphodiesterase inhibitors not frequently used in chronic heart failure?
Phosphodiesterase inhibitors (e.g., inamrinone, milrinone) are not used in chronic heart failure as they increase morbidity and mortality.
These drugs increase cAMP, leading to increased intracellular calcium and vasodilation.
What is the role of vasodilators in heart failure?
Vasodilators like nitroprusside and nitroglycerin are used in acute severe heart failure with congestion.
They reduce cardiac size and improve heart efficiency by adjusting preload and afterload.
Nesiritide is also used for vasodilation in acute failure, requiring renal function monitoring.
Hydralazine and isosorbide dinitrate are used in combination for chronic heart failure.
What non-pharmacologic therapies are available for heart failure?
Non-pharmacologic therapies include surgical procedures to remove nonfunctional myocardium (with mixed results), pacemaker resynchronization for patients with conduction abnormalities, and coronary revascularization, which has proven beneficial in heart failure treatment.
How does digoxin affect intracellular calcium and cardiac contractility?
Digoxin inhibits Na+/K+ ATPase, leading to a slight increase in intracellular Na+, which alters the Na+/Ca2+ exchange, resulting in increased intracellular Ca2+.
This increase in Ca2+ enhances cardiac contractility.
What are the cardiovascular effects of digoxin?
Digoxin increases cardiac contractility, resulting in higher ejection fraction, decreased end-systolic and end-diastolic size,
increased cardiac output, and reduced compensatory sympathetic and renal responses (lower HR, preload, and afterload).
What are the early parasympathetic effects of digoxin?
Early effects include prolongation of the PR interval and flattening of T-waves.
It also influences parasympathetic tone on the AV node and atria, which can be blocked by atropine to prevent excessive slowing of the AV node firing.
What are the toxic effects of digoxin on the heart?
Digoxin toxicity can cause increased automaticity due to elevated intracellular Ca2+, leading to delayed afterdepolarizations, extrasystoles, tachycardia, and fibrillation. Premature ventricular beats and bigeminy are also common toxic effects.
What factors amplify digoxin toxicity?
Hypokalemia, hypomagnesemia, and hypercalcemia can amplify digoxin’s toxicity.
Additionally, interactions with drugs like quinidine, amiodarone, and verapamil can increase digoxin serum levels and exacerbate toxicity.
What are the clinical uses of digoxin in heart failure?
Digoxin is used as a positive inotropic agent in chronic heart failure to reduce symptoms and improve functional status but does not prolong life.
It is more toxic than other heart failure drugs and has a long half-life, requiring careful dosing and monitoring.
What are the signs and symptoms of digoxin toxicity?
Symptoms of digoxin toxicity include arrhythmias, nausea, vomiting, diarrhea, confusion, hallucinations (rare), and visual or endocrine abnormalities. Severe intoxication can result in cardiac arrest.
How is digoxin toxicity treated?
Digoxin toxicity is treated by correcting electrolyte imbalances (potassium or magnesium), using antiarrhythmic drugs in mild cases, and administering digoxin-specific antibodies (Digibind) in severe cases.
9.1 What factors influence the distribution of drugs in the body?
The distribution of drugs is influenced by:
Size of the organ
Blood flow to the organ
Solubility of the drug
Binding of the drug to macromolecules in the blood or tissues
How does the size of an organ affect drug distribution?
Larger organs can take up more drug because the concentration gradient between the blood and the organ remains high even after a significant amount of drug has been transferred.
For example, skeletal muscle can accumulate large amounts of drug due to a low tissue concentration relative to blood.
How does blood flow impact drug distribution?
Blood flow to a tissue affects the rate of drug uptake but does not change the amount of drug in the tissue at equilibrium.
Well-perfused tissues (e.g., brain, heart, kidney) reach high tissue concentrations more quickly than poorly perfused tissues (e.g., fat, bone).
How does drug solubility affect its distribution?
Drug solubility influences the concentration of the drug in the extracellular fluid surrounding blood vessels.
Lipid-soluble drugs can rapidly distribute into tissues with high lipid content, such as the brain, while water-soluble drugs may remain in the extracellular space.
What is the role of drug binding in distribution?
Binding of drugs to macromolecules (e.g., plasma proteins or tissue proteins) increases the drug’s concentration in that compartment.
For example, warfarin binds strongly to plasma albumin, restricting its diffusion out of the vascular compartment, while chloroquine binds to tissue proteins, reducing its plasma concentration.
What is the apparent volume of distribution (Vd)?
The apparent volume of distribution (Vd) is a pharmacokinetic parameter that reflects how a drug distributes throughout the body.
It is the ratio of the amount of drug in the body to its plasma concentration.
Vd is termed “apparent” because it does not correspond to a physical volume but represents how extensively a drug disperses into tissues.
What does a high Vd indicate about a drug?
A high Vd indicates that the drug extensively distributes into tissues outside the plasma, suggesting high tissue binding or solubility.
Conversely, a low Vd suggests the drug is primarily confined to the plasma compartment.
What does a low Vd suggest about a drug’s distribution?
A low Vd suggests that the drug is primarily confined to the plasma compartment, potentially due to high binding to plasma proteins or poor permeability into tissues.
Why might a drug’s Vd be low even if a large amount is present in the body?
A drug’s Vd might be low if it is highly bound in tissues and not free in the plasma.
This means that although a large amount of the drug is in the body, it is not available in the plasma for measurement.
9.2 What is the role of the sympathetic nervous system (SANS) in the body?
The SANS prepares the body for “fight or flight” by:
Increasing blood flow to skeletal muscles
Enhancing cardiac rate and contractility
Diverting blood from splanchnic vessels to muscles
Slowing intestinal peristalsis and increasing sphincter function
Releasing glucose and free fatty acids into the blood
Dilating bronchi to increase oxygen uptake
Stimulating sweat glands to release heat
What neurotransmitter is used at preganglionic sites in the sympathetic nervous system?
Acetylcholine is used as the neurotransmitter at preganglionic sites between the first and second neurons in the sympathetic nervous system.
How does the postsynaptic (second) neuron in the sympathetic nervous system differ from other systems?
The postsynaptic neuron in the sympathetic nervous system branches out and makes multiple en-passant contacts with several cells, forming varicosities.
This allows activation of many cells from a single neuron. Norepinephrine, the mediator at these synapses, is confined to each ending.
How is the sympathetic nervous system different in the adrenal medulla?
In the adrenal medulla, the first neurons do not synapse before reaching the medulla.
Instead, they synapse directly on neuroendocrine cells in the medulla via acetylcholine, which causes the secretion of epinephrine into the blood.
How is norepinephrine (NE) stored and released in adrenergic synapses?
In adrenergic synapses, norepinephrine is stored in small, membrane-enclosed vesicles within the varicosities.
NE is released from these vesicles and reacts with adrenoceptors on effector cells or presynaptically on the varicosities.
What is the function of presynaptic alpha2 adrenoceptors in the sympathetic nervous system?
Presynaptic alpha2 adrenoceptors act as a negative feedback mechanism.
When activated, they inhibit the release of norepinephrine from the varicosities.
What are the main types of adrenoceptors in the sympathetic nervous system?
: The main types of adrenoceptors are:
α1
α2
β (with further subtypes)
What is the effect of adrenergic stimulation on the cardiovascular system?
Adrenergic stimulation increases cardiac rate and contractility, leading to enhanced cardiac output and better blood flow to muscles and other vital organs.
What are the effects of sympathetic activation on the gastrointestinal system?
Sympathetic activation decreases peristalsis and increases sphincter function in the gastrointestinal system, slowing down digestion and propulsion of intestinal contents.
How does sympathetic stimulation affect respiratory function?
Sympathetic stimulation dilates the bronchi, increasing tidal volume and alveolar oxygen uptake, which improves respiratory efficiency.
9.3 What is the primary mechanism of action of Quinidine?
Quinidine primarily blocks the fast inward sodium current (INa), causing a decrease in the phase 0 depolarization of the action potential (AP) by reducing the maximum rate of depolarization (Vmax).
It also blocks other ion currents, including sodium, calcium, and potassium channels.
What are the main effects of Quinidine on the cardiac action potential and ECG?
Quinidine prolongs the cardiac action potential and the QT interval on the ECG.
It can cause a wide notched P wave, a wide QRS complex, a depressed ST segment, and U waves due to its effects on depolarization and repolarization.
What is Quinidine’s half-life and how is it metabolized?
Quinidine has a half-life of 6-8 hours when taken orally and is primarily eliminated by the liver enzyme cytochrome P450 (CYP450).
It also inhibits CYP450 2D6, potentially increasing the blood levels of other drugs metabolized by this enzyme.
What are some common adverse effects of Quinidine?
Adverse effects of Quinidine include thrombocytopenia, granulomatous hepatitis, myasthenia gravis, torsades de pointes,
and cinchonism (tinnitus, reversible deafness, blurred vision, confusion, flushed skin, headaches, abdominal pain, vertigo, nausea, vomiting, and diarrhea).
What are the primary uses of Lidocaine?
Lidocaine is used as a local anesthetic for relieving itching, burning, and pain from skin inflammation, as a dental anesthetic,
for minor surgery, and intravenously for treating ventricular arrhythmias (such as during acute myocardial infarction, digoxin poisoning, cardioversion, and cardiac catheterization).
It is also used inhaled as an antitussive to reduce cough reflex.
How does Lidocaine work as an antiarrhythmic agent?
Lidocaine works by blocking sodium channels in both the conduction system and myocardial cells, leading to an increased depolarization threshold and a reduced likelihood of early action potentials that can cause arrhythmias.
What are the main characteristics of Quinidine compared to Lidocaine?
Quinidine is a Class Ia antiarrhythmic drug that prolongs the cardiac action potential and QT interval and blocks multiple ion channels.
Lidocaine is a Class Ib antiarrhythmic drug that primarily blocks sodium channels, increases depolarization threshold, and is used for acute ventricular arrhythmias and as a local anesthetic.
What additional actions does Quinidine have aside from its primary antiarrhythmic effects?
Quinidine inhibits Na+/K+ ATPase at micromolar concentrations, similar to digitalis glycosides, and affects several ion currents, including the delayed rectifier potassium currents and ATP-sensitive potassium channels.
What are the common adverse effects and drug interactions associated with Lidocaine?
Lidocaine is generally well-tolerated, but adverse effects can include dizziness, drowsiness, and at higher doses, seizures or cardiac toxicity.
It may interact with other antiarrhythmic drugs and local anesthetics, potentially enhancing their effects or toxicity.
What is the mechanism of action of Lidocaine in anesthesia?
Lidocaine blocks fast voltage-gated sodium channels in neurons, preventing the propagation of action potentials.
This stops pain signals from being transmitted, thereby providing local anesthesia.
What are the absolute contraindications for using Lidocaine?
Absolute contraindications for Lidocaine include:
Heart block (2nd or 3rd degree without a pacemaker)
Severe SA block (without a pacemaker)
Serious adverse drug effects or
hypersensitivity to Lidocaine or corn/corn-related products
Concurrent use of other Class I antiarrhythmic agents
WPW syndrome, Adams-Stokes syndrome
Tooth pain in children and infants
What are some partial contraindications for Lidocaine?
Partial contraindications for Lidocaine include:
Elderly individuals
Hypotension
Bradycardia
Accelerated idioventricular rhythm
Porphyria
What are the adverse effects of Lidocaine when used as a local anesthetic?
Adverse effects of Lidocaine, especially with excessive systemic exposure, can include:
CNS effects: nervousness, anxiety, tingling around the mouth, headache, tremor, dizziness, pupillary changes, hallucinations, seizures, drowsiness, lethargy, loss of consciousness, respiratory depression, apnea
CV effects: hypotension, bradycardia, arrhythmias, flushing, venous insufficiency, cardiac arrest
Other: bronchospasm, dyspnea, tinnitus, local burning of eyes, conjunctival hyperemia, visual changes, skin itching, rash, urticaria, edema, angioedema, methemoglobinemia, and allergies
What is the mechanism of action of Amiodarone?
Amiodarone is a Class III antiarrhythmic agent that prolongs the phase 3 repolarization stage of the cardiac action potential.
It is a potassium channel blocker but also has properties similar to Class Ia, II, and IV antiarrhythmics.
It affects the SA and AV nodes, increases the refractory period via Na+ and K+ channel effects, and slows intra-cardiac conduction of the AP.
For which types of cardiac arrhythmias is Amiodarone used?
Amiodarone is used for various types of cardiac arrhythmias, including:
Ventricular arrhythmias (e.g., shock-refractory ventricular fibrillation, hemodynamically stable ventricular tachycardia)
Atrial arrhythmias (e.g., atrial fibrillation during and after open-heart surgery, and to manage Afib before other measures)
What are the contraindications for using Amiodarone?
Contraindications for Amiodarone include:
Pregnancy and breastfeeding
SA nodal bradycardia
AV block (2nd and 3rd degree without a pacemaker)
Patients with depressed lung function
Neonates (due to fatal gasping syndrome)
Digitalis toxicity
What are the common adverse effects of Amiodarone?
Common adverse effects of Amiodarone include:
Pulmonary toxicity (e.g., interstitial pneumonitis)
Thyroid dysfunction (e.g., hyperthyroidism or hypothyroidism)
Liver toxicity
Skin changes (e.g., photosensitivity, blue-gray discoloration)
Neurological effects (e.g., tremors, ataxia)
Gastrointestinal disturbances
Cardiac effects (e.g., bradycardia, heart block)
Corneal deposits and visual disturbances
What is the most serious adverse effect of Amiodarone?
The most serious adverse effect of Amiodarone is interstitial lung disease, also known as pulmonary fibrosis.
Risk factors include high doses for prolonged periods, decreased lung function, increased age, and preexisting pulmonary disease.
What thyroid abnormalities can occur with Amiodarone use?
Amiodarone can cause thyroid abnormalities because it is structurally similar to thyroxine (T4). This can result in:
Hypothyroidism
Hyperthyroidism
What are the common eye problems associated with Amiodarone?
Common eye problems with Amiodarone include:
Corneal microdeposits (cornea verticillata)
occurring in 90% of patients on high doses for more than 6 months; usually asymptomatic
Bluish halo around lights (affecting about 10% of patients)
Optic neuropathy (1-2% of patients)
Bilateral optic disc swelling and mild/reversible visual field defects
What gastrointestinal and liver issues are associated with Amiodarone?
Amiodarone can cause:
Abnormal liver enzymes
Jaundice
Hepatitis
Hepatomegaly (less common)
Pseudoalcoholic cirrhosis
What skin problems are associated with long-term use of Amiodarone?
Long-term use of Amiodarone can lead to:
Light-sensitive blue-gray discoloration of the skin
Patients should avoid sun and UV light exposure to prevent this effect
What are the potential neurological and reproductive side effects of Amiodarone?
Neurological side effects of Amiodarone include peripheral neuropathy with long-term use.
Reproductive side effects include epididymitis, which is inflammation of the epididymis, potentially affecting one or both sides and resolving with drug cessation.
What are the risks of cancer associated with Amiodarone?
Amiodarone is associated with an increased risk of cancer, particularly in males, and this risk is dose-dependent.
- What is the difference between elimination and excretion of drugs?
Elimination of drugs refers to the removal of drugs from the body through various processes, including metabolism and excretion.
Excretion specifically refers to the removal of drug metabolites or unchanged drugs from the body, primarily via the kidneys.
For some drugs, elimination may occur long before excretion.
What characterizes first-order elimination kinetics?
In first-order elimination kinetics, the rate of drug elimination is proportional to the drug concentration in the plasma.
This means that a higher concentration of the drug results in a greater amount being eliminated per unit time.
The concentration of the drug decreases exponentially, and the half-life of elimination is constant regardless of the drug concentration.
How does zero-order elimination differ from first-order elimination?
In zero-order elimination, the rate of drug elimination is constant and does not depend on the drug concentration.
This occurs when the elimination mechanisms are saturated, leading to a linear decrease in drug concentration over time.
Zero-order kinetics is typical of drugs like ethanol, phenytoin, and aspirin at high therapeutic or toxic concentrations.
What is the half-life (T₁/₂) of a drug, and how is it calculated for first-order kinetics?
The half-life (T₁/₂) of a drug is the time required for the concentration of the drug in the body or blood to decrease by 50%.
For drugs following first-order kinetics, the half-life is constant regardless of drug concentration and can be calculated using the formula:
Why is understanding the half-life of a drug important in clinical settings?
Understanding the half-life of a drug helps predict the duration of its action and the time required to reach steady-state concentrations.
It also informs dosing schedules and helps assess how long it will take for the drug to be eliminated from the body, which is crucial for managing drug therapy and avoiding toxicity.
How many half-lives are typically required to reach steady-state concentrations with chronic dosing?
It generally takes 3 to 4 half-lives of dosing at a constant rate to reach steady-state concentrations, where the drug’s effect is clinically indistinguishable from the steady-state effect.
What factors can alter the half-life of a drug?
Factors that can alter the half-life of a drug include changes in clearance (CL), volume of distribution (V_d), disease state, age, and other individual patient variables.
Changes in clearance usually have a greater impact on drug half-life than changes in volume of distribution.
10.2 How can norepinephrine (NE) synthesis be pharmacologically altered?
NE synthesis can be influenced by:
Alpha-methyltyrosine: Inhibits tyrosine hydroxylase, used rarely to treat pheochromocytoma.
Carbidopa: Inhibits dopa decarboxylase, used in the treatment of Parkinson’s disease.
Methyldopa: Used to treat hypertension during pregnancy; acts as a false transmitter.
6-Hydroxydopamine: Selectively destroys noradrenergic nerve terminals by forming a reactive quinone; not used clinically.
What is the mechanism of action of reserpine, and how does it affect norepinephrine (NE) levels?
Reserpine blocks the vesicular monoamine transporter, which prevents NE and other amines from being stored in synaptic vesicles.
As a result, NE accumulates in the cytoplasm where it is degraded by monoamine oxidase (MAO).
This decreases NE levels and reduces its release during sympathetic transmission.
How does guanethidine affect norepinephrine (NE) release?
Guanethidine inhibits the release of NE from sympathetic nerve terminals. It has little effect on the adrenal medulla and
does not impact nerve terminals releasing neurotransmitters other than NE.
What are indirect-acting sympathomimetic drugs, and what is their effect on norepinephrine (NE) release?
Indirect-acting sympathomimetic drugs like Tyramine, Amphetamine, and Ephedrine increase the release of NE from nerve terminals.
They act by promoting the release of NE rather than directly stimulating adrenergic receptors.
How do alpha-2 agonists influence norepinephrine (NE) release?
Alpha-2 agonists inhibit NE release by binding to presynaptic alpha-2 adrenergic receptors. This decreases NE release from sympathetic nerve terminals.
What is the effect of MAO inhibitors on norepinephrine (NE) release?
MAO inhibitors affect NE release by preventing the breakdown of NE in the nerve terminal.
This can lead to increased levels of NE available for release during sympathetic transmission.
- What is clearance (CL) in pharmacology, and how is it defined?
Clearance (CL) is a measure of the rate at which a drug is removed from the plasma. It is defined by the formula:
