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4th year > Pharm T1-7 > Flashcards

Pharm T1-7 Flashcards

1
Q

1 What is pharmacodynamics?

A

Pharmacodynamics is the study of what a drug does to the body.

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2
Q

What are the three main ways drugs affect the body?

A
  • Mimic or inhibit normal physiological/biochemical processes
  • Inhibit pathological processes
  • Inhibit vital processes of endo- or ectoparasites and microorganisms
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3
Q

What are the 7 main drug actions?

A
  1. Stimulatory action via direct receptor agonist and its downstream effect
  2. Depressing action via direct receptor agonist and its downstream effect (including inverse agonists)
  3. Antagonizing (blocking) action
  4. Stabilizing action

5.Exchanging/replacing/accumulating substances in the body (e.g., glycogen storage)

  1. Direct beneficial chemical reaction (e.g., free radical scavenging)
  2. Direct harmful chemical reactions leading to cellular damage or death (e.g., cytotoxicity or irritation)
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4
Q

What are the desired activities of drugs?

A
  1. Disruption of the cell membrane
  2. Chemical reactions with downstream effects
  3. Interactions with enzymes, structural proteins, carrier proteins, ion channels

4.Ligand binding to receptors (hormone, neuromodulator, neurotransmitter receptors)

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5
Q

What are some undesired effects of drugs?

A
  • Increased probability of cell mutation (carcinogenic effects)
  • Damaging effects and harmful interactions (e.g., additive action)
  • Induced physiological damage and chronic damaging effects
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6
Q

What is the therapeutic window of a drug?

A

The therapeutic window refers to the amount of medication that is effective before reaching a dose that causes more adverse effects than desired.

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7
Q

Why is drug duration and half-life important?

A

The duration (half-life) of a drug is important because drugs can be harmful in large or prolonged doses.

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8
Q

What is a receptor in pharmacodynamics?

A

A receptor is a macromolecule or cell component that interacts with a drug and initiates biochemical/physiological events, leading to the observed drug effects.

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9
Q

What do receptors in target cells/tissues determine?

A

Receptors determine the dose or concentration of the drug required to form a significant number of drug-receptor complexes.

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10
Q

What factors influence drug binding to receptors?

A

Receptor selectivity for size, shape, and electrical charge of the drug

Changes in the drug’s chemical structure, which can alter receptor affinity and affect therapeutic or toxic actions.

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11
Q

What can limit the maximum effect of a drug?

A

The number of receptors available may limit the maximum effect that a drug can produce.

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12
Q

Give an example of an enzyme acting as a receptor.

A

Dihydrofolate reductase is a receptor for Methotrexate.

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12
Q

What are the main types of receptors?

A

Regulatory proteins
Enzymes
Transport proteins
Structural proteins

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13
Q

Give an example of a transport protein acting as a receptor.

A

Na+/K+ ATPase is a receptor for Digoxin.

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13
Q

Give an example of a structural protein acting as a receptor.

A

Tubulin is a receptor for Colchicine.

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14
Q

What are the four types of receptors based on their mechanism?

A

Voltage or Ligand gated (ionotropic)
G-protein coupled (metabotropic)
Kinase linked
Nuclear receptors

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15
Q

What is the mechanism and speed of Voltage or Ligand gated (ionotropic) receptors?

A

They cause hyperpolarization or depolarization, act fast (milliseconds), and do not use second messengers.
Examples: Nicotinic receptor, AChR, GABAA.

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16
Q

How do G-protein coupled (metabotropic) receptors work?

A

They use second messengers to cause effects like Ca2+ release or protein phosphorylation, and act quickly (seconds).

Examples: Muscarinic, AChR.

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17
Q

What is the mechanism and speed of Kinase linked receptors?

A

They trigger phosphorylation, gene transcription, and protein synthesis, but act slowly (hours).
Examples: Cytokine receptors, erythropoietin receptor.

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18
Q

How do nuclear receptors function?

A

They regulate gene transcription and protein synthesis, acting slowly (hours).
Examples: Estrogen, steroid, thyroid, and vitamin D receptors.

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19
Q

1.2 What is the parasympathetic nervous system (PNS)?

A

The parasympathetic nervous system (PNS) is one of the two major subdivisions of the autonomic nervous system (ANS),

with preganglionic motor fibers originating in cranial nuclei III, VII, IX, and X, and sacral segments (S2-S4) of the spinal cord.

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20
Q

Where are most parasympathetic ganglia located?

A

Most parasympathetic ganglia are located in the organs they innervate, resulting in long preganglionic fibers and short postganglionic fibers.

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21
Q

What is the primary neurotransmitter in the parasympathetic nervous system?

A

Acetylcholine (ACh) is the primary neurotransmitter in parasympathetic synapses between postganglionic neurons and their effector cells, as well as in all autonomic ganglia.

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22
Q

What are the key roles of acetylcholine (ACh)?

A
  • Primary transmitter in all autonomic ganglia (both parasympathetic and sympathetic).
  • Transmitter between parasympathetic postganglionic neurons and effector cells.
  • Primary transmitter at the somatic skeletal muscle neuromuscular junction (NMJ).
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23
Q

How is acetylcholine (ACh) synthesized?

A

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).

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24
Q

Which drug inhibits choline transport into nerve terminals?

A

Hemicholinium, a research drug, inhibits choline transport into nerve terminals.

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25
Q

How is acetylcholine stored in nerve terminals?

A

ACh is actively transported into vesicles for storage via the vesicle-associated transporter (VAT).

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26
Q

Which drug inhibits the vesicle-associated transporter (VAT)?

A

Vesamicol, a research drug, inhibits the VAT, preventing ACh storage in vesicles.

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27
Q

What triggers the release of acetylcholine (ACh) from nerve terminals?

A

ACh release is triggered by the entry of Ca2+ through calcium channels,

which activates SNARE proteins (VAMPs and SNAPs) to dock vesicles to the terminal membrane and release ACh into the synaptic cleft.

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28
Q

What role do SNARE proteins play in ACh release?

A

SNARE proteins like VAMPs (vesicle-associated membrane proteins, e.g., synaptobrevin, synaptotagmin)

and SNAPs (synaptosome-associated proteins, e.g., SNAP-25, syntaxin) are involved in vesicle docking and fusion with the terminal membrane for ACh release.

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29
Q

How do botulinum toxins affect acetylcholine release?

A

Botulinum toxins enzymatically alter SNARE proteins (e.g., synaptobrevin) to prevent the release of acetylcholine by inhibiting vesicle docking and fusion.

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30
Q

Which receptors does acetylcholine bind to?

A

Acetylcholine binds to cholinergic receptors, specifically muscarinic and nicotinic receptors.

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31
Q

What do muscarinic receptors respond to?

A

Muscarinic receptors respond to muscarine (a natural alkaloid from the fungus A. muscaria) and acetylcholine (ACh).

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32
Q

Where are muscarinic receptors located?

A

Muscarinic receptors are located on autonomic effector cells, such as the heart, vascular endothelium, nerve endings, smooth muscles, and exocrine glands.

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33
Q

Which drugs inhibit all muscarinic receptors?

A

All muscarinic receptors can be inhibited by atropine and scopolamine.

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34
Q

What type of receptor are muscarinic receptors?

A

Muscarinic receptors are G-protein coupled receptors (GPCRs) with five subtypes: M1, M2, M3, M4, and M5.

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35
Q

Where are M1 muscarinic receptors located, and what is their mechanism?

A

M1 receptors are found in peripheral nerve endings, parietal cells, and the CNS.

They are Gq-coupled, increasing IP3 and DAG, leading to excitatory effects via decreased K+ conductance and depolarization.

Selective antagonist: Pirenzepine.

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36
Q

Where are M2 muscarinic receptors located, and what is their mechanism?

A

M2 receptors are found in the heart and some nerve endings.

They are Gi-coupled, decreasing cAMP, activating K+ channels, and inhibiting Ca2+ channels.

This results in inhibitory effects.

Selective antagonist: Gallamine.

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37
Q

Where are M3 muscarinic receptors located, and what is their mechanism?

A

M3 receptors are found in smooth muscles, glands, and endothelium.

They are Gq-coupled, increasing IP3 and DAG, leading to excitatory effects such as glandular secretion, smooth muscle contraction, and vascular endothelium relaxation.

Selective antagonist: Darifenacine.

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38
Q

What are the roles of M4 and M5 muscarinic receptors?

A

M4 receptors are found in the CNS and are associated with decreased locomotion. They are Gi-coupled, reducing cAMP and Ca2+ levels.

M5 receptors are found in the CNS and are Gq-coupled, increasing IP3 and DAG.

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39
Q

What do nicotinic receptors respond to?

A

Nicotinic receptors respond to acetylcholine and nicotine, opening Na+/K+ ion channels.

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40
Q

What are the two major subtypes of nicotinic receptors?

A

NN receptors: Located in autonomic ganglia, triggering depolarization and action potentials via Na+/K+ channels.

NM receptors: Located at the neuromuscular endplate, triggering depolarization and action potentials via Na+/K+ channels.

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41
Q

What additional function do nicotinic receptors have besides their role in the ANS and skeletal muscle?

A

Nicotinic receptors also stimulate the release of adrenaline from chromaffin cells of the adrenal medulla when activated by noradrenaline.

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42
Q

What are the antagonists for nicotinic receptors?

A
  • Ganglionic blocking agents: Hexamethonium (research drug), Trimethaphan.
  • Nondepolarizing neuromuscular blocking agents: Atracurium.
  • Depolarizing neuromuscular blocking agent: Succinylcholine.
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43
Q

1.3 What are thiazide diuretics used to treat?

A

Thiazide diuretics are used to treat hypertension and edema (caused by heart, liver, or kidney failures).

They are effective in lowering mortality from stroke, myocardial infarction, and heart failure.

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44
Q

What is the typical duration of action for thiazide diuretics?

A

Thiazide diuretics have a duration of action of 6-14 hours, longer than most loop diuretics.

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45
Q

What is the basic structure of thiazide diuretics?

A

Thiazide diuretics are sulfonamide derivatives with a thiazide ring in their structure, such as Hydrochlorothiazide, Bendroflumethiazide, and Xipamide.

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46
Q

What is the difference between thiazide-like drugs and thiazides?

A

Thiazide-like drugs are also sulfonamide derivatives but lack the thiazide ring.

However, this does not affect their diuretic effects.

Examples include Indapamide, Clopamide, and Chlorthalidone.

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47
Q

Where do thiazide diuretics exert their effect in the kidney?

A

Thiazide diuretics are actively secreted into the proximal tubule, but their action occurs in the distal convoluted tubules (DCT).

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48
Q

What is the mechanism of action for thiazide diuretics?

A

Thiazide diuretics inhibit the NaCl symporter in the early segments of the distal convoluted tubules (DCT),

causing moderate but sustained diuresis of sodium and chloride.

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49
Q

How do thiazide diuretics affect calcium reabsorption?

A

Thiazides increase calcium reabsorption from urine by promoting Na+-Ca2+ exchange in the basolateral membrane, leading to decreased urine calcium levels.

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50
Q

What is a potential side effect of thiazide diuretics related to water balance?

A

Thiazide diuretics may cause dilutional hyponatremia due to their action on the DCT, reducing water excretion.

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51
Q

What are the renal effects of thiazide diuretics?

A

Inhibition of Na+ reabsorption in the DCT, reducing Na+ retention.

Increased calcium reabsorption from the lumen, leading to lower urine calcium levels.

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52
Q

What are the extrarenal effects of thiazide diuretics?

A

Decreased preload and afterload on the heart.

Long-term use (2-3 weeks) reduces pulmonary vascular resistance.

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53
Q

What are the major indications for the use of thiazides and thiazide-like drugs?

A
  • Arterial hypertension – Major application for these drugs
  • Milder forms of chronic heart failure
  • Recurrent kidney stones from idiopathic hypercalciuria
  • Nephrotic syndrome
  • Nephrogenic diabetes insipidus (when kidneys are unresponsive to ADH)
  • Corticosteroid and estrogen therapy patients
  • Might be useful in osteoporosis
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54
Q

What are the adverse effects associated with the use of thiazides and thiazide-like drugs?

A

Hypokalemia and metabolic alkalosis =
Due to compensation by cortical collecting tubules, wasting K+ and H+ via excretion

Impaired glucose tolerance =
Due to hypokalemic inhibition of insulin secretion

Dyslipidemia = Increases total cholesterol, LDL, and potentially TAGs

Hyperuricemia = Blocking effects (prevented/corrected with allopurinol)

Hypercalcemia, hyponatremia, and hypovolemia

Allergic reactions to the sulfonamide structure = Skin rashes and rarely hemolytic anemia

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55
Q

What is the recommended dosing for thiazides in the treatment of hypertension?

A

The recommended dose for hypertension is 6.25/12.5 – 25 mg/day.

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56
Q

Why is it recommended to use thiazides in low doses?

A

It is recommended to use thiazides in low doses because this does not affect the therapeutic response of the drug but lowers the risk of complications.

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57
Q

How do the diuretic effects of thiazides compare to loop diuretics?

A

Loop diuretics have much higher diuretic effects compared to thiazides.

However, the antihypertensive properties of thiazides make them one of the primary drugs in the treatment of hypertension.

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58
Q

What is Mannitol, and how is it administered?

A

Mannitol is the prototypical osmotic diuretic and is given intravenously. It is administered as a 10-20% solution.

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59
Q

How does Mannitol act as an osmotic diuretic?

A

Mannitol is freely filtered in the glomerulus and poorly reabsorbed in the tubules.

It remains in the lumen and “holds” water there by osmotic effects, primarily in the proximal convoluted tubule (PCT), descending loop of Henle, and collecting tubule.

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60
Q

Where in the nephron is Mannitol effective?

A

Mannitol is effective mainly in the proximal convoluted tubule (PCT), descending loop of Henle, and collecting tubule, where the nephron is permeable to water.

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61
Q

What are the primary uses of Mannitol?

A

Mannitol is used to:

  • Prevent anuria in acute renal failure (ARF) due to a load of pigments (e.g., hemolysis or rhabdomyolysis).
  • Decrease pathologically elevated intracranial or intraocular pressures by increasing plasma osmolarity, resulting in extraction of water from these compartments and increasing urine output.
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62
Q

What are the adverse effects of Mannitol?

A

Adverse effects of Mannitol include:

Pronounced water extraction from intracellular compartments and expansion of intravascular and interstitial fluid volume, which can lead to:

Acute pulmonary edema
Heart failure
Headaches, nausea, and vomiting (common)
Dehydration and hypernatremia (overdose)

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63
Q
  1. What is a dose-response curve?
A

A dose-response curve is a graph that measures the potency and efficacy of a drug.

It plots the response of a particular receptor-effector system against increasing concentrations of the drug.

The curve can be plotted on a linear or semilogarithmic concentration axis, with the latter often giving a sigmoid curve for easier mathematical manipulation.

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64
Q

What does a smaller EC50/ED50 indicate?

A

A smaller EC50/ED50 indicates greater potency of the drug.

EC50 (effective concentration 50) or ED50 (effective dose 50) is the concentration or dose of the drug required to achieve 50% of the maximum effect.

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65
Q

How can parallel lines on a dose-response graph be interpreted?

A

Parallel lines on a dose-response graph suggest that the drugs in question act on the same receptor. This allows for comparison of:

Affinity: The drug with the line shifted more to the left has greater affinity.

Potency: The drug with the line shifted more to the left is more potent.

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66
Q

What is the significance of potency (EC50/ED50) in a dose-response curve?

A

Potency denotes the amount of drug needed to produce a given effect.

It is determined by the drug’s affinity for the receptor and the number of available receptors.

Potency can be assessed in both graded and quantal dose-response curves.

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67
Q

How is efficacy (Emax) defined and measured?

A

Efficacy (Emax) is the greatest effect an agonist can produce if the dose is increased to the highest tolerated level.

It is measured using a graded dose-response curve and can be used for both agonists and partial agonists.

Efficacy is reflected in how high the response reaches on the graph.

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68
Q

What does it mean if the dose-response curves of two drugs do not have parallel lines?

A

If the dose-response curves of two drugs do not have parallel lines, it indicates that the drugs do not act on the same receptor.

This means that affinity cannot be compared, though efficacy and potency can still be evaluated according to the principles of their respective dose-response curves.

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69
Q

2.2 What are cholinomimetics?

A

Cholinomimetics are drugs that mimic the effects of acetylcholine.

They can act directly on acetylcholine receptors or indirectly by inhibiting cholinesterase.

Direct-acting cholinomimetics target either muscarinic or nicotinic receptors.

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70
Q

What are the two main categories of directly acting cholinomimetics?

A

Directly acting cholinomimetics can be categorized into:

Choline esters: Acetylcholine, methacholine, carbachol, and bethanechol.

Naturally occurring alkaloids: Muscarine, pilocarpine, nicotine, and lobeline.

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71
Q

What are muscarinic agonists and their general characteristics?

A

Muscarinic agonists mimic the actions of parasympathetic nerve stimulation by acting on muscarinic receptors.

There are five types of muscarinic receptors, and all clinically available muscarinic agonists are nonselective across these receptors.

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72
Q

How do nicotinic agonists differ from muscarinic agonists?

A

Nicotinic agonists are less specific and can act on either ganglions or neuromuscular junctions (NMJ).

There are selective antagonists for the two types of nicotinic receptors: NM (neuromuscular) and NN (neuronal).

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73
Q

What are the key properties and clinical uses of acetylcholine?

A

Properties: Works on both M and N receptors, rapidly hydrolyzed by cholinesterase (ChE), with a duration of action of 5-30 seconds, and poor lipid solubility.

Clinical Use: Only endogenous, not used clinically.

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74
Q

What are the key properties and uses of bethanechol?

A

Properties: Works only on M receptors, resistant to ChE, active orally, with a duration of action of 30 minutes to 2 hours, and poor lipid solubility.

Clinical Use: Used to treat paralytic ileus and urinary retention.

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75
Q

What are the key properties and uses of carbachol?

A

Properties: Works on both M and N receptors, similar to bethanechol in effects.

Clinical Use: Similar to bethanechol, used in various conditions requiring muscarinic and nicotinic stimulation.

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76
Q

What are the key properties and uses of pilocarpine?

A

Properties: Works on M receptors, not an ester, high lipid solubility, with a duration of action of 30 minutes to 2 hours.

Clinical Use: Used topically as eye drops for glaucoma, xerostomia (dry mouth) in Sjögren’s syndrome, and in the sweat test for diagnosing cystic fibrosis.

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77
Q

What are the key properties and uses of nicotine?

A

Properties: Works on N receptors, high lipid solubility, with a duration of action of 1-6 hours.

Clinical Use: Primarily used in smoking cessation therapies.

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78
Q

What are the key properties and uses of varenicline?

A

Properties: Works on N receptors as a partial agonist, high lipid solubility, with a duration of action of 12-24 hours.

Clinical Use: Used in smoking cessation therapies.

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79
Q

What are the toxic effects of muscarinic cholinomimetics?

A

Toxic effects of muscarinic cholinomimetics include:

  • CNS stimulation
  • Miosis
  • Spasm in accommodation
  • Bronchoconstriction
  • Increased smooth muscle activity in GI and genitourinary tracts

-Increased secretory mechanisms and excessive vasodilation

  • Transient bradycardia with compensatory reflex tachycardia
  • Diarrhea and vomiting
  • Hepatic and renal necrosis (especially in mushroom poisoning), which can be lethal.
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80
Q

What are the toxic effects of nicotinic cholinomimetics?

A

Toxic effects of nicotinic cholinomimetics include:

Ganglionic stimulation and block

Neuromuscular end-plate depolarization leading to fasciculations and paralysis

CNS toxicity resulting in convulsions and stimulation followed by depression

Nicotine addiction, even at very small doses.

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81
Q

What are the major chemical classes of indirectly acting cholinomimetics?

A

The major chemical classes of indirectly acting cholinomimetics are:

Carbamic acid esters (carbamates) – e.g., neostigmine

Phosphoric acid esters (organophosphates) – e.g., parathion

A third class includes: 3. Alcohol – e.g., edrophonium (only one drug with clinical significance).

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82
Q

How do indirectly acting cholinomimetics work?

A

Indirectly acting cholinomimetics inhibit cholinesterase by binding to the enzyme and undergoing rapid hydrolysis.

This releases the alcohol portion of the molecule quickly, while the acidic part (carbamate or phosphate) is released more slowly.

This inhibition prevents the hydrolysis of endogenous acetylcholine (ACh), amplifying its effects throughout the body.

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83
Q

What are the properties and uses of edrophonium?

A

Properties: Alcohol, poor lipid solubility (quaternary structure), not orally active, duration of action 5-15 minutes.

Uses: Used for the rapid reversal of non-depolarizing neuromuscular blockade, and for diagnosing and differentiating myasthenia gravis from cholinergic crisis.

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84
Q

What are the properties and uses of neostigmine?

A

Properties: Carbamate, poor lipid solubility (quaternary structure), orally active, duration of action 30 minutes to 2 hours.

Uses: Used in the treatment of myasthenia gravis.

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85
Q

What are the properties and uses of physostigmine?

A

Properties: Carbamate, good lipid solubility (tertiary structure), orally active, duration of action 30 minutes to 2 hours.

Uses: Used in the treatment of myasthenia gravis and for reversing anticholinergic toxicity.

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86
Q

What are the properties and uses of pyridostigmine?

A

Properties: Carbamate, poor lipid solubility (quaternary structure), orally active, duration of action 4-8 hours.

Uses: Used in the treatment of myasthenia gravis.

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87
Q

What are the properties and uses of echothiopate?

A

Properties: Organophosphate, moderate lipid solubility, duration of action 2-7 days.

Uses: Used in the treatment of glaucoma.

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88
Q

What are the properties and uses of parathion?

A

Properties: Organophosphate, high lipid solubility, duration of action 7-30 days.

Uses: Primarily used as a pesticide, not for clinical use.

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89
Q

What are the clinical uses of carbamates and organophosphates?

A

Carbamates (e.g., neostigmine, physostigmine, pyridostigmine, and ambenonium) are used primarily in the treatment of myasthenia gravis. Rivastigmine (a carbamate) is used for Alzheimer’s disease.

Organophosphates are used mainly as scabicides (e.g., malathion) and antihelminthic agents (e.g., metrifonate).

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90
Q

What is the major toxic effect of organophosphates, especially parathion?

A

Organophosphates, especially parathion, are highly toxic and can be rapidly lethal if not treated quickly.

The primary antidote for muscarinic toxicity is atropine, which does not affect nicotinic receptor toxicity.

Nicotinic toxicity is treated with pralidoxime, which regenerates active cholinesterase (ChE).

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91
Q

What are the DUMBBLESS symptoms of cholinomimetic toxicity?

A

DUMBBLESS symptoms include:

Diarrhea
Urination
Miosis (pupil constriction)
Bronchoconstriction
Bradycardia (slow heart rate)
Excitation of skeletal muscles and CNS
Lacrimation (excessive tearing)
Salivation
Sweating

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92
Q

How do cholinomimetics affect the CNS?

A

Nicotine: Elevates mood, increases alertness, and is addictive.

Physostigmine: Can cause convulsions and, in excess, coma.

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93
Q

What are the effects of cholinomimetics on the eye?

A

Contraction (miosis) of the sphincter muscle of the iris.

Contraction (cyclospasms) of the ciliary muscle, facilitating accommodation for near vision and increasing outflow of aqueous humor into the canal of Schlemm.

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94
Q

What are the effects of cholinomimetics on the heart?

A

SA Node: Negative chronotropic effects (decreased firing rate). Baroreceptor reflexes can cause compensatory sympathetic discharge, potentially leading to tachycardia.

Atria: Negative inotropic effects (decreased contractile force), leading to a decrease in the refractory period.

AV Node: Negative dromotropic effects (decreased conduction velocity), resulting in an increased refractory period.

Ventricles: Small negative inotropic effects.

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95
Q

How do cholinomimetics affect blood vessels?

A

Cholinomimetics cause dilation via the release of endothelium-derived relaxing factors (EDRF), such as NO. This effect is indirect and not due to direct action on blood vessels.

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96
Q

What is the impact of cholinomimetics on the bronchi?

A

Cholinomimetics cause bronchoconstriction.

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97
Q

What are the effects of cholinomimetics on the GI tract?

A

Increased smooth muscle contraction and peristalsis, leading to increased motility.

Decreased tone and relaxation of sphincter muscles (except the gastroesophageal sphincter, which contracts).

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98
Q

How do cholinomimetics affect the urinary bladder?

A

ncreased contraction of the detrusor muscle.
Relaxation of the bladder trigone and sphincters, facilitating voiding.

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99
Q

What are the effects of cholinomimetics on skeletal muscles?

A

Cholinomimetics activate neuromuscular (NM) end plates, resulting in muscle contraction.

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100
Q

How do cholinomimetics impact exocrine glands?

A

Cholinomimetics increase secretion from exocrine glands, including:

Thermoregulatory sweating
Lacrimation (tears)
Salivation
Bronchial secretion
GI gland secretion

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101
Q

2.3 What is the general mechanism of action for calcium channel blockers?

A

Calcium channel blockers inhibit the influx of Ca²⁺ through the L-type Ca²⁺ channels located in the myocardium, His bundle, Purkinje fibers, and vascular smooth muscles.

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102
Q

Into how many subgroups are calcium channel blockers divided therapeutically?

A

Calcium channel blockers are divided into three subgroups:

Dihydropyridine derivatives
Non-dihydropyridine derivatives
T-type selective blockers

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103
Q

What are examples of dihydropyridine calcium channel blockers, and what are their effects?

A

Examples: Amlodipine, felodipine, nifedipine.

They cause vasodilation of resistance vessels, reduce blood pressure (BP), and reduce afterload, making them vasoselective Ca²⁺ antagonists.

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104
Q

What are the therapeutic uses of dihydropyridine calcium channel blockers?

A

Dihydropyridine calcium channel blockers are used in:

Angina pectoris
Hypertension

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105
Q

What are the adverse effects of dihydropyridine calcium channel blockers?

A

Adverse effects include:

Reflex tachycardia due to hypotension
Headaches
GI disturbances
Gingival hyperplasia
Pretibial edema

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106
Q

What are examples of non-dihydropyridine calcium channel blockers, and what is their mechanism of action?

A

Examples: Verapamil, diltiazem.

They block both L-type and T-type Ca²⁺ channels and have affinity for cardiac myocytes and vascular smooth muscle, causing negative chronotropic, dromotropic, and inotropic effects.

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107
Q

What are the therapeutic uses of non-dihydropyridine calcium channel blockers?

A

Non-dihydropyridine calcium channel blockers are used in:

Supraventricular tachyarrhythmias (SA nodal inhibition)
Atrial flutter and fibrillation (reduces ventricular firing rate by AV nodal inhibition)
Hypertension
Angina pectoris

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108
Q

What are the adverse effects of non-dihydropyridine calcium channel blockers?

A

Adverse effects include:

GI disturbances
AV blocks
Myocardial insufficiency
Bradycardia (due to lack of reflex tachycardia)

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109
Q

What is an example of a T-type selective calcium channel blocker, and what are its characteristics?

A

Example: Mibefradil

It shows relative selectivity for T-type Ca²⁺ channels and does not have negative inotropic effects.

However, its use is contraindicated due to drug interactions and its inhibition of cytochrome P450 (CYP 1A2, 2D6, and 3A4).

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110
Q

How are doses of calcium channel blockers titrated?

A

Doses of calcium channel blockers are titrated against the patient’s response to achieve the best possible BP control.

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111
Q
  1. What does a graded dose-response curve measure?
A

A graded dose-response curve measures the potency and efficacy of a drug by plotting the response of a receptor-effector system against increasing drug concentrations.

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112
Q

What is the shape of the graded dose-response curve on a semilogarithmic axis?

A

The graded dose-response curve on a semilogarithmic axis forms a sigmoid shape, simplifying the mathematical manipulation of dose-response data.

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113
Q

What parameters can be derived from a graded dose-response curve?

A

Efficacy (Emax): The maximum effect a drug can produce.

Potency (EC50/ED50): The concentration or dose at which 50% of the drug’s maximum effect is observed.

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114
Q

What does a smaller EC50/ED50 value indicate about a drug’s potency?

A

A smaller EC50/ED50 value indicates that the drug is more potent.

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115
Q

What does a quantal dose-response relationship describe?

A

A quantal dose-response relationship describes the minimum dose required to produce a specified response in each member of a population.

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116
Q

What are the key metrics derived from quantal dose-response relationships?

A

Median effective dose (ED50): Dose that produces the desired effect in 50% of the population.

Median toxic dose (TD50): Dose that produces toxicity in 50% of the population.

Median lethal dose (LD50): Dose that is lethal in 50% of animals tested.

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117
Q

What is the difference between ED50 in graded and quantal dose-response curves?

A

In graded dose-response curves, ED50 measures a drug’s potency, while in quantal dose-response curves, ED50 represents the dose needed to produce a response in 50% of the population.

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118
Q

What does a steep sigmoid curve in a quantal dose-response relationship suggest?

A

A steep sigmoid curve suggests small variation in drug sensitivity among individuals in a population.

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119
Q

What is the therapeutic index, and how is it calculated?

A

The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, providing an estimate of a drug’s safety. A larger therapeutic index indicates a safer drug.

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120
Q

What can a small therapeutic index indicate about a drug’s safety?

A

A small therapeutic index suggests the drug has a narrow safety margin, meaning the toxic dose is close to the effective dose, requiring careful monitoring.

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121
Q

What is the therapeutic window?

A

The therapeutic window is the dosage range between the minimum effective dose and the minimum toxic dose, providing a more clinically useful measure of drug safety.

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122
Q

3.2 What are parasympatholytics?

A

Parasympatholytics are substances that act antagonistically at muscarinic cholinergic receptors, blocking the parasympathetic nervous system.

Atropine is the prototype parasympatholytic.

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123
Q

What challenges affect the therapeutic use of parasympatholytics?

A

Therapeutic use is complicated by low organ selectivity, but can be improved by:

Local application
Receptor subtype selectivity
Drugs with good or poor membrane permeability

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124
Q

How are parasympatholytics used to inhibit exocrine gland secretion?

A

Bronchial secretion: Atropine prevents hypersecretion during anesthesia and intubation, especially when the patient cannot cough.

Gastric secretion: Pirenzepine (an M1 and M3 inhibitor) is used to treat gastric and duodenal ulcers by reducing HCl secretion from parietal cells.

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125
Q

Which parasympatholytic is used for bronchodilation, and what conditions does it treat?

A

Ipratropium is used to treat conditions with increased airway resistance like chronic obstructive bronchitis and bronchial asthma.

It is inhaled, having mainly local effects with low systemic absorption.

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126
Q

What is NE-butylscopolamine used for, and what makes it especially effective?

A

NE-butylscopolamine is used for biliary and renocolic spasms.

Its effectiveness comes from its quaternary nitrogen structure, preventing BBB penetration, and its additional ganglionic blocking and direct muscle relaxant effects.

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127
Q

Which drugs cause pupillary dilation (mydriasis), and what are they used for?

A

Homatropine and tropicamide cause pupillary dilation, used for diagnostic purposes to examine the optic fundus.

These drugs have short durations, while pure atropine has a longer effect (harmful for prolonged eye function).

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128
Q

How are parasympatholytics used for cardioacceleration?

A

Ipratropium is used for bradycardia and AV blocks to raise heart rate and improve cardiac impulse conduction.

It doesn’t penetrate the BBB, avoiding brain complications.

Atropine is used to prevent cardiac arrest.

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129
Q

Why is ipratropium a good choice for treating bradycardia?

A

Ipratropium is a quaternary compound that doesn’t cross the BBB, so it doesn’t affect the brain.

However, it requires high oral doses due to its poor intestinal absorption.

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130
Q

What is scopolamine used for?

A

Scopolamine is used for:

Prophylaxis for motion sickness (kinetosis)

Sedation in cases of psychotic excitement

Anesthesia in some cases due to its fast penetration of the BBB (faster than atropine)

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131
Q

How are parasympatholytics used in Parkinson’s disease treatment?

A

Parasympatholytics, like benzatropine, are used to restore the dopamine-cholinergic balance in the corpus striatum.

Benzatropine penetrates the BBB easily and has fewer peripheral effects than atropine.

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132
Q

What are the contraindications for using parasympatholytics?

A

Glaucoma:

Relaxation of the pupillary sphincter blocks aqueous humor drainage, raising intraocular pressure, harmful in glaucoma patients.

Prostatic hypertrophy with impaired micturition:

Loss of parasympathetic control of the detrusor muscle leads to difficulty voiding.

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133
Q

What are the key symptoms of atropine poisoning?

A

Tachycardia (due to cardiac effects)

Dry mouth (inhibition of salivary secretions)

Hyperthermia (inhibition of sweat glands)

Constipation (decreased GI motility)

CNS effects: motor restlessness, manic behavior, psychic disturbances, disorientation, and hallucinations (especially in the elderly).

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134
Q

What drug can reverse atropine poisoning?

A

Atropine poisoning can be reversed by the direct parasympathomimetic physostigmine, which counteracts muscarinic receptor blockage.

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135
Q

What happens in the case of an overdose of muscarinic antagonists?

A

Overdosing on muscarinic antagonists results in:

Cardiotoxicity
Convulsions
Coma

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136
Q

3.3 What are sympathoplegic agents, and what do they reduce?

A

Sympathoplegic agents are compounds that decrease the activity of the SANS (sympathetic nervous system). They can reduce:

Venous tone
Heart rate, cardiac output (CO), and total peripheral resistance (TPR)
Contractile force of the heart

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137
Q

What are baroreceptor-sensitizing agents, and are they used clinically?

A

Baroreceptor-sensitizing agents are natural alkaloids that increase the sensitivity of baroreceptor sensory nerves.

They reduce SANS outflow and increase vagal tone to the heart.

However, they are NOT used clinically due to their toxicity.

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138
Q

How do CNS-active agents like methyldopa and clonidine work?

A

CNS-active agents are alpha-2 selective agonists that decrease SANS outflow by activating alpha-2 receptors in the CNS.

These drugs easily pass the BBB and reduce BP by lowering CO and/or TPR.

139
Q

What are the side effects of methyldopa and how is it metabolized?

A

Methyldopa is converted into methylnorepinephrine in the brain.

Side effects include:

Immunotoxicity, possibly leading to hemolytic anemia (detected with a Coombs test)

Sedation (greater than clonidine)
Salt retention

140
Q

What happens when clonidine is discontinued abruptly?

A

When clonidine is stopped suddenly, it can cause rebound hypertension.

Therefore, it is crucial to gradually taper off the drug to avoid this effect.

141
Q

Why are ganglion-blocking drugs (e.g., hexamethonium, trimethaphan) no longer used clinically?

A

Ganglion-blocking drugs are non-depolarizing nicotinic blockers that act on NN receptors in the autonomic ganglia.

Although powerful BP-lowering drugs, they cause severe adverse effects such as:

Orthostatic hypotension
Sexual dysfunction (SANS effects)
Constipation, urinary retention, glaucoma, and xerostomia (PANS effects)

142
Q

What are postganglionic sympathetic nerve terminal blockers, and why aren’t they used clinically?

A

These drugs deplete NE stores in nerve terminals (e.g., reserpine) or block NE release (e.g., guanethidine, guanadrel).

They lower BP but have high adverse effects at clinical doses.

Salt and water retention is a major compensatory response.

143
Q

What was the function of MAO inhibitors, and why were they discontinued?

A

MAO inhibitors once formed a false transmitter (octopamine) in nerve terminals, which competed with real ACh for binding, thus reducing sympathetic activity

However, due to side effects, they are no longer used clinically.

144
Q

What are α1-selective adrenoceptor blockers, and how do they work?

A

α1-selective agents like prazosin, doxazosin, and terazosin are moderately effective anti-hypertensive drugs.

They work by:

Reducing vascular resistance
Decreasing venous return

145
Q

What are the uses and limitations of non-selective α-blockers (e.g., phentolamine, phenoxybenzamine)?

A

Non-selective α-blockers affect both α1 and α2 receptors, causing intense hypotension.

They are not used for chronic hypertension due to their vasodilatory effects that can cause reflex tachycardia.

They are mainly used in hypertensive crises, such as those caused by pheochromocytoma.

146
Q

What are the benefits and side effects of α1-selective adrenoceptor blockers?

A

α1-selective blockers, unlike non-selective agents, are relatively free from severe adverse effects.

However, they can cause orthostatic hypotension, especially with the first doses.

These drugs also relax smooth muscle in the prostate, making them useful in treating benign prostatic hyperplasia (BPH).

147
Q

What is the prototype β-blocker, and how do β-blockers work in hypertension?

A

The prototype β-blocker is propranolol.

β-blockers like atenolol, metoprolol, and carvedilol reduce cardiac output (CO) initially, followed by a decrease in vascular resistance.

They may also reduce angiotensin levels by blocking renin release from the kidneys.

148
Q

What is special about the newer β-blocker nebivolol?

A

Nebivolol is a newer β-blocker that has a more pronounced vasodilatory mechanism compared to other β-blockers, adding to its effectiveness in treating hypertension.

149
Q

4.1 What is an agonist, and how does it function?

A

An agonist is a chemical (endogenous or exogenous) that binds to a receptor and activates it to produce a biological response.

Agonists can be blocked by antagonists, which compete for the same receptor.

150
Q

What is a full agonist, and what effect does it have on receptors?

A

A full agonist fully activates the receptor, producing a maximal biological response.

It has a high affinity for the activated receptor state, and when all receptors are occupied, a maximal effect is achieved.

Example: Morphine (μ-opioid receptor), Isoproterenol (β-adrenoreceptor).

151
Q

What is a partial agonist?

A

A partial agonist binds to the receptor but produces less than the full effect, even when all receptors are occupied.

It has lower intrinsic activity compared to a full agonist and can act as an inhibitor in the presence of a full agonist.

Example: Buspirone, Norclozapine.

152
Q

What is an inverse agonist, and how does it differ from a full agonist?

A

An inverse agonist binds to the same receptor as an agonist but inhibits constitutive activity of the receptor, producing the opposite effect of a receptor agonist.

It has a higher affinity for the inactive state of the receptor.

Example: Rimonabant (cannabinoid inverse agonist).

153
Q

What is a neutral agonist?

A

A neutral agonist binds with equal affinity to both the active and inactive states of the receptor and does not produce any stimulatory or inhibitory response.

154
Q

What is an antagonist, and how does it work?

A

An antagonist is a substance that blocks or dampens the agonist-mediated response by binding to the same receptor.

It competes for the binding spot on the receptor and has affinity but no efficacy (it doesn’t activate the receptor).

155
Q

What is a competitive (reversible, surmountable) antagonist?

A

A competitive antagonist binds to the active site of a receptor and progressively blocks the agonistic response.

The degree of inhibition depends on the antagonist concentration, but increasing the agonist concentration can overcome the antagonist’s effect.

Example: Propranolol (β-antagonist).

156
Q

How can the effect of a competitive antagonist be overcome?

A

The effect of a competitive antagonist can be overcome by increasing the concentration of the agonist, which can force the antagonist away from the receptor’s binding site, restoring the agonistic response.

Example: During exercise, increased norepinephrine (NE) can overcome the blockade by propranolol.

157
Q

What is an irreversible (non-competitive, non-surmountable) antagonist?

A

An irreversible antagonist binds covalently to a receptor (either active or allosteric site), making it non-surmountable.

The duration of its effect depends on the turnover rate of the receptor, as new receptors need to be synthesized to restore function.

Example: Phenoxybenzamine (α-antagonist).

158
Q

Why is Phenoxybenzamine used in pheochromocytoma, and how does it work?

A

Phenoxybenzamine is used in pheochromocytoma to control hypertensive crises caused by excessive catecholamine release from the adrenal medulla.

It irreversibly blocks α-receptors, reducing vasoconstriction and lowering blood pressure.

159
Q

What is a chemical antagonist, and how does it work?

A

A chemical antagonist doesn’t require a receptor.

It works by binding directly to another drug or substance to inactivate its effect.

Example: Protamine (positively charged) binds to and inactivates heparin (negatively charged).

160
Q

Can you provide examples of irreversible antagonists besides phenoxybenzamine?

A

Yes, examples of irreversible antagonists include:

Digoxin
Allopurinol
Proton pump inhibitors (e.g., omeprazole)
Aspirin

161
Q

What is the mechanism of action of allosteric antagonists?

A

Allosteric antagonists bind to a site on the receptor that is different from the active site (the allosteric site), which changes the receptor’s shape and reduces or blocks its activity.

These sites can sometimes be on coreceptors.

162
Q

4.2 What are sympathomimetics, and what conditions are they used for?

A

Sympathomimetic drugs mimic the effects of the neurotransmitters of the sympathetic nervous system (SANS).

They are used for cardiovascular, respiratory, preterm labor, and other conditions.

163
Q

How are sympathomimetic drugs classified based on their mode of action?

A

They are classified into:

Direct-acting: Activate adrenoreceptors directly (α and β agonists).

Indirect-acting: Increase the concentration of endogenous catecholamines in the synapse.
Releasers (e.g., amphetamines, tyramine).

Reuptake inhibitors (e.g., cocaine, tricyclic antidepressants).

Metabolism blockers (e.g., COMT and MAO inhibitors).

164
Q

What is the mechanism of direct-acting sympathomimetics?

A

Direct-acting sympathomimetics work by binding directly to and activating adrenoreceptors (both α and β receptors), mimicking the effects of endogenous neurotransmitters like norepinephrine and epinephrine.

165
Q

How do indirect-acting sympathomimetics work?

A

Indirect-acting sympathomimetics increase the concentration of endogenous catecholamines in the synapse by:

Releasing stored catecholamines (e.g., amphetamines and tyramine).

Inhibiting reuptake of catecholamines (e.g., cocaine, tricyclic antidepressants).

Blocking metabolism of catecholamines via COMT or MAO inhibitors.

166
Q

What role do reuptake inhibitors play in the action of indirect-acting sympathomimetics?

A

Reuptake inhibitors like cocaine and tricyclic antidepressants block the reuptake of catecholamines through norepinephrine transporters (NET) and dopamine transporters (DAT),

increasing the concentration of neurotransmitters in the synapse.

167
Q

What are the effects of α1-selective agonists?

A

α1-selective agonists (e.g., phenylephrine) cause:

Vascular smooth muscle contraction → Increased vascular resistance.

Pupillary dilator muscle contraction → Mydriasis (pupil dilation).

Pilomotor smooth muscle contraction → Hair erection.

Increased glycogenolysis (in some animals).

168
Q

What is the action of α2-selective agonists?

A

α2-selective agonists (e.g., clonidine, methyldopa) cause:

Inhibition of neurotransmitter release at adrenergic and cholinergic nerve terminals.

Platelet aggregation stimulation.

Inhibition of lipolysis in adipocytes.

Inhibition of insulin release from pancreatic β-cells.

169
Q

What is the role of COMT and MAO inhibitors in indirect sympathomimetics?

A

COMT and MAO inhibitors block the metabolism of catecholamines, increasing their storage in synaptic vesicles.

This potentiates the action of other indirect-acting sympathomimetics that cause the release of stored transmitters.

170
Q

What are β-agonists, and how are they classified?

A

β-agonists are sympathomimetics that act on β-adrenoceptors (Gs-coupled).

They are classified as:

Nonselective (e.g., isoproterenol).
β1-selective (e.g., dobutamine).
β2-selective (e.g., albuterol, salmeterol).
β3-selective (stimulates lipolysis in adipocytes).

171
Q

What are the effects of nonselective β-agonists like isoproterenol?

A

Nonselective β-agonists like isoproterenol stimulate both β1 and β2 receptors, leading to:

Increased heart rate (β1) and force of contraction (β1).

Bronchial and vascular smooth muscle relaxation (β2).

Glycogenolysis and insulin release.

172
Q

What are the effects of β1-selective agonists like dobutamine?

A

β1-selective agonists like dobutamine increase:

Heart rate and force of contraction.
Renin release from juxtaglomerular cells in the kidneys.

173
Q

What effects do β2-selective agonists like albuterol and salmeterol have?

A

β2-selective agonists cause:

Bronchial, uterine, and vascular smooth muscle relaxation.

Glycogenolysis in the liver.

Insulin release from pancreatic β-cells.

Tremors in somatic motor neurons.
Increased heart rate and force of contraction.

174
Q

What is the role of β3-selective agonists?

A

β3-selective agonists stimulate lipolysis in adipocytes, promoting the breakdown of fat stores.

175
Q

What effects does dopamine have as a dopamine agonist?

A

Dopamine activates D1 and D2 receptors:

D1 receptors (Gs-coupled): cause renal and splanchnic blood vessel dilation and decreased resistance.

D2 receptors (Gi-coupled): inhibit adenylyl cyclase in nerve terminals and play a role in the brain.

176
Q

How does dopamine act on α and β receptors?

A

Dopamine can activate:

β receptors at intermediate doses, increasing heart rate and contractility.
α receptors at high doses, leading to vasoconstriction.

177
Q

4.3 What is the role of renin in the renin-angiotensin-aldosterone system?

A

Renin is a glycoprotein enzyme released from the juxtaglomerular cells in response to:

Drop in renal perfusion pressure.
Decreased Na+ or Cl- delivered to the distal convoluted tubules.

β-adrenoreceptor mediated sympathoactivation.

Renin converts angiotensinogen to angiotensin I.

178
Q

What is ACE and what is its function in the renin-angiotensin-aldosterone system?

A

ACE (Angiotensin-Converting Enzyme) is a non-specific peptidase that:

Converts angiotensin I into angiotensin II.
Inactivates kinins like bradykinin when working as kininase II.

ACE is predominantly found on the luminal side of vascular endothelium, especially in the lungs, kidneys, and heart.

179
Q

What are the physiological effects of angiotensin II?

A

Angiotensin II raises blood pressure through:

Vasoconstriction of both arteries and veins.
Stimulation of aldosterone secretion from the adrenal cortex.

Central increase in sympathetic tone.

Peripheral increase in the release and effect of norepinephrine (NE).

180
Q

Why is it important to control the renin-angiotensin-aldosterone system in conditions like heart failure and hypertension?

A

In conditions like heart failure, malignant hypertension, renal failure, and diabetes:

The RAA system can exacerbate the condition by further increasing blood pressure, venous return, cardiac output (CO), and total peripheral resistance (TPR).

Excessive activation of this system can be harmful, so controlling it helps manage blood pressure and reduce adverse effects.

181
Q

What types of drugs are used to inhibit the renin-angiotensin-aldosterone system?

A

Drug inhibitors targeting various steps of the RAA system include:

ACE inhibitors (e.g., enalapril, lisinopril) to block the conversion of angiotensin I to angiotensin II.

Angiotensin II receptor blockers (ARBs) (e.g., losartan, valsartan) to block the action of angiotensin II.

Renin inhibitors (e.g., aliskiren) to directly inhibit renin.

Aldosterone antagonists (e.g., spironolactone, eplerenone) to block the effects of aldosterone.

182
Q

How does ACE contribute to the inactivation of bradykinin?

A

ACE acts as kininase II and contributes to the inactivation of bradykinin, a peptide involved in vasodilation, by cleaving it, which reduces its effects.

183
Q

What is the primary mechanism of action of ACE inhibitors?

A

ACE inhibitors block the enzyme Angiotensin-Converting Enzyme (ACE), which prevents the conversion of angiotensin I to angiotensin II.

This results in:

Lower levels of angiotensin II, leading to vasodilation and reduced aldosterone secretion.

Decreased inactivation of bradykinin, causing further vasodilation.

184
Q

What are the main cardiovascular effects of ACE inhibitors?

A

ACE inhibitors reduce:

Vascular resistance, venous tone, and blood pressure.

Preload and afterload, leading to improved cardiac output (CO).

Angiotensin II-mediated increases in norepinephrine (NE).

Aldosterone release, resulting in lower blood volume.

185
Q

What are the primary indications for ACE inhibitors?

A

ACE inhibitors are indicated for:

Heart failure (HF) in all stages and hypertension.

Low ejection fraction (EF) patients benefit significantly.

Post-myocardial infarction (MI) recovery.
Mild dyspnea on exertion without signs of volume overload.

Can be used alone or with diuretics, β-blockers, digoxin, and aldosterone antagonists.

186
Q

What is the dosing schedule for older versus newer ACE inhibitors?

A

Older ACE inhibitors have half-lives of 2-12 hours and usually require multiple daily doses.

Newer ACE inhibitors can be administered once daily due to longer half-lives.

187
Q

What are common adverse effects of ACE inhibitors?

A

Adverse effects include:

Postural hypotension (orthostatic), especially in patients with electrolyte imbalances, heart failure, or renal arterial stenosis.

Persistent dry cough due to reduced bradykinin inactivation.

Hyperkalemia, angioedema, and renal insufficiency (rare).

Contraindicated in pregnancy due to fetotoxicity.

188
Q

How are ACE inhibitors usually administered, and what is their metabolism?

A

ACE inhibitors are incompletely absorbed orally and should be taken on an empty stomach.

Many are prodrugs (except captopril) that need activation by liver enzymes.

They are primarily excreted by the kidneys.

189
Q

What are Angiotensin Receptor Blockers (ARBs) and their primary mechanism of action?

A

ARBs (e.g., losartan, valsartan, candesartan) are:

Non-peptide, orally active, and potent competitive antagonists of angiotensin type 1 (AT1) receptors.

They block the effects of angiotensin II but do not affect bradykinin levels as they do not act on ACE.

190
Q

When are ARBs typically used in clinical practice?

A

ARBs are often used as second-line drugs when:

ACE inhibitors are not tolerated or are contraindicated.

They provide similar benefits in heart failure and hypertension as ACE inhibitors.

191
Q

When are Angiotensin Receptor Blockers (ARBs) used in clinical practice?

A

ARBs are used when:

ACE inhibitors cannot be tolerated, such as in patients who experience severe cough or angioedema.

They are used for the treatment of hypertension and heart failure (HF) when ACE inhibitors are contraindicated.

192
Q

How frequently are ARBs administered, and what is unique about losartan?

A

ARBs generally require once-daily dosing.

Losartan differs from other ARBs as it undergoes first-pass hepatic metabolism to be converted into an active metabolite.

Elimination of ARBs is via the kidneys and feces.

193
Q

What are the adverse effects of ARBs, and what is their pregnancy status?

A

Adverse effects of ARBs are similar to those of ACE inhibitors:

No dry cough, which is a notable difference from ACE inhibitors.

Not used in pregnancy due to potential fetotoxicity.

194
Q
  1. What is the definition of a non-receptor antagonist?
A

A non-receptor antagonist is a substance that inhibits the action of an agonist without binding to the same receptor as the agonist.

These antagonists can act through:

Direct inhibition of the agonist (e.g., antibodies)

Inhibition of downstream molecules in the activation pathway

Activation of pathways opposing the agonist’s action

195
Q

What are chemical antagonists, and can you provide an example?

A

Chemical antagonists do not interact with receptors but inactivate the agonist before it can exert its effect.

They work by neutralizing or binding to the agonist chemically.
Examples:

Protamine: Binds to and counteracts the effects of heparin (a negatively charged anticoagulant).

Dimercaprol: Chelates and inactivates toxic metals like lead.

196
Q

What is a physiologic antagonist, and how does it work?

A

A physiologic antagonist activates or blocks a receptor that mediates a physiological response opposite to the agonist’s effect.

This mechanism counteracts the effects of the agonist through a different physiological pathway.
Example:

β-adrenergic antagonists (β-blockers): Used to counteract the tachycardic effects of hyperthyroidism.

Although thyroid hormone doesn’t directly act on β-adrenergic receptors, β-blockers help relieve tachycardia induced by sympathetic stimulation associated with hyperthyroidism.

197
Q

5.2 What are the main effects of non-selective α-adrenoreceptor blockers?

A

Non-selective α-adrenoreceptor blockers affect both α1 and α2 receptors and produce several key effects:

Cardiovascular System:

Vaso/venodilation: Decreases vascular sympathetic tone, leading to reduced arterial and venous pressures.

Baroreceptor Reflex-mediated Tachycardia:

Significant decrease in mean arterial pressure (MAP) can cause reflex tachycardia due to reduced α2 receptor-mediated inhibition of norepinephrine (NE) release.

Epinephrine Reversal:

At high doses, epinephrine shifts from a pressor response (mediated by α receptors) to a depressor response (mediated by β2 receptors), which is not seen with norepinephrine or phenylephrine.

198
Q

What are the clinical uses of non-selective α-adrenoreceptor blockers?

A

Non-selective α-adrenoreceptor blockers have specific applications:

Presurgical Treatment of Pheochromocytoma:

Phenoxybenzamine: Used preoperatively to manage severe hypertension and blood volume issues before surgery.

Phentolamine: Sometimes used during surgery.

199
Q

What are the clinical uses of non-selective α-adrenoreceptor blockers?

Other uses.

A
  • Carcinoid Tumors: Phenoxybenzamine may be used due to its serotonin receptor-blocking effects.
  • Mastocytosis: Phenoxybenzamine can help due to its H1 antihistaminic effect.
  • Tissue Damage Prevention: Phentolamine can prevent ischemia and necrosis from local α-agonist infiltration (e.g., norepinephrine).
  • Rebound Hypertension: Phentolamine helps manage rebound hypertension following sudden cessation of clonidine.
  • Hypertension from Stimulant Overdose: Used to correct severe hypertension from amphetamine, cocaine, or phenylpropanolamine overdoses.
  • Raynaud’s Phenomenon: Sometimes responds to α-blockers.
  • Erectile Dysfunction: Direct injection of phentolamine or yohimbine can induce penile erection.
200
Q

What are the potential toxicities associated with non-selective α-adrenoreceptor blockers?

A

Toxicities primarily include:

Severe Reflex Tachycardia: Due to the significant drop in blood pressure.

Nausea and Vomiting

201
Q

5.3 What are antiarrhythmic drugs used for?

A

Suppress Abnormal Cardiac Rhythms:

Atrial Fibrillation and Flutter

Atrioventricular Nodal Reentry (SVT)

Premature Ventricular Beats (PVBs)

Ventricular Tachycardia and Fibrillation (VFib)

202
Q

Cardiac Action Potentials Phases + channels

A

Fast Na+ Channels: Phase 0

Slow Ca2+ Channels: Phase 2 (also Phase 0 in nodal AP)

Slow Delayed Rectifier K+ Channels: Phase 2-3 (also Phase 3 in nodal AP)

Fast Delayed Rectifier K+ Channels: Phase 3

Inward Rectifier K+ Channels: Phase 3-4

Transient Ca2+ Channels: Phase 3 of nodal AP

203
Q

What is the Vaughan-Williams classification of antiarrhythmic drugs?

A

Class I: Na+ Channel Blockers

Subclasses: IA, IB, IC
Class II: β-Adrenoceptor Blockers

Class III: K+ Channel Blockers

Class IV: Ca2+ Channel Blockers

Class V: Other or Unknown Mechanisms

204
Q

How are Class I and III antiarrhythmic drugs used in atrial fibrillation?

A

Class I and III: Used as rhythm controllers to restore normal rhythm.

Class II and IV: Used as medical cardioversion agents to control heart rate.

205
Q

Class Ia Antiarrhythmics - Action

A

Block fast Na+ channels in activated state. Slows down the action potential.

206
Q

Class Ia Antiarrhythmics - Effect on AP

A

Increases AP duration (APD) and effective refractory period (ERP). Blocks K+ channels, prolonging repolarization.

207
Q

Class Ia Antiarrhythmics - Examples

A

Quinidine, procainamide, disopyramide.

208
Q

Class Ia Antiarrhythmics - Uses

A

Ventricular arrhythmias, paroxysmal recurrent atrial fibrillation (vagal overactivity).

Procainamide is used in Wolff-Parkinson-White syndrome.

209
Q

Class Ib Antiarrhythmics - Action

A

Block fast Na+ channels in inactivated state. Shortens AP duration and prolongs refractory period.

210
Q

Class Ib Antiarrhythmics - Benefit

A

Useful in hypoxic myocardial tissue to allow more diastole for perfusion.

211
Q

Class Ib Antiarrhythmics - Examples

A

Lidocaine, mexiletine, tocainide, phenytoin.

212
Q

Class Ib Antiarrhythmics - Uses

A

Post-MI treatment, open-heart surgery, ventricular tachycardia.

213
Q

Class Ic Antiarrhythmics - Action

A

Non-selectively block all Na+ channels, especially in His-Purkinje system.

214
Q

Class Ic Antiarrhythmics - Usage

A

Considered “last-resort” drugs when others are ineffective

215
Q

Class Ic Antiarrhythmics - Examples

A

Flecainide, encainide, propafenone.

216
Q

Class Ic Antiarrhythmics - Uses

A

Paroxysmal atrial fibrillation, recurrent tachyarrhythmias.

217
Q

Class Ic Antiarrhythmics - Contraindications

A

Post-MI patients, can cause Torsade de Pointes due to prolonged AP.

218
Q

Class II Antiarrhythmics - Mechanism

A

Decrease slope of phase 4 by blocking β1-receptors. Reduces sympathetic activity on the heart.

219
Q

Class II Antiarrhythmics - Effects

A

Decrease SA and AV nodal activity.
Makes parasympathetic system predominant.

220
Q

Class II Antiarrhythmics - Uses

A

Prophylaxis post-MI to decrease O2 demand.
Supraventricular tachyarrhythmias.
Decrease AV node conduction.

221
Q

Class II Antiarrhythmics - Selective Examples

A

Acebutolol, esmolol, metoprolol, nebivolol.

222
Q

Class II Antiarrhythmics - Non-Selective Examples

A

Propranolol, carvedilol, sotalol.

223
Q

Class III Antiarrhythmics - Mechanism

A

Block K+ channels, slowing phase 3 of the action potential.

224
Q

Class III Antiarrhythmics - Effects

A

Increase APD and ERP.
Prolong QT interval.
Markedly prolong repolarization.

225
Q

Class III Antiarrhythmics - Uses

A

Atrial fibrillation and flutter.
Ventricular tachycardias.

226
Q

Class III Antiarrhythmics - Examples

A

Sotalol, amiodarone, ibutilide.

227
Q

Class III Antiarrhythmics - Toxicity

A

Sotalol: Torsades de Pointes, excessive β-blockade
.
Ibutilide: Torsades de Pointes.

Amiodarone: Pulmonary fibrosis, hepatotoxicity, thyroid issues, corneal and skin deposits, photodermatitis, neurologic effects, constipation, CV effects (bradycardia, AV block, CHF).

228
Q

Class IV Antiarrhythmics - Mechanism

A

Block Ca2+ channels, affecting phase 0 and 4 of the action potential.

229
Q

Class IV Antiarrhythmics - Effects

A

Decrease conduction velocity.
Increase ERP and PR interval.
Reduce SA and AV nodal activity.

230
Q

Class IV Antiarrhythmics - Uses

A

Prevention of nodal arrhythmias.
Rate control in atrial fibrillation

231
Q

Class IV Antiarrhythmics - Toxicity

A

Constipation.
Flushing.
Edema.
CV effects: CHF, AV block, sinus node depression.

232
Q

Class IV Antiarrhythmics - Examples

A

Verapamil, diltiazem.

233
Q
  1. How does GRK and β-Arrestin control receptor signaling?
A

GRK phosphorylates the receptor.

β-Arrestin binds to the phosphorylated receptor, inhibiting the signal cascade.

234
Q

What is the role of phosphorylation in receptor control?

A

Phosphorylated β-Arrestin turns off the signal.

Leads to downregulation of gene expression and receptor internalization by endocytosis

235
Q

What is the consequence of a leptin receptor mutation?

A

Leads to resistance to leptin.
Results in obesity.

236
Q

What are the effects of tyrosine kinase receptor mutations (e.g., EGF, VEGF)?

A

Leads to tumor growth due to receptor hyperfunction.

Results in uncontrollable cell cycle (gain of function mutation).

VEGF is targeted by chemotherapy to inhibit vascular supply to the tumor

237
Q

How does androgen receptor malfunction affect prostate development and cancer?

A

Required for normal prostate development and prostate cancer.

Malfunction leads to prostate tumor and female phenotype in males (loss of function mutation).

238
Q

What is the impact of β2-integrin receptor defects in leukocyte adhesion disease?

A

Leads to high susceptibility to infections (loss of function mutation).

239
Q

What causes muscle paralysis in myasthenia gravis?

A

Autoantibody attack against nicotinic acetylcholine receptor.

240
Q

How does α1 agonist stimulation affect adrenaline receptors?

A

Leads to chronic hypertension due to high catecholamine levels.

241
Q

What is the effect of pheochromocytoma on catecholamine levels and α1 receptors?

A

Malignancy leading to high catecholamine secretion.
Activates α1 receptor.

242
Q

How are 1- and 2-Adrenoceptor antagonists used in pharmacologic research?

A

Used to explore autonomic nervous system function.

243
Q

What are the clinical uses of nonselective and 1-selective adrenoceptor antagonists?

A

Nonselective antagonists: Used in pheochromocytoma treatment.

1-Selective antagonists: Used in primary hypertension and benign prostatic hyperplasia.

244
Q

In what conditions are β-receptor antagonists commonly used?

A

Treatment of hypertension, ischemic heart disease, arrhythmias, endocrine and neurologic disorders, glaucoma, and more.

245
Q

What effects does insulin binding to its receptor have?

A

Leads to glucose uptake, glycogen synthesis, and protein synthesis.

Insulin is an anabolic hormone.

246
Q

What causes insulin resistance and functional receptor downregulation?

A

Aberrant serine and threonine phosphorylation of insulin receptor β-subunits.

Issues with IRS molecules.

247
Q

6.2 What are β-Adrenoreceptor Blockers and their general mechanism?

A

β-Adrenoreceptor blockers are drugs that target β-adrenoreceptors found on myocardial cells, arterial and bronchial smooth muscle cells, kidneys, and other tissues under the influence of the sympathetic nervous system (SANS).

They interfere with the binding of NE, E, and other stress hormones to their receptors, weakening the effects of SANS.

248
Q

Who introduced the first β-Adrenoreceptor blocker and when?

A

Propanolol was the first β-adrenoreceptor blocker introduced in 1965

249
Q

What are the key structural components of β-Adrenoreceptor Blockers?

A

Basic structure includes:

Side chain (shared by most)

Aromatic nucleus:
Determines if the compound has intrinsic sympathomimetic activity (partial agonist) or acts as a partial antagonist.

Levorotatory enantiomer form has 100x higher affinity for β-receptors than the dextrorotatory form, making them very selective.

250
Q

What is meant by cardioselectivity in β-Adrenoreceptor Blockers?

A

Some β-adrenoreceptor blockers have higher affinity for cardiac β1-receptors, such as metoprolol, acebutolol, and bisoprolol.

251
Q

What are the therapeutic effects of β-Adrenoreceptor Blockers on cardiac function?

A

Block cardiac β-receptors:
Protect the heart from oxygen-wasting effects of SANS stimulation.

Used prophylactically in angina to prevent myocardial stress and possible ischemia.

Lower cardiac rate (sinus tachycardia) and blood pressure due to reduced cardiac output.

Topical treatment for glaucoma to lower aqueous humor production without affecting drainage.

252
Q

What are the indications for using β-Adrenoreceptor Blockers?

A

Angina pectoris

Atrial fibrillation and other cardiac arrhythmias (e.g., esmolol, sotalol, landilol)

Congestive heart failure (e.g., carvedilol, sustained-release metoprolol, nebivolol)

Essential tremor (e.g., propranolol)
Glaucoma (e.g., betaxolol, carteolol, levobunolol)

Hypertension

Myocardial infarction (e.g., atenolol, metoprolol, propranolol)

Mitral valve prolapse
Pheochromocytoma (in combination with α-blockers, e.g., propranolol)

253
Q

What are some additional therapeutic uses of β-Adrenoreceptor Blockers?

A

Symptomatic control in anxiety and hyperthyroidism

Acute aortic dissection

Hypertrophic obstructive cardiomyopathy

Marfan syndrome

Prevention of variceal bleeding in portal hypertension

254
Q

What are some common adverse effects of β-Adrenoreceptor Blockers?

A

Nausea, diarrhea

Bronchospasm, dyspnea

Cold extremities, Raynaud’s syndrome

Bradycardia, hypotension

Heart failure, heart block

Fatigue, dizziness

Alopecia, abnormal vision

Hallucinations, insomnia

Sexual dysfunction, erectile dysfunction

Alteration of glucose and lipid metabolism

255
Q

What are some specific adverse effects associated with certain β-Adrenoreceptor Blockers?

A
  • Mixture of α1/β-antagonist therapy commonly causes orthostatic hypotension
  • Carvedilol is commonly associated with edema
  • Lipophilic β-blockers (e.g., propranolol, metoprolol) cross the BBB and are more likely to cause sleep disturbances
  • β2-blockers more commonly cause bronchospasm, peripheral vasoconstriction, and alteration of glucose and lipid metabolism
  • β1-blockers inhibit renin release, decreasing aldosterone release, leading to hyponatremia and hyperkalemia
  • Hypoglycemia due to β2-blockers (glycogenolysis and glucagon release inhibited)

– use β1-receptors instead

  • Not used in treatment of cocaine/amphetamine overdose – increases hypertension and decreases coronary blood flow
256
Q

What are some contraindications for using β-Adrenoreceptor Blockers?

A

Patients with asthma

Drug stimulant overdose (e.g., cocaine, amphetamines)

257
Q

What are some common nonselective β-Adrenoreceptor Blockers?

A

Carvedilol (has additional α-blocking activity)
Propranolol
Sotalol
Nadolol

258
Q

What are some common β1-selective β-Adrenoreceptor Blockers?

A

Atenolol

Acebutolol (intrinsic sympathomimetic activity – partial agonist)

Bisoprolol, Esmolol

Metoprolol, Nebivolol (increases NO release for vasodilation)

259
Q

What is a common β2-selective β-Adrenoreceptor Blocker?

A

Butaxamine

260
Q

Which β-Adrenoreceptor Blockers have intrinsic sympathomimetic actions?

A

Acebutolol
Mepindolol
Pindolol

261
Q

What are some hydrophilic β-Adrenoreceptor Blockers?

A

Atenolol
Sotalol

262
Q

Which β-Adrenoreceptor Blockers have membrane-stabilizing properties?

A

Acebutolol
Propranolol

263
Q

6.3 What is angina pectoris and how does it present?

A

Angina pectoris is a type of chest pain caused by cardiac ischemia.

The pain is usually substernal but can also be felt in the neck, shoulder, arm, and epigastrium.

It often occurs later in women than in men.

264
Q

What are the different types of angina and their characteristics?

A

Atherosclerotic Angina (Classic Angina/Angina of Effort):

Accounts for 90% of cases.
Caused by atherosclerotic plaques that partially occlude coronary arteries.
Pain occurs with increased workload and is relieved by rest within 15 minutes.
Vasospastic Angina (Rest Angina/Variant Angina/Prinzmetal’s Angina):

Less than 10% of cases.
Caused by reversible coronary spasms, often around a plaque.
Can occur at any time, including at night.
Unstable Angina (Acute Coronary Syndrome):

Increased frequency and severity of attacks due to a combination of atherosclerotic plaques, platelet aggregation, and vasospasm.
Immediate precursor to myocardial infarction; considered an emergency.

265
Q

What factors determine cardiac oxygen demand?

A

Preload (Diastolic Filling Pressure):

Function of blood volume and venous tone, primarily controlled by sympathetic outflow.
Afterload:

Determined by arterial blood pressure and large artery stiffness.
Heart Rate:

Faster heart rates increase myocardial tension and oxygen demand; reduced diastole time decreases coronary oxygenation.
Double Product:

Product of heart rate and systemic arterial blood pressure; a major contributor to increased oxygen demand and sensitive to sympathetic activity.
Force of Contraction:

Controlled by the sympathetic nervous system; increased ejection time raises oxygen demand.

266
Q

What is the main goal of pharmacological treatment for angina pectoris?

A

The main goal is to increase oxygen delivery to the myocardium and reduce oxygen demand.

267
Q

What are the traditional pharmacological treatments for angina pectoris?

A

Nitrates: Relieve angina by dilating veins and reducing preload.

Calcium Channel Blockers: Reduce myocardial contraction and lower heart rate.

Beta-Blockers: Decrease heart rate and myocardial oxygen demand.

268
Q

What are partial fatty acid oxidation (pFOX) inhibitors and their purpose in angina treatment?

A

pFOX inhibitors shift the heart’s energy substrate preference from fatty acids to glucose.

This improves the efficiency of oxygen utilization.

269
Q

What are some newer treatments for angina besides traditional medications?

A

Partial Fatty Acid Oxidation (pFOX) Inhibitors: Improve oxygen utilization efficiency.

Myocardial Revascularization: Corrects obstruction via bypass or angioplasty.

270
Q

What is the main therapeutic nitrate used for angina pectoris and its duration of action?

A

Nitroglycerin (Glyceryl Trinitrate) is the most important therapeutic nitrate.

Sublingual Administration: Duration of 10-20 minutes for acute attacks.

Transdermal Administration: Duration of 8-10 hours for prophylaxis

271
Q

Why is sublingual nitroglycerin effective despite the high first-pass effect when taken orally?

A

Nitroglycerin is rapidly denitrated in the liver and smooth muscle.

Sublingual Administration: Bypasses the liver’s first-pass metabolism, making it very effective

272
Q

What are other commonly used nitrates besides nitroglycerin?

A

Isosorbide Dinitrate:
Available in sublingual and oral forms.

Rapidly denitrated in liver and smooth muscle.

Isosorbide Mononitrate:
Active orally.

Amyl Nitrate:
Volatile, rapidly acting vasodilator, inhaled.
Rarely prescribed

273
Q

What is the mechanism of action of nitrates?

A

Nitrates release nitric oxide (NO) in smooth muscle.

NO stimulates guanylyl cyclase (GC) and increases cGMP.

cGMP leads to smooth muscle relaxation by dephosphorylating the myosin light-chain phosphate.

274
Q

What are the cardiovascular effects of nitrates?

A

Venodilation: Reduces cardiac size and output by decreasing preload.

Leads to reduced diastolic heart size and myocardial fiber tension.

Increased Coronary Blood Flow: Relaxation of arterial smooth muscle improves flow through partially occluded coronary arteries.

Reduced Afterload: Relaxation of resistant arteries increases ejection and decreases cardiac size.

Reflex Tachycardia: Compensatory mechanism due to hypotensive effects.

275
Q

What are the effects of nitrates on other organs?

A

Smooth Muscle Relaxation: Affects bronchi, gastrointestinal tract, and genitourinary tract.

Clinically insignificant due to small effects.

Intravenous Nitroglycerine: Used in unstable angina to reduce platelet aggregation

276
Q

What are the common toxicities associated with nitrates?

A

Reflex Tachycardia: Due to baroreceptor response.

Orthostatic Hypotension: Resulting from venodilation.

Throbbing Headache: Due to vasodilation of meningeal arteries, increasing intracranial pressure.

Erectile Dysfunction: Especially when combined with sildenafil and similar drugs.

Methemoglobinemia: High serum levels; nitrates can be used as antidotes in cyanide poisoning.

277
Q

Which calcium channel blockers are used in the treatment of angina?

A

Nifedipine: A dihydropyridine.
Diltiazem: A non-dihydropyridine.
Verapamil: A non-dihydropyridine.

278
Q

What is the mechanism of action of calcium channel blockers?

A

Blockage of Voltage-Gated L-Type Calcium

Channels:
Most important in cardiac and smooth muscle.
Reduces intracellular calcium concentration and myocardial contractility.

279
Q

What are the actions of calcium channel blockers?

A

Relax Blood Vessels: Primarily, but also affects uterus, bronchi, and gut to a lesser extent.

Rate and Contractility of the Heart:
Reduced by diltiazem and verapamil.

Used to treat AV-nodal arrhythmias.

Nifedipine and Dihydropyridines: Greater vasodilation, potentially causing reflex tachycardia.

Reduce Blood Pressure and Double Product in Angina.

Effective Prophylactic Agents: In effort and vasospastic angina.

Important in Combination with Nitrates: For treating severe/unstable angina.

Other Uses: Hypertension, supraventricular tachycardia, migraine, preterm labor, stroke, and Raynaud’s phenomenon.

280
Q

What are the common toxicities associated with calcium channel blockers?

A

General Toxicities:

Constipation
Pretibial edema
Nausea
Flushing
Dizziness

Specific Toxicities:

Verapamil: Heart failure, AV blockade, sinus node depression.

281
Q

How do beta-blockers benefit angina management?

A

Anti-Anginal Effects:

Decrease heart rate, cardiac force, and blood pressure.

Reduce cardiac work, double product, and oxygen demand.

Prophylactic Use: Effective for preventing exercise-induced angina but not for acute attacks or vasospastic angina.

Prevent Compensatory Effects of Nitrates:

Such as tachycardia and increased cardiac force.

282
Q

What are the limitations of beta-blockers in angina treatment?

A

Not Effective for Acute Attacks.

Ineffective Against Vasospastic Angina.

283
Q

What are the newer drugs for angina and their mechanisms?

A

Ranolazine

Ivabradine

284
Q

Ranolazine

A

Reduces the late, prolonged sodium current in myocardial cells.

May alter cardiac metabolism by switching substrate preference from fatty acids to glucose.

Moderately effective in prophylaxis of angina.

285
Q

Ivabradine

A

Experimental drug that inhibits the funny current in the SA node.

Decreases heart rate and cardiac work.

286
Q
  1. What is desensitization in the context of drug therapy?
A

Desensitization: A method to reduce or eliminate negative reactions to a drug.

Definition: Loss of responsiveness to a continuing or increasing dose of a drug.

Purpose: To manage drug hypersensitivity or allergies when alternative treatments are not available.

Process: Gradual exposure to increasing doses of the drug.

287
Q

What precautions should be taken during drug desensitization?

A

Informed Consent: Ensure the patient understands the risks.

Patient’s Health: Should be relatively good.
Review Drug History: Stop drugs that exacerbate allergic reactions (e.g., beta-blockers, NSAIDs).

Setting: Done in-patient or closely monitored.

Emergency Preparedness: Qualified staff must be present to administer emergency drugs.

Monitoring: Regularly check vital signs and for symptoms of allergic reactions.

Post-Desensitization Monitoring: At least an hour after the last dose.

288
Q

Give an example of desensitization.

A

Example: Desensitization to beef insulin in diabetes mellitus (DM) patients.

Method: Start with very small doses, gradually increase to the full dose to prevent allergic reactions.

Mechanism: Small doses produce an IgG response that overrides the hypersensitive IgE response.

289
Q

What is tachyphylaxis?

A

Tachyphylaxis: Acute, sudden decrease in drug response after administration.

Not Dose Dependent: Can occur after an initial dose or a series of small doses.

Restoration: Increasing the dose may restore the original response.

290
Q

List some examples of drugs or conditions where tachyphylaxis occurs.

A

Hormone Replacement: In menopausal women.

Psychedelic Mushrooms: Rapid tachyphylaxis; unable to ‘trip’ two days in a row.

Centrally Acting Analgesics.

Beta2-Agonists: Salbutamol for asthma.

Nicotine: Shows tachyphylaxis over the day.

Nitroglycerin: Requires drug-free intervals.

Epinephrine: Repeated doses show tachyphylaxis.

291
Q

What is tolerance in drug therapy?

A

Tolerance: Progressive reduction in a subject’s reaction to a drug, requiring increased concentration for the desired effect.

Types: Can be physiological or psychological.

Dose Dependent: Increased dose is needed to achieve the same effect.

292
Q

7.2 What are the major chemical classes of indirectly acting parasympathomimetics?

A

Carbamic Acid Esters (Carbamates): E.g., Neostigmine

Phosphoric Acid Esters (Organophosphates): E.g., Parathion

Alcohols: E.g., Edrophonium (only one with clinical significance)

293
Q

How do indirectly acting parasympathomimetics work?

A

Mechanism: Inhibit cholinesterase.

Process: Bind to cholinesterase and undergo rapid hydrolysis, releasing the alcohol portion while the acidic part (carbamate or phosphate) is released more slowly.

Effect: Inhibition of cholinesterase increases the levels of endogenous ACh, amplifying its effects wherever it is released.

294
Q

List the examples of indirectly acting cholinomimetics

A

Edrophonium
Neostigmine
Physostigmine
Pyridostigmine
Echothiopate
Parathion

295
Q

Edrophonium characteristics

A

Alcohol, poor lipid solubility (quaternary structure), not orally active, duration 5-15 minutes. Used to diagnose myasthenia gravis vs. cholinergic crisis.

296
Q

Neostigmine

A

Carbamate, poor lipid solubility (quaternary structure), orally active, duration 30 minutes to 2 hours. Used to treat myasthenia gravis and as an antidote to curare.

297
Q

Physostigmine

A

Carbamate, good lipid solubility (tertiary structure), orally active, duration 30 minutes to 2 hours. Antidote for atropine overdose.

298
Q

Pyridostigmine

A

Carbamate, poor lipid solubility (quaternary structure), orally active, duration 4-8 hours. Used in myasthenia gravis.

299
Q

Echothiopate

A

Organophosphate, moderate lipid solubility, duration 2-7 days. Used to treat glaucoma.

300
Q

Parathion

A

Organophosphate, high lipid solubility, duration 7-30 days. Used as a pesticide.

301
Q

What are the clinical uses of indirectly acting parasympathomimetics?

A

Carbamates (Neostigmine, Physostigmine, Pyridostigmine, Ambenonium): Primarily used in the treatment of myasthenia gravis.

Rivastigmine (Carbamate): Used in the treatment of Alzheimer’s disease.

Organophosphates (Malathion, Metrifonate): Used as scabicides and antihelminthic agents.

Edrophonium: Used for rapid reversal of non-depolarizing NM blockade and diagnosing myasthenia gravis versus cholinergic crisis.

302
Q

What are the toxic effects of indirectly acting parasympathomimetics, especially organophosphates?

A

Organophosphates (e.g., Parathion): Highly toxic, can be rapidly lethal if not treated.

Antidote: Atropine (muscarinic effects) and Pralidoxime (for nicotinic toxicity).

Symptoms (DUMBBLESS):

Diarrhea, Urination, Miosis, Bronchoconstriction, Bradycardia, Excitation of skeletal muscles and CNS, Lacrimation, Salivation, Sweating.

303
Q

What are the central nervous system effects of cholinomimetics?

A

Complex Stimulatory Effects: Varied effects depending on the specific drug.

Nicotine: Elevates mood, increases alertness, and is addictive.

Physostigmine: Can cause convulsions and, in excessive doses, coma due to central cholinergic stimulation.

304
Q

How do cholinomimetics affect the eye?

A

Miosis: Contraction of the sphincter muscle of the iris, leading to constriction of the pupil.

Accommodation: Contraction of the ciliary muscle for near vision and facilitation of aqueous humor outflow into the canal of Schlemm.

305
Q

What are the effects of cholinomimetics on the heart?

A

SA Node: Negative chronotropic effects (decreased firing rate). Baroreceptor reflexes may activate, causing compensatory sympathetic discharge that can lead to tachycardia.

Atria: Negative inotropic effects (decrease in contractile force) and decrease in the refractory period.

AV Node: Negative dromotropic effects (decreased conduction velocity) and increase in the refractory period.

Ventricles: Small negative inotropic effects.

306
Q

What is the impact of cholinomimetics on blood vessels?

A

Dilation: Via the release of Endothelial-Derived Relaxing Factor (EDRF), including Nitric Oxide (NO).

Note that this is not a direct action of cholinomimetics on blood vessels but rather an indirect effect.

307
Q

How do cholinomimetics affect the bronchi?

A

Bronchoconstriction: Constriction of bronchial smooth muscle leading to narrowing of the airways.

308
Q

What are the effects of cholinomimetics on the gastrointestinal (GI) tract?

A

Increased Motility: Increased smooth muscle contraction and peristalsis.

Relaxation of Sphincters: Decreased tone and relaxation of most sphincter muscles, except for the gastroesophageal sphincter which contracts.

309
Q

What are the effects of cholinomimetics on the urinary bladder?

A

Increased Contraction: Enhanced contraction of the detrusor muscle.

Relaxation of Sphincters: Relaxation of the bladder trigone and sphincters, facilitating voiding.

310
Q

How do cholinomimetics affect skeletal muscles?

A

Activation of NM End Plates: Leads to muscle contraction through stimulation of neuromuscular junctions.

311
Q

What are the effects of cholinomimetics on exocrine glands?

A

Increased Secretion: Enhanced secretion from thermoregulatory sweat glands, lacrimal glands, salivary glands, bronchial glands, and gastrointestinal glands.

312
Q

7.3 What are the consequences of atherosclerosis that lipid-lowering drugs aim to prevent?

A

Lipid-lowering drugs prevent MI, angina, peripheral artery disease, and ischemic stroke.

313
Q

What potential side effects can lipid-lowering drugs cause?

A

Lipid-lowering drugs can cause drug-drug interactions, and toxic reactions in skeletal muscle and the liver.

314
Q

Name the five major categories of lipid-lowering drugs.

A

HMG-CoA reductase inhibitors (e.g., lovastatin)
Resins
Ezetimibe
Niacin
Fibrates (e.g., gemfibrozil)

315
Q

What are the primary lipid abnormalities contributing to premature atherosclerosis?

A

Increased LDL, decreased HDL, hypertriglyceridemia, and genetic factors such as chylomicronemia.

316
Q

What genetic conditions can lead to primary disturbances in plasma lipoprotein regulation?

A

Mutations in apolipoproteins, their receptors, transport mechanisms, and lipid-metabolizing enzymes.

317
Q

What secondary factors are associated with disturbances in plasma lipoprotein regulation?

A

Western diet, endocrine conditions, liver, and kidney diseases.

318
Q

What is the treatment goal for managing hyperlipidemia?

A

To lower LDL levels and reduce atheroma plaque formation.

319
Q

What dietary changes can help manage hyperlipidemia?

A

Reduce intake of cholesterol, saturated fats, and alcohol (which raises triglyceride and VLDL levels).

320
Q

Which lipid-lowering drugs are used based on individual lipid abnormalities?

A

The choice of drug depends on the specific type of lipid abnormality.

321
Q

What is the mechanism of HMG-CoA reductase inhibitors (statins)?

A

Statins inhibit the rate-limiting step in hepatic cholesterol synthesis, converting HMG-CoA to mevalonate by HMG reductase.

322
Q

What structural property do statins have in relation to HMG-CoA?

A

Statins are structural analogs of HMG-CoA and completely inhibit the enzyme.

323
Q

Name two statins that are prodrugs.

A

Lovastatin and Simvastatin.

324
Q

Which statins are active as given, not prodrugs?

A

Atorvastatin, fluvastatin, pravastatin, and rosuvastatin.

325
Q

What effect does the inhibition of hepatic cholesterol synthesis have?

A

It contributes a small amount to the serum cholesterol-lowering effects, but the liver compensates by increasing LDL receptors, clearing LDL and VLDL from the blood.

326
Q

What other benefits do HMG-CoA reductase inhibitors provide besides lowering cholesterol?

A

They have direct anti-atherosclerotic effects and may help prevent bone loss.

327
Q

What are the primary actions of HMG-CoA reductase inhibitors (statins)?

A

Dramatically lower LDL cholesterol levels.

Reduce mortality from ischemic heart disease and stroke.

Rosuvastatin, atorvastatin, and simvastatin also reduce triglycerides and increase HDL.

328
Q

What are the potential toxicities of statins?

A

Mild elevations in serum aminotransferase.

Increased creatine kinase (from skeletal muscle), leading to muscle pain and rare rhabdomyolysis.

Interaction with foods that inhibit cytochrome P450 can increase risk of hepatotoxicity and myopathy.

329
Q

Why are statins contraindicated in pregnancy?

A

Statins have possible teratogenic effects.

330
Q

What are bile acid-binding resins, and how do they work?

A

Resins like cholestyramine, coletipol, and colesevelam are non-absorbable polymers that bind bile acids in the intestine,

preventing their absorption and diverting hepatic cholesterol to bile acid synthesis, reducing cholesterol levels.

331
Q

What is the effect of bile acid-binding resins on lipid levels?

A

In which conditions are bile acid-binding resins used?

Back: They are used for hypercholesterolemia and to reduce pruritus (itching) in patients with cholestasis and bile salt accumulation.

332
Q

What are the adverse effects of bile acid-binding resins?

A

Bloating, constipation, gritty taste, and decreased absorption of fat-soluble vitamins and some drugs (e.g., thiazides, warfarin, pravastatin, and fluvastatin).

333
Q

What is Ezetimibe, and how does it work?

A

Ezetimibe is a prodrug converted in the liver to its active form, inhibiting a transporter that mediates GI uptake of cholesterol and phytosterols, reducing cholesterol in the hepatic pool.

334
Q

How effective is Ezetimibe in reducing cholesterol, and how can its efficacy be enhanced?

A

Ezetimibe reduces cholesterol by about 18% and is more effective when combined with HMG-CoA reductase inhibitors (statins).

335
Q

What are the lipid effects of Niacin (nicotinic acid)?

A

Niacin reduces LDL, cholesterol, triglycerides, and VLDL while often increasing HDL.

336
Q

How does Niacin reduce VLDL and LDL levels in the liver?

A

Niacin reduces VLDL synthesis in the liver, which subsequently reduces LDL levels.

337
Q

What is Niacin’s effect on adipose tissue?

A

In adipose tissue, Niacin activates a signaling pathway that reduces hormone-sensitive lipase (HSL) activity, decreasing plasma free fatty acids and triglycerides, which reduces LDL formation.

338
Q

How does Niacin increase HDL levels?

A

Niacin reduces the catabolic rate for HDL, helping to maintain higher circulating HDL levels.

339
Q

What are some adverse effects of Niacin?

A

Cutaneous flushing (preventable with aspirin or NSAIDs).

Dose-dependent nausea and abdominal issues.

Pruritus and skin reactions.

Moderate liver enzyme elevation and possible severe hepatotoxicity.

Hyperuricemia (20%).

Impaired carbohydrate tolerance.

340
Q

What is the primary receptor targeted by fibric acid derivatives (gemfibrozil, fenofibrate)?

A

Fibric acid derivatives are ligands for peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates genes involved in lipid metabolism.

341
Q

What are the effects of fibric acid derivatives on lipid metabolism?

A

Increase lipoprotein lipase synthesis in adipose tissue, enhancing clearance of triglyceride-rich lipoproteins.

Stimulate fatty acid oxidation in the liver, limiting triglyceride supply and reducing VLDL synthesis.

342
Q

In what condition might fibric acid derivatives increase LDL levels?

A

Fibric acid derivatives can increase LDL levels in patients with familial combined hyperlipoproteinemia, a condition with elevated VLDL and LDL.

343
Q

What are fibric acid derivatives used to treat, and how are they often combined for better results?

A

ibric acid derivatives are used to treat hypertriglyceridemia and are often combined with other cholesterol-lowering drugs to improve LDL and VLDL levels.

344
Q

What are the adverse effects of fibric acid derivatives?

A

Common nausea.

Skin rashes, particularly with gemfibrozil.
Decreased white blood cell count and hematocrit.

Increased risk of cholesterol gallstones.

Increased risk of myopathy when combined with HMG-CoA reductase inhibitors (statins).

345
Q

What is the first line of treatment for all patients with hyperlipidemia?

A

The first line of treatment is dietary modification.

346
Q

Why might combination drug therapy be necessary in treating hyperlipidemia?

A

Combinations of drugs are often needed to achieve optimal effects on LDL, VLDL, and triglyceride levels.

4th year (26 decks)

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