Pharm T8-15 Flashcards
(282 cards)
1
Q
8.1 What is permeation in the context of drug movement?
A
Permeation refers to the movement of drug molecules into and within the biological environment.
2
Q
What is aqueous diffusion?
A
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.
3
Q
Where is aqueous diffusion not possible?
A
Aqueous diffusion is not possible through the blood-brain barrier (BBB), blood-testis barrier (BTB), and other organs that lack pores.
4
Q
What is lipid diffusion?
A
Lipid diffusion is the passive movement of molecules through membranes and other lipid environments, governed by Fick’s law.
5
Q
How are drugs that cannot readily diffuse across membranes transported?
A
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.
6
Q
What are some types of transporters involved in drug movement?
A
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)
7
Q
Why are selective inhibitors for transporters clinically important?
A
Selective inhibitors for transporters can have clinical value by regulating the movement of drugs or blocking unwanted drug effects.
8
Q
What is endocytosis?
A
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.
9
Q
What types of molecules are typically transported through endocytosis?
A
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.
10
Q
What is exocytosis?
A
Exocytosis is the reverse of endocytosis, where cells expel material, commonly neurotransmitters, through vesicle release.
11
Q
What is Fick’s law of diffusion?
A
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.
12
Q
How do surface area and membrane thickness affect drug absorption according to Fick’s law?
A
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).
13
Q
What affects the aqueous solubility of a drug?
A
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.
14
Q
How is lipid solubility related to charge?
A
Lipid solubility of a molecule is inversely proportional to its charge; the more charged a molecule is, the less lipid-soluble it becomes.
15
Q
Why are many drugs considered weak acids or weak bases?
A
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.
16
Q
What happens to weak bases when they are protonated?
A
Weak bases become ionized, more polar, and more water-soluble when protonated.
17
Q
What happens to weak acids when they are protonated?
A
Weak acids are not ionized when protonated, making them less water-soluble.
18
Q
Why is the Henderson-Hasselbalch equation clinically important?
A
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.
19
Q
How does pH affect the excretion of weak acid drugs?
A
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.
20
Q
How does pH affect the excretion of weak base drugs?
A
Excretion of weak base drugs, such as amphetamine, is faster in acidic urine because increased ionization reduces reabsorption from the renal tubules.
21
Q
What affects the aqueous solubility of a drug?
A
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.
22
Q
How is lipid solubility related to charge?
A
Lipid solubility of a molecule is inversely proportional to its charge; the more charged a molecule is, the less lipid-soluble it becomes.
23
Q
Why are many drugs considered weak acids or weak bases?
A
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.
24
Q
What happens to weak bases when they are protonated?
A
Weak bases become ionized, more polar, and more water-soluble when protonated.
25
What happens to weak acids when they are protonated?
Weak acids are not ionized when protonated, making them less water-soluble.
26
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.
27
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.
28
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.
29
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.
30
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.
31
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.
32
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.
33
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.
34
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.
35
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.
36
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.
37
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.
38
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.
39
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.
40
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).
41
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).
42
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.
43
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.
44
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.
45
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.
46
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.
47
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.
48
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.
49
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.
50
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).
51
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.
52
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.
53
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.
54
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.
55
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.
56
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.
57
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
58
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.
59
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).
60
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.
61
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.
62
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.
63
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.
64
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.
65
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.
66
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
67
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.
68
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.
69
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.
70
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.
71
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.
72
What are the main types of adrenoceptors in the sympathetic nervous system?
: The main types of adrenoceptors are:
α1
α2
β (with further subtypes)
73
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.
74
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.
75
How does sympathetic stimulation affect respiratory function?
Sympathetic stimulation dilates the bronchi, increasing tidal volume and alveolar oxygen uptake, which improves respiratory efficiency.
76
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.
77
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.
78
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.
79
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).
80
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.
81
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.
82
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.
83
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.
84
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.
85
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.
86
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
87
What are some partial contraindications for Lidocaine?
Partial contraindications for Lidocaine include:
Elderly individuals
Hypotension
Bradycardia
Accelerated idioventricular rhythm
Porphyria
88
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
89
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.
90
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)
91
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
92
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
93
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.
94
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
95
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
96
What gastrointestinal and liver issues are associated with Amiodarone?
Amiodarone can cause:
Abnormal liver enzymes
Jaundice
Hepatitis
Hepatomegaly (less common)
Pseudoalcoholic cirrhosis
97
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
98
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.
99
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.
100
10. 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.
101
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.
102
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.
103
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:
104
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.
105
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.
106
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.
107
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.
108
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.
109
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.
110
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.
111
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.
112
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.
113
How do tricyclic antidepressants (TCAs) affect norepinephrine (NE) uptake and sympathetic transmission?
Tricyclic antidepressants (TCAs), such as Desipramine, inhibit the reuptake of NE into presynaptic nerve terminals, increasing NE levels in the synaptic cleft.
This primarily affects the central nervous system (CNS) but can also lead to tachycardia and dysrhythmias.
114
What is the impact of cocaine on norepinephrine (NE) uptake and sympathetic transmission?
Cocaine inhibits the reuptake of NE, enhancing sympathetic transmission.
This results in increased NE levels, leading to tachycardia, elevated blood pressure, and CNS effects such as euphoria.
115
10.3 What is the main purpose of expectorants?
Expectorants are drugs that increase the hydration of secretions in the airways, reducing the viscosity and thickness of mucus.
This makes it easier to cough up and clear mucus from the respiratory tract. They also help to lubricate the irritated respiratory tract.
Common expectorants:
Guaifenesin
Potassium iodide
116
How do mucolytic agents work, and what is their purpose?
Mucolytic agents dissolve thick mucus by breaking down chemical bonds within the secretions.
They lower the viscosity of mucus by altering the mucin-containing components, making it easier to expel.
Common mucolytic:
Acetylcysteine
117
What is the primary function of antitussives?
Antitussives suppress the cough reflex.
They act through various mechanisms, often by affecting the central nervous system to reduce the urge to cough.
Prototypical antitussives include:
Codeine
Dextromethorphan
118
Describe the properties and effects of codeine as an antitussive.
Codeine is an opioid with antitussive effects due to its own action, not its conversion to morphine.
It is less potent as an analgesic compared to morphine but has higher oral effectiveness.
It is effective at doses that do not cause analgesia and has a lower potential for abuse and dependence compared to morphine.
It is often combined with aspirin or acetaminophen.
119
What are the effects of dextromethorphan and how does it compare to other antitussives?
Dextromethorphan is a non-opioid antitussive that works by inhibiting the reuptake of neurotransmitters like serotonin, norepinephrine, and dopamine.
It causes euphoria and self-confidence, which can lead to psychological dependence.
Overdose symptoms include agitation, restlessness, tachycardia, hyperthermia, hyperreflexia, and possibly seizures.
Antidepressant drugs may be used to manage withdrawal side effects.
120
How do expectorants and mucolytics differ in their mechanisms of action?
Expectorants work by increasing the hydration of secretions, reducing mucus viscosity, and making it easier to cough up.
Mucolytics, on the other hand, directly dissolve thick mucus by breaking down chemical bonds within the mucus, lowering its viscosity and facilitating clearance.
121
What are the clinical uses of acetylcysteine?
Acetylcysteine is used as a mucolytic agent to dissolve thick mucus in conditions such as chronic bronchitis and cystic fibrosis.
It also acts as an antidote for acetaminophen (paracetamol) overdose by replenishing glutathione levels.
122
What are some common side effects of dextromethorphan?
Common side effects of dextromethorphan include dizziness, drowsiness, nausea, and gastrointestinal discomfort.
Overdose can lead to more severe symptoms such as agitation, restlessness, tachycardia, hyperthermia, hyperreflexia, and seizures.
123
What are some key differences between codeine and dextromethorphan?
Codeine is an opioid with both antitussive and analgesic effects, with lower abuse potential compared to morphine.
It works effectively at doses that do not produce analgesia.
Dextromethorphan is a non-opioid that primarily acts on neurotransmitter reuptake, causing euphoria and potential psychological dependence,
with overdose leading to agitation, tachycardia, and other severe symptoms.
124
11. 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:
125
What factors influence clearance?
Clearance depends on:
Drug type: Different drugs have different clearance rates.
Blood flow: The rate of blood flow through the organs of elimination affects clearance.
Condition of the organs of elimination: The health status of organs like the liver and kidneys impacts how efficiently they can clear the drug.
126
How does clearance behave with first-order kinetics?
For drugs eliminated with first-order kinetics:
Clearance is constant.
The elimination rate is proportional to the plasma concentration.
As the plasma concentration decreases, the elimination rate slows, resulting in an exponential decrease in drug concentration over time.
127
How does clearance behave with zero-order kinetics?
For drugs eliminated with zero-order kinetics:
Clearance is not constant.
The elimination rate is independent of plasma concentration.
The drug is eliminated at a constant rate regardless of its concentration, leading to a linear decrease in drug concentration over time.
128
What are the primary routes of drug elimination?
Drugs are primarily eliminated from plasma by:
Kidneys: Through excretion.
Liver: Through metabolism and/or excretion
129
What is meant by "flow-limited clearance"?
Flow-limited clearance occurs when a drug is very effectively extracted by an organ, such as the kidneys, meaning the blood is completely cleared of the drug as it passes through that organ.
In this case, the total clearance is limited by the blood flow to the organ rather than the organ's ability to extract the drug.
130
How do conditions affecting blood flow impact drug clearance?
Conditions that affect blood flow, such as cardiac diseases or drugs that influence blood flow, can have more dramatic effects on drug clearance than diseases affecting the eliminating organ itself.
This is because clearance in flow-limited scenarios depends heavily on the rate of blood flow to the organ.
131
How does liver disease affect drug clearance?
Liver disease can impact drug clearance by impairing the liver's ability to metabolize drugs.
Since the liver is responsible for drug metabolism, any disease affecting its function can reduce the rate at which drugs are metabolized and thus affect overall clearance.
132
11.2 What are the main subgroups of α-adrenoceptor blockers based on receptor selectivity?
α-Adrenoceptor blockers can be classified into:
α1-selective blockers
α2-selective blockers
Non-selective blockers
They can also be classified based on their reversibility and duration of action.
133
Name a selective α1 receptor blocker and its uses.
Prazosin is a selective α1 receptor blocker used for:
Symptoms of benign prostatic hyperplasia (BPH)
Hypertension
Post-traumatic stress disorder (PTSD)
134
What are the common adverse effects of selective α1 receptor blockers like Prazosin, Tamsulosin, Doxazosin, and Terazosin?
Common adverse effects include:
First-dose orthostatic hypotension
Dizziness
Headache
135
Which selective α1 receptor blockers are used for both BPH and hypertension?
The selective α1 receptor blockers used for both BPH and hypertension include:
Doxazosin
Terazosin
136
Name selective α1 receptor blockers used specifically for BPH.
Selective α1 receptor blockers used specifically for BPH include:
Prazosin
Tamsulosin
137
What are the selective α2 receptor blockers and their uses?
Selective α2 receptor blockers include:
Mirtazapine: Used in the treatment of depression.
Yohimbine: Used in the treatment of depression.
138
What are potential side effects of selective α2 receptor blockers?
Potential side effects of selective α2 receptor blockers include:
Sedation
Increased serum cholesterol
Increased appetite
139
11.3 What is hepatotoxicity and what are some common causes?
Hepatotoxicity refers to liver damage caused by various substances. Common causes include:
Chemical-driven liver damage: Overdose of a drug or normal therapeutic use with underlying issues like enzyme polymorphisms or pre-existing liver damage.
Natural chemicals: Aflatoxins, microcystins.
Herbal remedies: Some herbal treatments can cause liver injury.
Drugs: More than 900 drugs have been implicated in liver injury, which is a major reason for drug withdrawal from the market.
140
How does drug-induced liver injury manifest, and what are its implications?
Drug-induced liver injury often:
Manifests as abnormal liver enzyme tests without symptoms (subclinical injury).
Is responsible for 5% of all hospital admissions and 50% of acute liver failures.
141
What role does the liver play in drug metabolism?
The liver acts as the principal "metabolic clearing-house" for:
Endogenous substances: Cholesterol, steroid hormones, fatty acids, proteins.
Exogenous substances: Drugs, alcohol.
It performs chemical transformations to make substances suitable for elimination, making it susceptible to drug-induced injury.
142
What occurs during Phase 1 of drug metabolism in the liver?
In Phase 1 of drug metabolism:
Processes: Oxidation, reduction, hydrolysis, hydration.
Location: Smooth endoplasmic reticulum (sER).
Effect: Increases water solubility of the drug and can generate metabolites that are more chemically active and potentially toxic.
143
What occurs during Phase 2 of drug metabolism in the liver?
In Phase 2 of drug metabolism:
Processes: Conjugation with endogenous compounds via transferase enzymes.
Location: Mainly in the cytosol.
Effect: Converts chemically active Phase 1 products into relatively inert forms that are suitable for elimination.
144
Why is the liver highly susceptible to drug-induced injury?
The liver is highly susceptible to drug-induced injury due to its central role in metabolizing both endogenous and exogenous substances.
Its extensive involvement in drug metabolism and detoxification processes makes it vulnerable to damage from various chemicals and drugs.
145
What are Cytochrome P450 enzymes and their role in drug metabolism?
Cytochrome P450 enzymes (CYP) are a superfamily of approximately 50 isoenzymes located in the smooth endoplasmic reticulum (sER) of liver hepatocytes.
Six of these enzymes metabolize 90% of all drugs, making them crucial for drug metabolism.
146
What are the key characteristics of the P450 system that impact drug-induced toxicity?
The key characteristics are:
Genetic Diversity (Polymorphism): Variations in P450 enzymes among individuals can affect drug metabolism, leading to differences in drug sensitivity or resistance.
Poor Metabolizers: Individuals with slower drug metabolism.
Extensive Metabolizers: Individuals with faster drug metabolism.
Polymorphisms cause variable drug responses among different ethnic groups.
Change in Enzyme Activity: Substances can influence CYP enzymes by:
Inhibitors: Block metabolic activity of CYPs, causing immediate effects.
Inducers: Increase CYP activity through enzyme synthesis, leading to progressive effects.
Competitive Inhibition: Some drugs compete for the same CYP enzyme, potentially leading to drug accumulation and altered metabolism.
147
How do CYP enzymes influence liver damage?
CYP enzymes can influence liver damage through:
Mitochondrial Damage: Chemicals causing mitochondrial injury lead to oxidative stress and hepatocyte damage.
Oxidative Stress: Activation of enzymes like CYP2E1 can cause oxidative stress.
Bile Acid Accumulation: Injury to hepatocytes and bile duct cells leads to bile acid accumulation, promoting further damage.
Role of Kupffer and Stellate Cells: These cells, along with leukocytes, contribute to liver damage mechanisms.
148
What are the types of hepatotoxicity and their characteristics?
Pharmacological (Type A) Hepatotoxicity:
Predictable: Dose-dependent with a well-characterized mechanism.
Examples: Most drug-induced liver damage falls into this category.
Dose-Response: Higher doses usually result in more damage.
Idiosyncratic (Type B) Hepatotoxicity:
Non-Predictable: Occurs without warning in susceptible individuals.
Not Dose-Related: Damage does not correlate directly with dose and has variable latency.
Examples: Reactions that are unexpected and not dose-dependent.
149
What are common biochemical markers used to indicate liver damage?
Common biochemical markers include:
Alanine Transaminase (ALT): Indicates hepatocellular injury.
Alkaline Phosphatase (ALP): Indicates cholestatic injury.
Bilirubin: Elevated levels indicate liver dysfunction or bile duct obstruction.
150
What is zonal necrosis, and what drugs are commonly associated with it?
Zonal necrosis is a type of liver cell necrosis characterized by:
High Levels of ALP: Leading to acute liver failure.
Common Drugs Causing Zonal Necrosis:
Paracetamol (Acetaminophen)
Carbon Tetrachloride
151
Describe the different types of hepatitis associated with drug-induced liver damage.
Viral Hepatitis:
Drugs: Phenytoin, Isoniazid, Halothane.
Similar to viral hepatitis.
Focal Hepatitis:
Drugs: Aspirin.
Scattered foci of necrosis with lymphocyte infiltration.
Chronic Hepatitis:
Drugs: Methyldopa, Diclofenac.
Similar to autoimmune hepatitis.
152
What are the different forms of cholestasis and their associated drugs?
Bland Cholestasis:
Drugs: Oral contraceptives, anabolic steroids, androgens.
Inflammatory Cholestasis:
Drugs: Allopurinol, Co-amoxiclav, Carbamazepine.
Ductal Cholestasis:
Drugs: Chlorpromazine, Flucloxacillin.
153
What are the types of steatosis and their associated drugs?
Microvesicular Steatosis:
Drugs: Aspirin (Reye’s syndrome in children), Ketoprofen, Tetracycline.
Macrovesicular Steatosis:
Drugs: Acetaminophen, Methotrexate.
Phospholipidosis:
Drugs: Amiodarone, Total parenteral nutrition.
154
What causes granulomas in drug-induced hepatic injury?
Drug-induced hepatic granulomas are usually associated with systemic vasculitis and hypersensitivity. Common drugs causing this include:
Allopurinol
Phenytoin
Isoniazid
Penicillin
155
What are the types of vascular lesions in drug-induced liver injury and their causes?
Venoocclusive Lesions:
Drugs: Chemo drugs, bush tea.
Peliosis Hepatitis:
Drugs: Anabolic steroids.
Hepatic Vein Thrombosis:
Drugs: Oral contraceptives.
156
What types of neoplasms are associated with prolonged exposure to certain drugs or toxins?
Neoplasms associated with prolonged exposure include:
Hepatocellular Carcinoma
Angiosarcoma
Liver Adenomas
Causes: Vinyl chloride, combined oral contraceptive pill, anabolic steroids, arsenic, aflatoxin
157
What is the enterohepatic circulation and its relevance to drug accumulation?
The enterohepatic circulation involves drugs being excreted into the bile, reabsorbed from the intestines, and returned to the liver. If a drug remains in this circulation for extended periods, it can accumulate in the liver and potentially become hepatotoxic.
158
159
12. What determines the rise and fall of drug concentration in the blood after repeated administration?
The relationship between the drug's elimination half-life and the time interval between doses.
160
What happens if the drug is fully eliminated before the next dose?
Repeated intake at constant intervals results in similar plasma levels with no accumulation.
161
What happens if repeated intake occurs before the previous dose is eliminated?
The next dose adds to the residual amount still present in the body, leading to drug accumulation.
162
How does the dosing interval relative to the drug’s half-life affect accumulation?
Shorter dosing intervals relative to the elimination half-life result in more extensive drug accumulation.
163
What happens to a drug's plasma concentration at a steady state?
The drug stops accumulating, and the rate of elimination becomes concentration-dependent.
164
What is the goal of an optimal dosage regimen?
To achieve therapeutic drug levels in the blood without exceeding the minimum toxic concentration.
165
What factors are considered when designing a dosage plan?
Knowledge of the drug’s minimum therapeutic concentration, minimum toxic concentration, clearance, and volume of distribution (Vd).
166
What is the purpose of a loading dose?
To achieve the target plasma concentration rapidly, especially when the volume of distribution (Vd) is large.
167
When is a loading dose typically used?
During the onset of therapy, for example, in cases like acute myocardial infarction (AMI) with drugs like heparin or cordarone.
168
What is the formula for calculating a loading dose?
Loading dose = (Target concentration × Volume of distribution) / Bioavailability.
169
What is a maintenance dose?
The rate of drug administration required to equal the rate of elimination at steady state.
170
What is the formula for calculating a maintenance dose?
Maintenance dose = (Target concentration × Clearance) / Bioavailability.
171
Why is it important to maintain a drug concentration above the minimum therapeutic level at all times?
To ensure therapeutic efficacy and prevent subtherapeutic levels.
172
What is the strategy when the difference between toxic and therapeutic levels is small?
Smaller and more frequent doses are needed to avoid toxicity and maintain therapeutic levels.
173
12.2 What are the key enzymes involved in the metabolism of catecholamines?
Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
174
What is the role of monoamine oxidase (MAO) in catecholamine metabolism?
MAO is located in the mitochondria and deaminates free catecholamines to scavenge them.
175
What does catechol-O-methyltransferase (COMT) do in catecholamine metabolism?
COMT is an intracellular enzyme that methylates catecholamines, prevalent in both neuronal nerve terminals and the liver
176
What are the end-stage metabolites of catecholamine metabolism?
Vanillylmandelic acid (VMA) and homovanillic acid (HVA).
177
How can the metabolites VMA and HVA be used in medical diagnosis?
Increased urine levels of VMA and HVA can indicate tumors that secrete catecholamines, such as pheochromocytoma and neuroblastoma.
178
What are the two isoforms of monoamine oxidase (MAO)?
MAO-A and MAO-B.
179
What does MAO-A deaminate?
MAO-A deaminates serotonin, melatonin, epinephrine (E), and norepinephrine (NE).
180
What does MAO-B deaminate?
MAO-B deaminates phenylethylamine and trace amines.
181
What is the effect of MAO inhibition on catecholamine levels?
Inhibition of MAO increases free levels of catecholamines, leading to increased storage of norepinephrine in synaptic vesicles and enhanced release during synapse.
182
What is the primary use of MAO inhibitors (MAOIs)?
MAOIs are mainly used in the treatment of depression and Parkinson’s disease.
183
What types of MAO inhibitors are used today?
Selective and reversible inhibitors of MAO are used, including non-selective antidepressive drugs and selective MAO-B inhibitors for Parkinson’s.
184
Name two non-selective MAO inhibitors.
Hydrazines like isoniazid and isocarboxazid, and non-hydrazines like tranylcypromine
185
Name two selective MAO-B inhibitors used for Parkinson’s treatment.
Rasagiline and selegiline.
186
How do COMT inhibitors help in treating Parkinson's disease?
COMT inhibitors prevent the methylation of L-Dopa and dopamine, increasing their concentration and prolonging "on-time" in patients.
187
What are the commonly used COMT inhibitors?
Entacapone (peripheral), Tolcapone (CNS + peripheral), and Nitecapone.
188
Which COMT inhibitor is non-hepatotoxic?
Entacapone.
189
Which COMT inhibitors are associated with hepatotoxicity?
Tolcapone and Nitecapone.
190
12.3 What characterizes asthma, and what types of drugs are used in its treatment?
Asthma is characterized by airway inflammation and episodic reversible bronchospasms.
Drugs used include bronchodilators (β2-selective agonists, muscarinic antagonists, methylxanthines, leukotriene receptor blockers) and anti-inflammatory drugs (corticosteroids, mast cell stabilizers, anti-IgE antibodies).
191
What are the key mediators involved in the pathophysiology of asthma?
Key mediators include LTC4, LTD4, LTB4 (leukotrienes that attract inflammatory cells),
cytokines (mediate chronic inflammation), and triggers such as cold air, antigens, histamine, muscarinic agonists, and irritants (e.g., SO2).
192
What are the two main categories of asthma treatment strategy?
"Reliever" drugs (e.g., β2-agonists, muscarinic antagonists, theophylline) and "Controller" drugs (e.g., corticosteroids, long-acting β2-agonists, anti-IgE antibodies).
Leukotriene antagonists can act as both relievers and controllers.
193
What are the main β2-agonists used for acute asthma treatment, and what is their duration of action?
Short-acting β2-agonists (e.g., albuterol, terbutaline, metaproterenol) last ≤4 hrs and are life-saving for acute bronchospasms.
Long-acting β2-agonists (e.g., salmeterol, formoterol, indacaterol) last ≥12 hrs and are used for prophylaxis.
194
What are the advantages and effects of β2-agonists administered via inhalation?
Inhalation (via aerosol canisters or nebulizers) delivers an effective local dose, reduces systemic side effects, and provides a 12–24 hr duration.
They stimulate AC via Gs to increase cAMP, resulting in powerful bronchodilation.
195
What adverse effect is commonly associated with β2-agonists?
Skeletal muscle tremor is a common adverse effect of β2-agonists.
196
What are the high-dose adverse effects of β2-agonists?
At high doses, β2-agonists can cause tachycardia and loss of responsiveness (tolerance/tachyphylaxis), especially with excessive use of short-acting types, more common in COPD patients.
197
What is the role of methylxanthine in asthma treatment, and what are its effects?
Theophylline (a methylxanthine) is used in asthma treatment. It inhibits phosphodiesterase (PDE), maintaining high intracellular cAMP levels, causing bronchodilation and increased diaphragm strength.
It is orally active, eliminated by cytP450, and clearance varies with age, smoking, and drug interactions.
198
What are the adverse effects of methylxanthine (theophylline)?
Theophylline can cause GI distress, tremor, insomnia, severe nausea, vomiting, and, in large overdoses, arrhythmias and seizures. Beta-blockers can be used in cases of overdose.
199
What are muscarinic antagonists used for in asthma, and how do they work?
Muscarinic antagonists like ipratropium and tiotropium are quaternary compounds that block muscarinic receptors in the airways, preventing bronchoconstriction mediated by vagal discharge.
They are used in children and COPD patients, though β2-agonists are preferred in asthma.
200
What are the adverse effects of muscarinic antagonists in asthma treatment?
Muscarinic antagonists have minimal adverse effects since they act locally. They do not cause tremors or arrhythmias.
201
What is the function of cromolyn and nedocromil in asthma treatment?
Cromolyn and nedocromil, given as aerosols, are rarely used today but are thought to decrease leukotrienes and histamines.
They prevent bronchoconstriction caused by allergic responses and have almost no systemic effects due to their high insolubility.
202
What is the role of corticosteroids in the treatment of asthma?
Corticosteroids are beneficial anti-inflammatory agents used for severe asthma. Systemic corticosteroids (e.g., prednisone) are toxic and reserved for prolonged treatment when other drugs fail.
Local corticosteroids (e.g., beclomethasone, budesonide, fluticasone) are 1st-line for moderate to severe asthma and are surface-active and relatively safe.
203
When are IV corticosteroids used in asthma treatment, and which ones are commonly used?
IV corticosteroids, such as prednisolone and hydrocortisone, are used in acute severe asthma (status asthmaticus).
204
How do corticosteroids reduce inflammation in asthma?
Corticosteroids reduce the synthesis of arachidonic acid by PLA2 and inhibit COX-2 expression.
They bind to intracellular receptors and activate glucose response elements, preventing inflammation and allergic responses mediated by cytokines and leukotrienes.
205
What are the adverse effects of aerosol corticosteroids in children?
Aerosol corticosteroids can cause oral candidiasis, mild adrenal suppression, and mild growth retardation in children, which is usually reversible as they grow.
206
What is the role of leukotriene antagonists in asthma treatment?
Leukotriene antagonists (e.g., zafirlukast, montelukast) interfere with leukotriene synthesis or action.
They are orally active and effective in preventing exercise-, antigen-, and aspirin-induced bronchospasms but are not recommended for acute episodes of asthma.
207
What are the adverse effects of leukotriene antagonists?
Adverse effects are rare, but Churg-Strauss syndrome and allergic granulomatous angiitis have been reported, although no direct connection has been found.
Their toxicity is generally very low.
208
13. What factors affect the absorption of drugs in the body?
Drugs require transport via circulation to reach the target tissue.
Absorption depends on the route of administration, blood flow at the site, and drug concentration at the administration site, which influences the concentration gradient according to Fick's law.
209
How does blood flow influence drug absorption?
High blood flow maintains a strong drug depot-to-blood concentration gradient, facilitating absorption.
Blood flow is especially important for drugs administered intramuscularly, subcutaneously, or in shock situations for GI-absorbed drugs.
210
What is bioavailability?
Bioavailability is the proportion of a drug absorbed into systemic circulation compared to the amount administered.
211
What is ion trapping, and how does it affect drug absorption?
Ion trapping occurs when a drug builds up across a cell membrane due to differences in pKa and pH across the membrane.
Alkaline drugs accumulate in acidic fluids (e.g., cytosol), while acidic drugs accumulate in basic fluids (e.g., mother's milk).
212
How does ion trapping affect drug excretion in the urine?
Acidic drugs are excreted in alkaline urine, while ingesting sodium bicarbonate decreases the excretion of amphetamines (a weak base) in urine, prolonging its action.
213
How can ion trapping reduce the effectiveness of certain treatments?
Ion trapping can lead to partial failure of some anticancer chemotherapies, reducing their therapeutic potential.
214
13.2 How is acetylcholine (ACh) eliminated from the synaptic cleft?
ACh is metabolized into acetate and choline by acetylcholinesterase (AChE) in the synaptic cleft. Acetate and choline are recycled, with choline being transported back into the nerve terminal.
215
What drugs can affect acetylcholine (ACh) metabolism or transport?
- Hemicholinium – Inhibits choline transport into the nerve terminal (research drug).
- Vesamicol – Inhibits ACh storage in vesicles by blocking the vesicle-associated transporter (VAT) (research drug).
- Botulinum toxin – Blocks ACh release by inhibiting SNARE proteins, used clinically for muscle spasms and cosmetic purposes.
216
What is botulinum toxin used for clinically?
Botulinum toxin is used for treating muscle spasms (e.g., in the eye) and as a cosmetic agent to reduce wrinkles on the face and neck.
217
How is norepinephrine (NE) eliminated from the synaptic cleft?
NE is either metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) or taken up by the norepinephrine transporter (NET) via uptake 1.
218
What drugs block norepinephrine (NE) reuptake via the norepinephrine transporter (NET)?
Cocaine
Tricyclic antidepressants (TCA)
Amphetamines
These drugs increase NE concentration in the synaptic cleft by blocking reuptake.
219
13.3 What are diuretics and how do they work?
Diuretics are drugs that increase urine production by inhibiting the reabsorption of NaCl and water in the nephron.
Their effects depend on the segment of the nephron in which they act.
220
What are the main therapeutic uses of diuretics?
Edema – Mobilizes fluid from the interstitial space for excretion by the kidneys.
Hypertension – Lowers blood pressure by decreasing blood volume and peripheral resistance.
Congestive heart failure – Reduces afterload, improving cardiac output and exercise tolerance.
Renal failure prophylaxis – Maintains urinary flow in conditions like anuria due to shock.
Alkalinizing urine – Useful in treating aspirin overdose.
221
What are potassium-sparing diuretics, and where do they act?
Potassium-sparing diuretics act in the distal part of the distal tubule and the proximal part of the collecting ducts. They inhibit Na+ reabsorption without increasing K+ secretion, reducing the risk of hypokalemia.
222
What are examples of potassium-sparing diuretics, and how do they work?
- Triamterene and amiloride – Inhibit Na+ entry into the luminal membrane, preventing Na+/K+ exchange, leading to Na+ excretion and K+ retention.
- Spironolactone and eplerenone – Aldosterone antagonists that block Na+ reabsorption in exchange for K+ in the collecting ducts, preventing K+ loss.
223
What are aldosterone antagonists, and how do they work?
Spironolactone and eplerenone are steroid derivatives that block aldosterone's effect in the collecting tubules.
Aldosterone normally promotes Na+ reabsorption and K+ excretion, so these drugs prevent this exchange.
224
What are the clinical uses and adverse effects of aldosterone antagonists?
Uses: Conditions of increased aldosterone secretion (e.g., liver cirrhosis with ascites, heart failure).
Adverse effects: Spironolactone may cause gynecomastia in males due to interference with gonadal hormones.
Eplerenone avoids this effect.
Both drugs carry a risk of hyperkalemia, especially when used with ACE inhibitors, ARBs, or potassium supplements.
225
14. What is bioavailability of a drug?
Bioavailability is the fraction of the administered dose of a drug that reaches systemic circulation.
It is 100% for intravenous (IV) administration but is typically less than 100% for extravascular routes.
226
What factors can reduce the bioavailability of a drug administered via extravascular routes?
Incomplete absorption from the site of administration
Expulsion of the drug by intestinal transporters
First-pass metabolism
Distribution into other tissues before reaching systemic circulation
Presence or absence of food
Drug interactions
Intestinal motility and microflora
227
What pathological factors can influence drug bioavailability?
Hepatic insufficiency
Poor renal function
228
What is the AUC (area under the curve) in pharmacokinetics?
The AUC represents the integrated total area under the plasma concentration-time curve, which accounts for the concentration of the drug in the plasma over time.
229
14.2 What receptors does Epinephrine activate, and what are its main uses?
Receptors Activated: α1, α2, β1, β2, β3
Main Uses:
Anaphylaxis: Drug of choice for immediate treatment (IV, IM, or intraosseous administration)
Hemostatic Agent: Topical use for superficial wounds
Cardiac Arrest: Increases peripheral resistance via α1 receptor-dependent vasoconstriction (IV and intracardiac injections)
Asthma: Used as a bronchodilator if other β2 agonists are not effective
230
What are the toxicities and adverse effects associated with Epinephrine?
Hypertension
Arrhythmia
Tachycardia
Palpitations
Stroke
Myocardial Infarction
Acute Pulmonary Edema
Headache
Tremor
Panic Attacks
Contraindicated: In patients taking non-selective β-blockers (can cause severe hypertension and cerebral hemorrhage)
231
What receptors does Norepinephrine activate, and what are its main uses?
Receptors Activated: α1, α2, β1
Main Uses:
Vasopressor Medication: Treatment of hypotension (IV only)
Shock Treatment: Particularly for vasodilatory shock, such as septic shock and neurogenic shock
232
What are the toxicities and adverse effects associated with Norepinephrine?
Peripheral Ischemia
Limb Death
Vasospasms
Tissue Necrosis
Excessive Blood Pressure
Increased Arrhythmias
Infarction
High Levels: Can be problematic, especially in combination with other vasopressors
233
What receptors does Isoprenaline activate, and what are its main uses?
Receptors Activated: β1, β2, β3
Main Uses:
Asthma: Primarily used as a nebulizer for acute asthma
AV Block: IV administration for treatment
Bradycardia: Treatment for low heart rate
234
14.3 What is the mechanism of action of Carbonic Anhydrase Inhibitors (e.g., Acetazolamide), and what are their primary uses?
Mechanism of Action:
Block carbonic anhydrase (CA) in the brush border and cytoplasm of the proximal tubule cells (PTC) of the kidneys.
Also affect cells in the choroid plexus and ciliary epithelium.
Primary Uses:
Glaucoma: Reduces intraocular pressure (e.g., dorzolamide, brinzolamide).
Acute Mountain Sickness: Preventative treatment.
Diuretic: Used if edema is accompanied by significant metabolic alkalosis.
Severe Acute Glaucoma: Parenteral use.
Additional Effects:
Protects against high-altitude sickness due to CSF acidosis.
235
What are the adverse effects of Carbonic Anhydrase Inhibitors?
Drowsiness
Paresthesia
Renal Stones: Due to alkalization of urine (calcium salts).
Hypokalemia
Hyperammonemia: Particularly in patients with hepatic diseases (risk of hepatic encephalopathy).
236
What is the mechanism of action and key features of Thiazides and Other Sulfonamide-Type Diuretics?
Mechanism of Action:
Inhibit the reabsorption of Na+ and Cl- in the distal convoluted tubule.
Key Features:
Uses: Primarily for hypertension and mild edema.
Effects: Reduce blood pressure and decrease edema.
Electrolyte Imbalance: Can cause hypokalemia.
237
What is the mechanism of action, duration, and key effects of Loop Diuretics (e.g., Furosemide, Bumetanide, Torsemide)?
Mechanism of Action:
Inhibit the cotransport of Na+/K+/Cl- in the thick ascending limb of the loop of Henle.
Duration:
Relatively short-acting, with diuresis starting ~4 hours after dose intake.
Key Effects:
Massive NaCl Diuresis: Significant reduction in blood volume.
Rapid Removal of Edema Fluid: Effective if tissue perfusion is good.
K+ Wasting: Leads to hypokalemia.
Metabolic Alkalosis: Due to excretion of protons.
Notable for: Powerful diuresis in cases of normal GFR.
238
What is the mechanism by which Loop Diuretics reduce pulmonary vascular pressures?
Loop diuretics reduce pulmonary vascular pressures via an unknown mechanism.
Their action can be reduced when used with NSAIDs due to inhibition of prostaglandins, which results in improved glomerular filtration and decreased efficacy of the loops.
239
What are the primary uses of Loop Diuretics?
Loop diuretics are used for:
Treatment of edematous states such as heart failure, ascites, and acute pulmonary edema.
Treatment of hypertension when thiazides are ineffective.
Treatment of severe hypercalcemia, often supplemented by Na+ and K+ to accommodate for losses.
240
What are the common adverse effects of Loop Diuretics?
Adverse effects include:
Hypokalemic metabolic acidosis
Hypovolemia and cardiovascular problems
Ototoxicity
Sulfonamide allergies (ethacrynic acid can be used in this case)
241
What is the primary function of antidiuretics and their typical use?
Antidiuretics are used to reduce diuresis in the body.
They are primarily used in the treatment of pituitary diabetes insipidus and are not used for nephrogenic diabetes insipidus.
242
What are some examples of antidiuretic antagonists and their effects?
Antidiuretic antagonists include:
Conivaptan, which inhibits both V1 and V2 receptors.
Tolvaptan, which is selective for V2 receptors.
Lithium also has antidiuretic effects but is not used for this purpose.
243
How does ADH facilitate water reabsorption and what are its agonists?
ADH facilitates water reabsorption from the collecting ducts by activating the V2 receptor, which stimulates adenylyl cyclase (AC) via Gs protein.
This increases cAMP levels, causing insertion of aquaporin-2 (AQP2) water channels into the luminal membrane of the collecting tubule.
Agonists include ADH and desmopressin, which reduce urine volume and are used in the treatment of pituitary diabetes insipidus.
244
How do antidiuretic agonists affect nephrogenic diabetes insipidus?
ADH and desmopressin do not affect nephrogenic diabetes insipidus, which is due to a lack of response to vasopressin.
Treatment for nephrogenic DI involves thiazides, loop diuretics, salt restriction, and water restriction to stimulate proximal tubular reabsorption.
245
What is the mechanism of action of thiazide diuretics in treating nephrogenic diabetes insipidus?
Thiazide diuretics decrease distal convoluted tubule reabsorption of sodium and water, leading to diuresis.
This reduces plasma volume, which lowers glomerular filtration rate (GFR) and enhances sodium and water absorption in the proximal nephron.
As less fluid reaches the distal nephron, overall fluid conservation is achieved.
246
What are antidiuretic antagonists and their use in treating SIADH?
Antidiuretic antagonists, such as conivaptan and tolvaptan, oppose the actions of ADH and other naturally occurring peptides acting on the V2 receptor.
These antagonists are used to treat syndrome of inappropriate ADH secretion (SIADH), a condition where there is excessive production of ADH, leading to water retention and dangerous hyponatremia, often caused by certain tumors like small cell carcinoma of the lung.
Lithium can also be used for this purpose but has greater toxicity.
247
How is nephrogenic diabetes insipidus treated if desmopressin is ineffective?
Nephrogenic diabetes insipidus is treated by reversing the underlying cause (if possible) and replacing the free water deficit.
248
What medications can be used to treat nephrogenic diabetes insipidus when desmopressin is ineffective?
Hydrochlorothiazide or indomethacin can be used to create mild hypovolemia, which encourages salt and water uptake in the proximal tubule.
249
How does hydrochlorothiazide or indomethacin help in nephrogenic diabetes insipidus?
They create mild hypovolemia, which encourages salt and water uptake in the proximal tubule, thus improving nephrogenic diabetes insipidus.
250
What is the role of amiloride in treating nephrogenic diabetes insipidus?
Amiloride blocks lithium uptake and is sometimes combined with thiazide diuretics to prevent hypokalemia.
251
Why might thiazide diuretics be used to treat nephrogenic diabetes insipidus despite causing diuresis?
Thiazide diuretics decrease distal convoluted tubule reabsorption of sodium and water,
leading to lower plasma volume and enhanced sodium and water absorption in the proximal nephron, resulting in overall fluid conservation.
252
15. What is the first-pass effect in drug metabolism?
The first-pass effect is a phenomenon where the concentration of a drug is greatly reduced before it reaches the systemic circulation.
It refers to the fraction of the drug lost during the process of absorption, primarily related to the liver and gut wall.
253
Which notable drugs experience a significantly high first-pass effect?
Notable drugs with a high first-pass effect include:
Imipramine (tricyclic antidepressant)
Morphine and Buprenorphine (opiates)
Propranolol (beta-blocker)
Diazepam (benzodiazepine)
Lidocaine (Na+ channel blocker and local anesthetic)
254
How does oral administration affect the first-pass effect of a drug?
After oral administration, a drug is absorbed by the digestive system and enters the hepatic portal circulation, where it is carried through the portal vein to the liver before reaching systemic circulation.
This process can significantly reduce the drug's bioavailability due to metabolism in the liver.
255
What are the four primary systems that affect the first-pass effect?
The four primary systems affecting the first-pass effect are:
Enzymes of the GI lumen (from pancreas and GI glands)
Gut wall enzymes
Bacterial enzymes
Hepatic enzymes (mainly the cytochrome family)
256
Which routes of administration bypass the GI/liver absorption pathway and reduce the first-pass effect?
Routes that bypass the GI/liver absorption pathway include:
Rectal suppository (partially avoids first-pass effects due to portocaval anastomoses)
Intravenous (100% bioavailability, direct entry into systemic circulation)
Intramuscular (often faster and with higher bioavailability)
Inhalational aerosols (rapid absorption into circulation)
Transdermal (slow absorption due to skin thickness)
Sublingual (direct absorption into the venous circulation)
Topical (applied on skin or mucosa)
257
15.2 What is acetylcholine (ACh) and its role in the nervous system?
Acetylcholine (ACh) is a primary neurotransmitter in all autonomic ganglia (both parasympathetic and sympathetic), in synapses between parasympathetic postganglionic neurons and their effector cells, and at the neuromuscular junction (NMJ) of somatic skeletal muscle.
258
How is acetylcholine (ACh) synthesized in the nerve terminal?
ACh is synthesized in the nerve terminal by choline acetyltransferase from acetyl-CoA (from the mitochondria) and choline (transported into the nerve terminal through the membrane).
259
What inhibits the membrane transport of choline?
The membrane transport of choline can be inhibited by hemicholinium (a research drug).
260
How is acetylcholine (ACh) stored in the nerve terminal?
ACh is actively transported into vesicles for storage via the vesicle-associated transporter (VAT). VAT can be inhibited by vesamicol (a research drug).
261
What is required for the release of acetylcholine (ACh) from storage vesicles?
The release of ACh requires the entry of Ca2+ through Ca2+ channels and the interaction between SNARE proteins, VAMPs, and SNAPs.
VAMPs (vesicle-associated membrane proteins) include synaptobrevin and synaptotagmin, while SNAPs (synaptosome-associated proteins) include SNAP-25 and syntaxin.
262
How does botulinum toxin affect ACh release?
Botulinum toxin inhibits ACh release by enzymatically altering synaptobrevin or other docking/fusion proteins, preventing the vesicle from fusing with the terminal membrane.
263
How is acetylcholine (ACh) eliminated from the synaptic cleft?
ACh is rapidly metabolized by the enzyme acetylcholinesterase (AChE) into acetate and choline.
Choline is recycled back into the presynaptic cell via membrane transport, while acetate is used to make acetyl-CoA.
264
15.3 What are the essential roles of blood cells in the body?
Blood cells are essential for oxygenation of tissues, coagulation, protection against infectious agents, and tissue repair.
265
What is the most common cause of anemia?
The most common cause of anemia is an insufficient supply of iron, vitamin B12, or folic acid, which are required for normal production of erythrocytes (red blood cells).
266
What is the role of iron in the body?
Iron is an essential component of heme, which is part of hemoglobin.
Most body iron is contained in hemoglobin, with the rest bound to transferrin (transport) or ferritin (storage).
267
Who is most likely to experience iron deficiency?
Iron deficiency is common in women (due to blood loss during menstruation), vegetarians or malnourished persons, children, and pregnant women (due to increased requirements).
268
Why is excessive iron intake highly toxic?
Excessive iron is toxic because the body has a strict system for iron absorption, transport, and storage, but no effective mechanism for excretion.
269
How is iron deficiency anemia treated?
Iron deficiency anemia is treated with dietary ferrous iron supplementation, including ferrous sulfate, ferrous gluconate, and ferrous fumarate,
as well as parenteral iron preparations like iron dextran, sodium ferric gluconate complex, and iron sucrose.
270
What are the contraindications for iron supplementation?
Iron supplementation is contraindicated in hemolytic anemia because iron stores are increased in these conditions.
271
What are the potential effects of iron toxicity?
Iron toxicity, common in children due to accidental intake of iron tablets, can result in necrotizing gastroenteritis, shock, metabolic acidosis, coma, and death. Chronic iron overload can lead to hemochromatosis, damaging the liver, heart, and pancreas.
272
How is acute iron toxicity treated?
Acute iron toxicity treatment involves removing tablets from the gut, correcting acid-base and electrolyte abnormalities, and administering deferoxamine, which chelates circulating free iron.
273
How is chronic iron toxicity managed?
Chronic iron toxicity is managed with phlebotomy (removal of blood via venipuncture), used in conditions like hemochromatosis, and chelators like deferoxamine and defrasirox.
274
What role does Vitamin B12 play in the body?
Vitamin B12, along with folate acid, is necessary for the synthesis of DNA.
It affects all cells but is most obvious in red blood cells (RBCs), which are continuously produced every 120 days.
Deficiency leads to macrocytic megaloblastic anemia and neurologic defects that can become irreversible.
275
How is Vitamin B12 produced and absorbed in the body?
Vitamin B12 is produced by bacteria only and is absorbed through the GI tract with the help of intrinsic factor, which is produced by parietal cells of the stomach.
It is stored in the liver in large amounts, so deficiency is quite rare, with stores usually sufficient for about 5 years.
276
What is the treatment for Vitamin B12 deficiency?
The treatment for Vitamin B12 deficiency involves supplements such as cyanocobalamin and hydroxocobalamin.
These are also used in the treatment of pernicious anemia, especially following gastric resection where there is loss of intrinsic factor.
277
What is the role of folic acid in the body?
Folic acid, like Vitamin B12, is needed for normal DNA synthesis. Its deficiency results in megaloblastic anemia and an increased risk of neural tube defects.
Deficiency symptoms can appear within approximately 3 months.
278
How is folic acid deficiency treated?
Folic acid deficiency is treated with supplementary intake of folate.
It is also recommended to take folate before and during pregnancy to prevent neural tube defects.
279
What are erythropoiesis-stimulating agents used for?
Erythropoiesis-stimulating agents are used to treat anemia that can follow renal failure, post-chemotherapy/radiotherapy, or nephrotomy.
Examples include darbepoetin alfa (a glycosylated form of EPO with a longer half-life) and methoxy polyethylene glycol-epoetin beta (long-lasting, injected 1-2 times per month)
280
What are common complications of erythropoiesis-stimulating agents?
The most common complications of erythropoiesis-stimulating agents include hypertension (HTN) and thrombosis.
281
What are myeloid growth factors and their uses?
Myeloid growth factors, such as filgrastim and sargramostim, stimulate the production and function of neutrophils.
They are primarily used to restore blood components after chemotherapy and to treat other types of neutropenia.
282
What is the role of megakaryocyte growth factors?
Megakaryocyte growth factors, such as oprelvekin (IL-11), increase the number of peripheral platelets.
