Pharm T16-21 Flashcards
16.1 What is biotransformation in drug metabolism?
Biotransformation refers to the chemical modification of drugs in the body, often leading to a loss of biological activity and increased hydrophilicity (water solubility), which promotes drug excretion via the renal route.
What are the four potential outcomes of drug biotransformation?
Active drug to inactive metabolite
Active drug to active metabolite
Active drug to toxic metabolite
Inactive drug to active metabolite
What are Phase I reactions in drug metabolism?
Phase I reactions include oxidative, reductive, and hydrolytic reactions.
They may involve cytochrome P450 enzymes (e.g., hydroxylation, dealkylation, oxidation) or be independent of P450 (e.g., amine oxidation, ethanol dehydrogenation).
What are examples of cytochrome P450-dependent Phase I oxidative reactions?
Hydroxylation: Amphetamines, warfarin, barbiturates
N-dealkylation: Caffeine, morphine
O-dealkylation: Codeine
N-oxidation: Nicotine
S-oxidation: Chlorpromazine, cimetidine
Deamination: Amphetamine, diazepam
What are examples of oxidative Phase I reactions independent of cytochrome P450?
Amine oxidation: Epinephrine
Dehydrogenation: Ethanol, chloral hydrates
What are examples of reductive and hydrolytic Phase I reactions?
Reductions: Chloramphenicol, clonazepam, dantrolene
Hydrolyses (esters): Aspirin, procaine, succinylcholine
Hydrolyses (amides): Indomethacin, lidocaine, procainamide
What are Phase II reactions in drug metabolism?
Phase II reactions involve conjugation (synthetic) reactions, where subgroups like –OH, –NH2, or –SH are added to make drugs more water-soluble and less lipid-soluble, aiding in excretion.
What are some examples of Phase II conjugation reactions?
Glucuronidation: Acetaminophen, diazepam, digoxin, morphine
Acetylation: Isoniazid, sulfonamides
Glutathione conjugation: Ethacrynic acid
Glycine conjugation: Niacin, salicylic acid
Sulfation: Methyldopa, acetaminophen
Methylation: Dopamine, norepinephrine (NE), epinephrine (E), histamine
What is the role of cytochrome P450 in drug metabolism?
Cytochrome P450 enzymes are found in the smooth endoplasmic reticulum of the liver and are not highly selective, allowing them to metabolize thousands of different drugs.
What are the main cytochrome P450 enzyme subtypes involved in drug metabolism?
1A2
2C9
2C19
2E1
3A4
2D6 (3A4 and 2D6 account for approximately 75% of active cytochromes)
16.2 What type of neurotransmitter is ATP, and where is it located?
ATP is a non-peptide neurotransmitter found in postganglionic sympathetic neurons (e.g., in blood vessels and vas deferens).
What is the function of ATP in NANC transmission?
ATP causes fast depolarization and contraction, including vasoconstriction.
GABA is a non-peptide neurotransmitter. Where is it located, and what is its function?
GABA is located in enteric nervous systems (ENS) and its function is peristalsis.
Where is serotonin (5-HT) found in the nervous system, and what is its role?
Serotonin (5-HT) is found in the ENS and plays a role in peristalsis.
What is the role of dopamine in NANC transmission, and where is it located?
Dopamine is located in some sympathetic nervous systems (SNS), such as the kidney, and its function is vasodilation.
Nitric oxide (NO) is a non-peptide neurotransmitter. What are its locations and functions?
NO is found in pelvic nerves and gastric nerves. It functions in erection and gastric emptying.
What is the function of neuropeptide Y (NPY), and where is it located?
NPY is located in postganglionic sympathetic neurons (e.g., blood vessels) and enhances the vasoconstrictor action of noradrenaline, also acting as a noradrenaline release inhibitor.
What is the role of vasoactive intestinal peptide (VIP) in NANC transmission, and where is it found?
VIP is found in parasympathetic nerves to salivary glands, NANC innervation to the smooth muscle of airways, and parasympathetic ganglia in sphincters, gallbladder, and small intestine.
Its functions include vasodilation, being an acetylcholine cotransmitter, bronchodilation, and relaxation of intestinal smooth muscle and sphincters.
Where is gonadotropin-releasing hormone (GnRH) located, and what is its function?
GnRH is located in sympathetic ganglia and functions in slow depolarization and as an acetylcholine cotransmitter.
Substance P is a peptide neurotransmitter. Where is it located, and what are its functions?
Substance P is located in sympathetic ganglia and ENS, and its function is slow depolarization and acetylcholine cotransmission.
What is the function of calcitonin gene-related peptide (CGRP), and where is it found?
CGRP is found in non-myelinated sensory neurons, and its functions include vasodilation, increased vascular permeability, and neurogenic inflammation.
16.3 What are the two major groups of drugs used in clotting and bleeding disorders?
Anticlotting drugs (to decrease clotting or dissolve clots)
Drugs that facilitate clotting (to increase clotting in patients with clotting deficiencies)
What are the types of anticlotting drugs?
Anticoagulants
Thrombolytics
Antiplatelet drugs
Name examples of anticoagulant drugs.
Heparins
Direct thrombin inhibitors
Indirect thrombin inhibitors
Warfarin
What are examples of thrombolytic drugs?
t-PA derivatives
Streptokinase
Which drugs are categorized as antiplatelet drugs?
Aspirin
GP IIb/IIIa inhibitors
ADP inhibitors (e.g., Clopidogrel)
PDE/adenosine uptake inhibitors
What drugs are used to facilitate clotting in patients with clotting deficiencies?
Replacement factors
Vitamin K
Antiplasmin drugs
What is the main function of anticoagulants?
Anticoagulants inhibit the formation of fibrin clots.
What are the three major categories of anticoagulants?
Heparin and related products (used parenterally)
- Direct thrombin and factor X inhibitors (used parenterally or orally)
- Coumarin derivative (Warfarin, used orally)
How is Heparin administered, and what is its source?
Heparin is administered IV or subcutaneously and is a large sulfated polysaccharide polymer obtained from animals.
What is LMWH, and how is it different from unfractionated heparin?
LMWH (low molecular weight heparin), such as Enoxaparin, is smaller (2000-6000 Daltons), has better bioavailability, and is longer-lasting.
LMWH is more selective, primarily binding to ATIII.
How does unfractionated heparin work, and how is it monitored?
Unfractionated heparin binds to ATIII and thrombin, forming a complex that inactivates thrombin and factor Xa.
Its effects are monitored using activated partial thromboplastin time (aPTT).
What are the uses of heparin?
Immediate anticoagulation (e.g., treatment of DVT, pulmonary embolism, AMI)
Combined with thrombolytics for revascularization
Combined with GP IIb/IIIa inhibitors during angioplasty and coronary stent placement
Safe during pregnancy as it does not cross the BPB
What are the potential toxicities associated with unfractionated heparin?
Increased bleeding and risk of hemorrhagic stroke
Moderate transient thrombocytopenia
Severe thrombocytopenia and thrombosis in some cases (HIT: Heparin-Induced Thrombocytopenia)
Long-term use can lead to osteoporosis
What is Heparin-Induced Thrombocytopenia (HIT)?
HIT occurs when antibodies bind to a complex of heparin and platelet factor 4, causing severe thrombocytopenia and thrombosis.
What are the Direct Thrombin Inhibitors based on?
They are based on proteins made by Hirudo medicinalis (medicinal leech).
Name some direct thrombin inhibitors and their mode of administration.
Lepirudin, Desirudin, Bivalirudin, Argatroban (all given parenterally)
Dabigatran (orally active)
What is a clinical use of Bivalirudin?
Bivalirudin is used in combination with aspirin during percutaneous coronary angioplasty.
Name two direct oral Factor Xa inhibitors and their characteristics.
Rivaroxaban and Apixaban
They have a rapid onset of action and shorter half-lives than warfarin.
What is the mechanism of action of Warfarin
Warfarin inhibits vitamin K epoxide reductase (VKOR), interfering with the post-translational modification of clotting factors in the liver, which depends on reduced vitamin K.
How can Warfarin’s effects be reversed?
Slowly with Vitamin K (requires the synthesis of new clotting factors).
Rapid reversal can be done by injecting fresh or frozen plasma containing normal clotting factors.
How is Warfarin monitored?
Warfarin is monitored using the prothrombin test (PT) and INR values.
What are the clinical uses of Warfarin?
Chronic anticoagulation in clinical situations like DVT, pulmonary embolism, and atrial fibrillation. Warfarin is never used during pregnancy.
What is a major caution with Warfarin use?
It has a narrow therapeutic window and bleeding tendencies are common, so it needs to be tightly monitored.
What are Thrombolytic Agents, and how do they work?
Thrombolytic agents include endogenous tissue plasminogen activators (e.g., alteplase, tenecteplase) and streptokinase (synthesized by streptococci).
They work by turning plasminogen into plasmin, which degrades clots.
What are the uses of thrombolytic agents in medical emergencies?
Alternative drug for percutaneous coronary angioplasty
Emergency treatment of coronary artery thrombosis
Treatment of acute pulmonary embolism
What is the major contraindication for thrombolytic agents?
Thrombolytic agents are contraindicated in patients with cerebral hemorrhage.
What is a significant limitation of streptokinase use?
Streptokinase can only be used once during a patient’s lifetime because it can evoke the production of antibodies, causing loss of effectiveness or severe allergic reactions.
Name some antiplatelet drugs.
Aspirin
NSAIDs
GP IIb/IIIa receptor inhibitors (abciximab, tirofiban, eptifibatide)
ADP receptor antagonists (clopidogrel, ticlopidine)
Phosphodiesterase 3 inhibitors (dipyridamole, cilostazol)
17.1 What are the determinants of biotransformation rate?
Biotransformation rates vary due to factors such as genetics, drug-induced differences, smoking, drug compositions, food intake (e.g., grapefruit juice and warfarin), disease, and sometimes gender.
How do genetic factors influence drug metabolism?
Polymorphisms in cytochrome enzyme genes affect metabolism.
Abnormal hydrolysis of esters like succinylcholine can lead to prolonged drug effects (paralysis for hours instead of minutes in rare cases).
Differences in acetylation rates can affect responses to drugs like isoniazid and hydralazine, with 50% of White and African American individuals being slow acetylators.
Which populations are typically faster acetylators?
Asian and Eskimo populations are usually faster acetylators compared to White and African American individuals.
What are enzyme inducers, and which drugs commonly induce them?
Enzyme induction leads to increased synthesis of drug-oxidizing enzymes. Common inducers include carbamazepine, phenobarbital, phenytoin, and rifampin.
What is enzyme inhibition, and which drugs are known to inhibit drug metabolism?
Enzyme inhibition slows drug metabolism. Notable inhibitors include amiodarone, cimetidine, grapefruit juice (furanocoumarins), azole antifungals, and the HIV protease inhibitor ritonavir.
What are suicide inhibitors?
Suicide inhibitors are drugs metabolized to products that irreversibly inhibit metabolizing enzymes, such as spironolactone, allopurinol, and fluroxene.
What is an important modulator of intestinal drug transport?
P-glycoprotein (P-gp) is an important modulator of intestinal drug transport, usually functioning to expel drugs from the intestinal mucosa into the lumen, contributing to presystemic elimination
Where else, besides the intestines, is P-glycoprotein found?
P-glycoprotein is also found in the blood-brain barrier (BBB) and in drug-resistant cancer cells.
What happens when drugs inhibit P-glycoprotein?
Drugs that inhibit P-glycoprotein mimic drug metabolism inhibitors by increasing drug bioavailability, potentially resulting in toxic plasma concentrations of normally non-toxic dosages.
Which drugs inhibit P-glycoprotein?
Verapamil and furanocoumarins (grapefruit juice) inhibit P-glycoprotein.
What are examples of drugs expelled by P-glycoprotein?
Important drugs expelled by P-glycoprotein include digoxin, cyclosporine, and saquinavir.
17.2 What regulates the activity of ligand-gated ion channels?
The activity of ligand-gated ion channels is regulated by the binding of a ligand to the channel. The response is rapid (a few milliseconds).
Give an example of a ligand-gated ion channel and its function.
An example is the nicotinic receptor, which, when stimulated by acetylcholine (ACh), results in sodium influx and generation of an action potential. Another example is the GABA receptor, enhanced by benzodiazepines, resulting in increased chloride influx and hyperpolarization.
What are G protein-coupled receptors and how do they work?
G protein-coupled receptors are single peptides with seven membrane-spanning regions, linked to a G protein.
When activated by a ligand, the G protein dissociates, leading to changes in second messenger concentrations. Stimulation lasts from several seconds to minutes
What is an enzyme-linked receptor, and what is its function?
An enzyme-linked receptor binds to a ligand on its extracellular domain, activating or inhibiting cytosolic enzyme activity.
The response duration is minutes to hours, commonly seen with receptors like EGF and insulin.
What is the role of intracellular receptors?
Intracellular receptors are lipid-soluble ligands that, once activated, migrate to the nucleus and bind to specific DNA sequences, regulating gene expression.
Cellular responses are seen after 30 minutes or more and can last hours to days.
Define a substrate in pharmacology.
A substrate is a substance acted upon by an enzyme. In pharmacological terms, it can be understood as an agonist, a drug that activates its receptor upon binding.
What is a pharmacologic antagonist?
A pharmacologic antagonist is a drug that binds to a receptor without activating it, preventing the activation of the receptor by an agonist.
What is the difference between a reversible and irreversible antagonist?
A reversible antagonist can be overcome by increasing the agonist concentration, while an irreversible antagonist cannot be overcome by increasing agonist concentration.
What is a chemical antagonist?
A chemical antagonist is a drug that counters the effects of another by binding to the agonist drug itself, not the receptor.
What is a physiologic antagonist?
A physiologic antagonist is a drug that counters the effects of another by binding to a different receptor and causing opposing effects.
What is a partial agonist?
A partial agonist is a drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist. Sometimes, it can act as an antagonist.
17.3 What are antacids and how do they work?
Antacids are weak bases that neutralize stomach acid by reacting with protons in the gut lumen.
They may also stimulate gastric mucosa functions. Regular high doses reduce the recurrence of peptic ulcers.
What are the common antacids used and their effects?
Magnesium hydroxide: Strong laxative action
Aluminum hydroxide: Strong constipation action
Calcium carbonate & sodium bicarbonate: Weak bases that are significantly absorbed from the gut, leading to systemic effects.
What are H2 receptor antagonists and what do they treat?
H2 receptor antagonists, like cimetidine, ranitidine, famotidine, and nizatidine, inhibit stomach acid production.
They treat GERD, peptic ulcer disease, non-ulcer dyspepsia, and prevent stress-related gastritis in seriously ill patients.
Why are H2 receptor antagonists being replaced?
H2 receptor antagonists are widely used but are being replaced by more effective and equally safe proton pump inhibitors (PPIs).
What are proton pump inhibitors (PPIs), and how do they work?
PPIs, such as omeprazole, esomeprazole, lansoprazole, and rabeprazole, are lipophilic weak bases that diffuse into parietal cell canaliculi and become protonated, concentrating more than 1000-fold.
They irreversibly inactivate the parietal cell H+/K+ ATPase, the primary transporter responsible for producing stomach acid.
What are the formulations and pharmacokinetics of PPIs?
PPI oral formulations are enteric-coated to prevent acid inactivation in the stomach.
After absorption, they are rapidly metabolized in the liver to become active.
They have a half-life of 1-2 hours, but the duration of action lasts around 24 hours. Full effectiveness takes about 3-4 days.
What conditions are treated with proton pump inhibitors?
PPIs are used to treat GERD, peptic ulcer disease, non-ulcer dyspepsia, stress-related gastritis prevention in seriously ill patients, and Zollinger-Ellison syndrome.
What are the adverse effects of proton pump inhibitors (PPIs)?
Adverse effects include diarrhea, abdominal pain, headache, hypergastrinemia (with chronic use), decreased bioavailability of vitamin B12 and drugs requiring stomach acidity (e.g., digoxin, ketoconazole), and a slight increase in the risk of respiratory and enteric infections.
What is sucralfate, and how does it work?
Sucralfate (aluminum sucrose sulfate) is a poorly soluble molecule that polymerizes in the acidic stomach.
It binds to injured tissue, forming a protective coating over ulcer beds, accelerating healing, and reducing ulcer recurrence. It must be taken 4 times daily and has very low systemic effects.
What is misoprostol, and what are its uses?
Misoprostol is a PGE1 analog that increases mucosal protection and inhibits acid secretion.
It is effective in reducing ulcer risk in chronic NSAID users but requires multiple daily doses and can cause diarrhea and GI irritation.
What are the actions and effects of colloidal bismuth?
Colloidal bismuth coats ulcers, stimulates mucosal protective mechanisms, has direct antimicrobial effects, sequesters enterotoxins, and reduces stool frequency and liquidity in infectious diarrhea.
Bismuth subsalicylate causes black stools.
What antibiotics are used to treat Helicobacter pylori infection?
Antibiotics used to treat Helicobacter pylori infection include clarithromycin, amoxicillin, and sometimes metronidazole.
- What is drug excretion in pharmacology?
Drug excretion (elimination) refers to the process by which a drug is removed from the body, either in its unaltered form (free drugs) or as metabolites (after biotransformation).
The primary organ for excretion is the kidney, although the liver, skin, lungs, glands, and other organs also play a role.
What are the common pathways for drug elimination?
Common pathways for drug elimination include:
Urine
Tears
Saliva
Sweat
Respiration
Mother’s milk
Feces
Bile
How are most drugs eliminated by the kidneys?
Most drugs are eliminated in urine, either in their chemically unaltered form or as metabolites, because the glomeruli filter molecules smaller than 5000 daltons.
Drugs may undergo:
Glomerular filtration
Active secretion in the proximal tubules (energy-consuming, limited capacity)
Passive reabsorption in the distal tubules (dependent on urinary pH)
What is ion trapping, and how is it used in poisoning treatment?
Ion trapping refers to a mechanism where weak acids or weak bases are trapped in a form that cannot be easily reabsorbed.
For weak acids, excretion is enhanced when the tubular fluid is alkaline, and for weak bases, excretion is enhanced when the fluid is acidic.
This principle is used in poisoning treatment with forced diuresis to eliminate toxic substances.
What role does the enterohepatic circulation play in drug excretion?
Drugs absorbed from the gut enter the portal circulation, are sent to the liver, where they are biotransformed into metabolites.
These metabolites can be conjugated with glucuronic or sulfuric acid and passed into the bile, eventually becoming part of the enterohepatic circulation.
How does the conjugation status of drugs affect their excretion?
Drugs can be eliminated through feces or urine based on their conjugation status:
Hydrophilic conjugates are more likely to be excreted via urine.
Lipophilic substances may be excreted via feces.
Which drugs are excreted via respiration?
Respiration can excrete certain substances, such as alcohol and anesthetic gases, to a limited extent.
Why is drug elimination via mother’s milk important?
Drug elimination via mother’s milk is significant because many drugs excreted this way can be harmful to newborns, whose organs (especially liver and kidneys) are not yet fully developed.
18.2 What are the effects of α2-selective (Gi-coupled) sympathomimetics like clonidine?
α2-selective sympathomimetics, such as clonidine, cause:
Inhibition of neurotransmitter release at adrenergic and cholinergic nerve terminals.
Platelet aggregation stimulation.
Vascular smooth muscle contraction.
Inhibition of lipolysis in adipocytes.
Inhibition of insulin release from pancreatic β-cells.
What is the concept of a false transmitter?
A false transmitter is a substance that is stored in presynaptic vesicles and released into the synaptic cleft but lacks the full biological effect of the true neurotransmitter.
Examples:
- Octopamine – mimics norepinephrine but has weaker effects.
- 5-Methoxytryptamine (5-MeOHT) – mimics serotonin with reduced efficacy.
How does octopamine function as a false transmitter?
Octopamine is stored in place of norepinephrine in vesicles and released upon stimulation but does not produce the same strong adrenergic effects as norepinephrine, leading to diminished physiological responses.
How does 5-Methoxytryptamine (5-MeOHT) act as a false transmitter?
5-MeOHT mimics serotonin by occupying serotonin receptors, but it lacks the full efficacy of true serotonin, resulting in a reduced or altered effect on synaptic signaling.
18.3 What are the mechanisms of action for laxatives?
Laxatives increase the probability of bowel movement by:
Irritant or stimulating action on the bowel wall (e.g., Aloe, Senna, Cascara, Castor oil, Bisacodyl)
Bulk-forming action on stool evoking reflex contractions of the bowels (e.g., Psyllium, Methylcellulose, Polycarbophil)
Softening action on hard/impacted stools (e.g., Docusate, Glycerin, Mineral oil)
Lubricating action easing passage of stool through the rectum.
What are examples of osmotic laxatives?
Osmotic laxatives include Magnesium oxide, Sorbitol, Lactulose, Magnesium citrate, Sodium phosphate, and Polyethylene glycol
What drug is a chloride channel activator used as a laxative?
Lubiprostone is a chloride channel activator used as a laxative.
What drugs are used for pain relief in bowel movements?
Methylnaltrexone and Alvimopan are used for pain relief in bowel movements.
What are the most effective types of antidiarrheal agents?
The most effective antidiarrheal agents are opioids and their derivatives, specifically Diphenoxylate and Loperamide.
How is Diphenoxylate formulated to reduce the likelihood of abuse?
Diphenoxylate is formulated with anti-muscarinic alkaloids, such as Atropine, to reduce the likelihood of abuse.
What is Kaolin, and how is it used as an antidiarrheal?
Kaolin is a naturally occurring hydrated magnesium aluminum silicate combined with pectin (derived from apples) to absorb bacterial toxins and fluid, reducing the liquidity of stools.
What are aminosalicylates, and how are they used in IBD treatment?
Aminosalicylates, such as 5-aminosalicylic acid (5-ASA) or Mesalamine, are used as topical therapy for IBD, involving inhibition of prostaglandins, inflammatory leukotrienes, and cytokines.
What are the types of drugs used in the treatment of Crohn’s disease and ulcerative colitis?
Antibiotics
Glucocorticoids
Immunosuppressive antimetabolites (Azathioprine, 6-Mercaptopurine, Methotrexate)
Anti-Tumor Necrosis Factor (TNF) drugs (e.g., Infliximab)
Humanized monoclonal antibody (e.g., Natalizumab)
What is Natalizumab, and what is it used for?
Natalizumab is a humanized monoclonal antibody that blocks integrins on circulating leukocytes.
It is used for severe, refractory Crohn’s disease and has a possible association with multifocal leukoencephalopathy
What are the mechanisms by which anti-obesity drugs work?
Anti-obesity drugs work by:
Altering appetite
Reducing the absorption of calories
What is the main FDA-approved drug for long-term treatment of obesity in the USA, and how does it work?
Orlistat (Xenical) is the main FDA-approved drug for long-term obesity treatment. It reduces intestinal fat absorption by inhibiting pancreatic lipase.
What are the side effects of Orlistat (Xenical)?
Side effects of Orlistat include steatorrhea and, in rare cases, severe liver damage.
What is Rimonabant, and why is it not widely used?
Rimonabant is a drug used in Europe that blocks the endocannabinoid system to reduce cravings for food (“the munchies”).
It is not approved in the USA or Canada and is not widely used due to concerns over side effects.
21.1 Clinical phase of drug development
Summary of clinical trial phase
