Pharm T1-7 Flashcards

Question

How is acetylcholine (ACh) synthesized?

Answer 1

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).

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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.

Answer 6

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.

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

All muscarinic receptors can be inhibited by atropine and scopolamine.

Answer 12

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

Answer 13

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.

Answer 14

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.

Answer 15

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.

Answer 16

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.

Answer 17

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

Answer 18

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.

Answer 19

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

Answer 20

- Ganglionic blocking agents: Hexamethonium (research drug), Trimethaphan. - Nondepolarizing neuromuscular blocking agents: Atracurium. - Depolarizing neuromuscular blocking agent: Succinylcholine.

Answer 21

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.

Answer 22

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

Answer 23

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

Answer 24

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.

Answer 25

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

Answer 26

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.

Answer 27

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

Answer 28

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

Answer 29

Inhibition of Na+ reabsorption in the DCT, reducing Na+ retention. Increased calcium reabsorption from the lumen, leading to lower urine calcium levels.

Answer 30

Decreased preload and afterload on the heart. Long-term use (2-3 weeks) reduces pulmonary vascular resistance.

Answer 31

- 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

Answer 32

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

Answer 33

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

Answer 34

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.

Answer 35

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.

Answer 36

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

Answer 37

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.

Answer 38

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

Answer 39

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.

Answer 40

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)

Answer 41

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.

Answer 42

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.

Answer 43

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.

Answer 44

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.

Answer 45

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.

Answer 46

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.

Answer 47

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.

Answer 48

Directly acting cholinomimetics can be categorized into: Choline esters: Acetylcholine, methacholine, carbachol, and bethanechol. Naturally occurring alkaloids: Muscarine, pilocarpine, nicotine, and lobeline.

Answer 49

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.

Answer 50

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).

Answer 51

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.

Answer 52

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.

Answer 53

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.

Answer 54

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.

Answer 55

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.

Answer 56

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.

Answer 57

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.

Answer 58

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.

Answer 59

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).

Answer 60

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.

Answer 61

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.

Answer 62

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.

Answer 63

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.

Answer 64

Properties: Carbamate, poor lipid solubility (quaternary structure), orally active, duration of action 4-8 hours. Uses: Used in the treatment of myasthenia gravis.

Answer 65

Properties: Organophosphate, moderate lipid solubility, duration of action 2-7 days. Uses: Used in the treatment of glaucoma.

Answer 66

Properties: Organophosphate, high lipid solubility, duration of action 7-30 days. Uses: Primarily used as a pesticide, not for clinical use.

Answer 67

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).

Answer 68

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).

Answer 69

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

Answer 70

Nicotine: Elevates mood, increases alertness, and is addictive. Physostigmine: Can cause convulsions and, in excess, coma.

Answer 71

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.

Answer 72

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.

Answer 73

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.

Answer 74

Cholinomimetics cause bronchoconstriction.

Answer 75

Increased smooth muscle contraction and peristalsis, leading to increased motility. Decreased tone and relaxation of sphincter muscles (except the gastroesophageal sphincter, which contracts).

Answer 76

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

Answer 77

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

Answer 78

Cholinomimetics increase secretion from exocrine glands, including: Thermoregulatory sweating Lacrimation (tears) Salivation Bronchial secretion GI gland secretion

Answer 79

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.

Answer 80

Calcium channel blockers are divided into three subgroups: Dihydropyridine derivatives Non-dihydropyridine derivatives T-type selective blockers

Answer 81

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

Answer 82

Dihydropyridine calcium channel blockers are used in: Angina pectoris Hypertension

Answer 83

Adverse effects include: Reflex tachycardia due to hypotension Headaches GI disturbances Gingival hyperplasia Pretibial edema

Answer 84

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.

Answer 85

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

Answer 86

Adverse effects include: GI disturbances AV blocks Myocardial insufficiency Bradycardia (due to lack of reflex tachycardia)

Answer 87

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).

Answer 88

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

Answer 89

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.

Answer 90

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

Answer 91

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.

Answer 92

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

Answer 93

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

Answer 94

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.

Answer 95

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.

Answer 96

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

Answer 97

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.

Answer 98

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.

Answer 99

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.

Answer 100

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

Answer 101

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

Answer 102

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.

Answer 103

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.

Answer 104

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.

Answer 105

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).

Answer 106

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.

Answer 107

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.

Answer 108

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)

Answer 109

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.

Answer 110

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.

Answer 111

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).

Answer 112

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

Answer 113

Overdosing on muscarinic antagonists results in: Cardiotoxicity Convulsions Coma

Answer 114

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

Answer 115

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.

Answer 116

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.

Answer 117

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

Answer 118

When clonidine is stopped suddenly, it can cause rebound hypertension. Therefore, it is crucial to gradually taper off the drug to avoid this effect.

Answer 119

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)

Answer 120

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.

Answer 121

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.

Answer 122

α1-selective agents like prazosin, doxazosin, and terazosin are moderately effective anti-hypertensive drugs. They work by: Reducing vascular resistance Decreasing venous return

Answer 123

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.

Answer 124

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).

Answer 125

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.

Answer 126

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.

Answer 127

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.

Answer 128

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).

Answer 129

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.

Answer 130

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).

Answer 131

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.

Answer 132

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).

Answer 133

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).

Answer 134

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.

Answer 135

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).

Answer 136

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.

Answer 137

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).

Answer 138

Yes, examples of irreversible antagonists include: Digoxin Allopurinol Proton pump inhibitors (e.g., omeprazole) Aspirin

Answer 139

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.

Answer 140

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.

Answer 141

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).

Answer 142

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.

Answer 143

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.

Answer 144

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.

Answer 145

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).

Answer 146

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.

Answer 147

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.

Answer 148

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).

Answer 149

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.

Answer 150

β1-selective agonists like dobutamine increase: Heart rate and force of contraction. Renin release from juxtaglomerular cells in the kidneys.

Answer 151

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.

Answer 152

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

Answer 153

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.

Answer 154

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

Answer 155

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.

Answer 156

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.

Answer 157

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).

Answer 158

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.

Answer 159

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.

Answer 160

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

Answer 161

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.

Answer 162

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.

Answer 163

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.

Answer 164

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.

Answer 165

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.

Answer 166

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.

Answer 167

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.

Answer 168

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.

Answer 169

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.

Answer 170

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.

Answer 171

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.

Answer 172

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

Answer 173

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.

Answer 174

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.

Answer 175

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.

Answer 176

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.

Answer 177

- 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.

Answer 178

Toxicities primarily include: Severe Reflex Tachycardia: Due to the significant drop in blood pressure. Nausea and Vomiting

Answer 179

Suppress Abnormal Cardiac Rhythms: Atrial Fibrillation and Flutter Atrioventricular Nodal Reentry (SVT) Premature Ventricular Beats (PVBs) Ventricular Tachycardia and Fibrillation (VFib)

Answer 180

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

Answer 181

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

Answer 182

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.

Answer 183

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

Answer 184

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

Answer 185

Quinidine, procainamide, disopyramide.

Answer 186

Ventricular arrhythmias, paroxysmal recurrent atrial fibrillation (vagal overactivity). Procainamide is used in Wolff-Parkinson-White syndrome.

Answer 187

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

Answer 188

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

Answer 189

Lidocaine, mexiletine, tocainide, phenytoin.

Answer 190

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

Answer 191

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

Answer 192

Considered "last-resort" drugs when others are ineffective

Answer 193

Flecainide, encainide, propafenone.

Answer 194

Paroxysmal atrial fibrillation, recurrent tachyarrhythmias.

Answer 195

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

Answer 196

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

Answer 197

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

Answer 198

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

Answer 199

Acebutolol, esmolol, metoprolol, nebivolol.

Answer 200

Propranolol, carvedilol, sotalol.

Answer 201

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

Answer 202

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

Answer 203

Atrial fibrillation and flutter. Ventricular tachycardias.

Answer 204

Sotalol, amiodarone, ibutilide.

Answer 205

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).

Answer 206

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

Answer 207

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

Answer 208

Prevention of nodal arrhythmias. Rate control in atrial fibrillation

Answer 209

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

Answer 210

Verapamil, diltiazem.

Answer 211

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

Answer 212

Phosphorylated β-Arrestin turns off the signal. Leads to downregulation of gene expression and receptor internalization by endocytosis

Answer 213

Leads to resistance to leptin. Results in obesity.

Answer 214

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

Answer 215

Required for normal prostate development and prostate cancer. Malfunction leads to prostate tumor and female phenotype in males (loss of function mutation).

Answer 216

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

Answer 217

Autoantibody attack against nicotinic acetylcholine receptor.

Answer 218

Leads to chronic hypertension due to high catecholamine levels.

Answer 219

Malignancy leading to high catecholamine secretion. Activates α1 receptor.

Answer 220

Used to explore autonomic nervous system function.

Answer 221

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

Answer 222

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

Answer 223

Leads to glucose uptake, glycogen synthesis, and protein synthesis. Insulin is an anabolic hormone.

Answer 224

Aberrant serine and threonine phosphorylation of insulin receptor β-subunits. Issues with IRS molecules.

Answer 225

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.

Answer 226

Propanolol was the first β-adrenoreceptor blocker introduced in 1965

Answer 227

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.

Answer 228

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

Answer 229

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.

Answer 230

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)

Answer 231

Symptomatic control in anxiety and hyperthyroidism Acute aortic dissection Hypertrophic obstructive cardiomyopathy Marfan syndrome Prevention of variceal bleeding in portal hypertension

Answer 232

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

Answer 233

- 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

Answer 234

Patients with asthma Drug stimulant overdose (e.g., cocaine, amphetamines)

Answer 235

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

Answer 236

Atenolol Acebutolol (intrinsic sympathomimetic activity – partial agonist) Bisoprolol, Esmolol Metoprolol, Nebivolol (increases NO release for vasodilation)

Answer 237

Butaxamine

Answer 238

Acebutolol Mepindolol Pindolol

Answer 239

Atenolol Sotalol

Answer 240

Acebutolol Propranolol

Answer 241

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.

Answer 242

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.

Answer 243

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.

Answer 244

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

Answer 245

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.

Answer 246

pFOX inhibitors shift the heart’s energy substrate preference from fatty acids to glucose. This improves the efficiency of oxygen utilization.

Answer 247

Partial Fatty Acid Oxidation (pFOX) Inhibitors: Improve oxygen utilization efficiency. Myocardial Revascularization: Corrects obstruction via bypass or angioplasty.

Answer 248

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

Answer 249

Nitroglycerin is rapidly denitrated in the liver and smooth muscle. Sublingual Administration: Bypasses the liver's first-pass metabolism, making it very effective

Answer 250

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

Answer 251

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.

Answer 252

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.

Answer 253

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

Answer 254

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.

Answer 255

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

Answer 256

Blockage of Voltage-Gated L-Type Calcium Channels: Most important in cardiac and smooth muscle. Reduces intracellular calcium concentration and myocardial contractility.

Answer 257

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.

Answer 258

General Toxicities: Constipation Pretibial edema Nausea Flushing Dizziness Specific Toxicities: Verapamil: Heart failure, AV blockade, sinus node depression.

Answer 259

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.

Answer 260

Not Effective for Acute Attacks. Ineffective Against Vasospastic Angina.

Answer 261

Ranolazine Ivabradine

Answer 262

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.

Answer 263

Experimental drug that inhibits the funny current in the SA node. Decreases heart rate and cardiac work.

Answer 264

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.

Answer 265

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.

Answer 266

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.

Answer 267

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.

Answer 268

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.

Answer 269

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.

Answer 270

Carbamic Acid Esters (Carbamates): E.g., Neostigmine Phosphoric Acid Esters (Organophosphates): E.g., Parathion Alcohols: E.g., Edrophonium (only one with clinical significance)

Answer 271

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.

Answer 272

Edrophonium Neostigmine Physostigmine Pyridostigmine Echothiopate Parathion

Answer 273

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

Answer 274

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.

Answer 275

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

Answer 276

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

Answer 277

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

Answer 278

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

Answer 279

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.

Answer 280

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.

Answer 281

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.

Answer 282

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.

Answer 283

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.

Answer 284

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.

Answer 285

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

Answer 286

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.

Answer 287

Increased Contraction: Enhanced contraction of the detrusor muscle. Relaxation of Sphincters: Relaxation of the bladder trigone and sphincters, facilitating voiding.

Answer 288

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

Answer 289

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

Answer 290

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

Answer 291

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

Answer 292

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

Answer 293

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

Answer 294

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

Answer 295

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

Answer 296

To lower LDL levels and reduce atheroma plaque formation.

Answer 297

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

Answer 298

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

Answer 299

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

Answer 300

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

Answer 301

Lovastatin and Simvastatin.

Answer 302

Atorvastatin, fluvastatin, pravastatin, and rosuvastatin.

Answer 303

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.

Answer 304

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

Answer 305

Dramatically lower LDL cholesterol levels. Reduce mortality from ischemic heart disease and stroke. Rosuvastatin, atorvastatin, and simvastatin also reduce triglycerides and increase HDL.

Answer 306

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.

Answer 307

Statins have possible teratogenic effects.

Answer 308

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.

Answer 309

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.

Answer 310

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

Answer 311

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.

Answer 312

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

Answer 313

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

Answer 314

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

Answer 315

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.

Answer 316

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

Answer 317

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.

Answer 318

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

Answer 319

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.

Answer 320

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

Answer 321

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

Answer 322

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).

Answer 323

The first line of treatment is dietary modification.

Answer 324

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