Mechanism, clinical use, and toxicity of:

2. Antipsychotics (neuroleptics), low and high potency:

Basically the info about antipsychotics is in First Aid (p. 279).

Potency of drugs for the D2 R correlates w/ potency of drugs for treating psychosis.

High potency: perphenazine, trifluoperzine, flupentixol, haloperidol. Since they block DA R so well, they also give motor (extrapyramidal; see p 279) side effects. Block DA R in basal ganglia, striatuem, putamen. However, they do not give a lot of hypotension (adenergic R binding) or sedation (muscarinic R binding) because they bind the DA R preferentially.

3. Opiates (analgesics, antidiarrheal, antitussive) receptor types, agonists, mixed-agonist-antagonists.

Lippincotts Illustrated Review Pharm 2^nd Ed pp133-144, 222, 244, also Goodman Gilman, pp 521-545

Receptor types:

• there are 4 families of opioid receptor: m, k, s, and d, and each has a different specificity for drug(s) it binds.
• m-morphine
• k- dynorphin
• d-enkphalin
• The s receptor is less specific and is associated with the hallucinogenic properties some people experience with opioids.
• All opioid receptors are coupled to inhibitory G-proteins and inhibit adenylate cyclase.
• They may also be associated with ion channels to increase K+ efflux (hyperpolarization) or reduce Ca⁺⁺ influx, which would slow down neuronal firing, and reduce transmitter release.
• The m receptor is primarily related to analgesic properties, but the k receptors contribute to this.

Summary of receptor functions, agonists and antagonists by receptor:

m receptors mediate:	k receptors mediate:	s receptors mediate:
- supraspinal analgesia - pupil constriction - respiratory depression - euphoria/sedation - physical dependence - decreased GI motility	- spinal analgesia - sedation/dysphoria - pupil constriction	- dysphoria - hallucinations - psychotomimetic effects - pupil dilation
m agonists: - morphine - fentanyl - heroin - codeine - methadone	k agonists - morphine - fentanyl - heroin - codeine - pentazocine - meperidine* (note meperidine acts at all receptors, but specially likes K)	s agonists - morphine - fentanyl - heroin - codeine
m antagonists - pentazocine - naloxone - naltrexone	k antagonists - naloxone - naltrexone	s antagonists - naloxone - naltrexone

Receptor locations:

There are high densities of opioid receptors in the 5 areas of the CNS associated with processing information about pain.

1. There are also high densities of opioid receptors in areas of the periphery, especially peripheral sensory nerve fibers and terminals, immune cells and the GI tract

   Brainstem
2. Medial thalamus
3. spinal cord
4. hypothalamus
5. Limbic system

Note about mixed agonist/antagonists:

• These are drugs that stimulate one receptor and block another. (pentazocine and buprenorphine*)
• Effects of these drugs depends on previous exposure/use of opioids;
• in naïve patients mixed ag/antags act only as agonists and can be used to relieve pain.
• In opioid dependent patients, mixed ag/antags act as mostly blocking agents, produce withdrawl symptoms, mostly cause dysphoria rather than euphoria.

*Buprenorphine is classified as a partial agonist at the mu receptor, but behaves like morphine in naïve patients. But just to be fun, it can also antagonize morphine. This is way more than we need to know I think, but it is in Lippincott, so I include it here.

Summary of the main opioid agonists and antagonists and their associations with receptors:

• Morphine, Heroin, Codeine, and Fentanyl are all agonists at mu (m), kappa (k), and sigma (s) receptors.
• Methadone acts mostly at mu(m) receptors
• Meperidine acts at all receptors, but particularly at kappa (k)
• Pentazocine is a kappa (k) agonist and partial mu (m) antagonist. (mixed agonist-antagonist)
• Naloxone and naltrexone are both antagonists at mu (m), kappa (k), and sigma (s) receptors.

Please see continuation of this material in table format (Part B)

7. Laxatives

- stool softeners hydrate and soften stool by emulsifying feces, water, and fat

- docusate sodium, mineral oil

- bulk-forming laxatives are non-absorbable agents that increase stool bulk, retain water, and ease passage of feces

- psyllium

- osmotic laxatives are non-absorbable salts or carbs that dramatically increase water content of stool à can produce severe diarrhea if taken in large amounts

- magnesium salts, lactulose

- stimulant laxatives – promote accumulations of electrolytes and water in intestinal lumen and/or stimulate intestinal motility

- castor oil, Ex-Lax

- see table next page for more details.

Agent	Mechanism	CIs/SEs	DDIs	Other
Psyllium (OTC)	Absorbs liquid in GI tract à bulks up stool			Often used in IBS patients or short term constipation relief
Docusate sodium (Colace)	Surfactact that facilitates mixing of fat and water à soften stool
Magnesium citrate (Milk of magnesia)	Saline laxative à osmotically draws water into intestinal lumen à increased peristalsis and CCK release	Side effects: lyte imbalance, Mg accumulation in kidney, rectal skin irritation	Diuretics, digitalis, oral anticoagulants, tetracyclines, ciprofloxacin, sodium polystyrene sulfonate	Don’t give renal patients more than 50 mEq/day, be careful when giving to kids under 6
Lactulose	Acidifies stool and decreases diffusion of NH3 from colon	CI in patients on low galactose diet or diabetics	Other laxatives, neomycin (?)	Side effects: flatulence, belching, abdominal/intestinal cramps

Other laxatives:

- methyl cellulose (Citrucel)

- emollients

- lubricants

- mineral oil

- saline

8. Angiotensin II receptor blockers (e.g. Losartan)

9. Dermatologic agents (e.g. corticosteroids, retinoids, antifungal agents).

10. Other new pharmacologic agents (erythropoietin, RU486)

Losartan

Mechanism of Action

1. Highly selective AGII receptor blocker.

2. Produces VD and blocks aldosterone secretion

Clinical Use - Hypertension

Toxicity – fetotoxic, fewer adverse effects than ACE inhibitors

Dermatologic Agents (BRS Pharmacology, Lippincott’s Pharmacology)

Glucocorticoids

Mechanism of Action

Interact with intracellular receptors forming complexes that modulate the transcription rate of specific genes, leading to an increase or decrease in the levels of specific proteins

1. blood glucose by promoting gluconeogenesis

2. Stimulate protein catabolism (except in liver), leading to negative nitrogen balance

3. plasma fatty acids and ketone body formation via lipolysis and ¯ glc uptake into fat cells

4. resistance to stress

5. Immunologic effects. PMNs, ¯ lympho, mono, eos, baso

6. Anti-inflammatory action

7. ¯ plasma ACTH, possible adrenal atrophy

8. ¯ fibroblasts and collagen synthesis

9. Stimulates acid and pepsin secretion in stomach

10. Alters CNS responses and nm transmission

11. surfactant production in fetal lungs

Clinical Uses

1. Replacement tx for primary or secondary insufficiency (Addison’s disease) – usually need both glucocorticoid and mineralocorticoid

2. Inflammation and immunosuppression – RA, bursitis, SLE, asthma, nephritic syndrome, UC, ocular inflammation, hypersensitivity and allergic reactions, and organ and graft rejection

3. Sarcoidosis

4. Dermatologic disorders

5. Idiopathic nephrosis of children

6. Neuromuscular disorders – Bell’s Palsy

7. Shock

8. Adrenocortical hyperplasia – CAH disorders

9. Stimulation of surfactant production – acceleration of lung maturation in preterm infant

10. Neoplastic diseases – adult and childhood leukemias

11. Diagnosis of Cushing’s syndrome (dexamethasone suppression test)

Toxicity/Adverse Effects

1. Osteoporosis (¯ Ca)

2. Hyperglycemia

3. Hypertension, edema

4. infection risk, poor wound healing

5. Muscle weakness and tissue loss

6. appetite

7. Cushingoid features

8. Peptic ulcers

9. Euphoria, Psychoses

10. Potential mineralocorticoid effect - Na, hypokalemic, hypochloremic alkalosis

11. Adrenal suppression - Rapid withdrawal can be lethal – HPA imbalance

Mineralocorticoids

Clinical Uses – Replacement tx to maintain electrolyte and fluid balance in hypoadrenalism

Adverse effects - Na retention, hypokalemia, edema and hypertension

Retinoic Acid and Derivatives

Mechanisms of Action

1. Actions mediated via two main types of intracellular receptors: RAR and RXR

2. Each class has three distinct isoforms with unique biological properties

3. Retinoid receptors are members of the steroid-receptor family and act by modulating transcription of specific genes

4. Retinoids are morphogens, playing important roles during embryonic development, including the regulation of cellular proliferation and differentiation, and the modulation of immune function and cytokine function

Tretinoin (Retin A, Renova)

1. Topical preparation used for treatment of acne and photoaged skin
2. Adverse effects include tenderness, erythema, and burning. Also increased risk of sunburn

Isotretinoin (Accutane)

1. Oral agent used for treatment of severe acne

2. Adverse effects include arthralgia and myalgia. Retinoids tend to inhibit lipoprotein lipase ® serum triglycerides

3. Isotretinoin is teratogenic!

Etretinate (Tegison)

1. Oral agent approved for treatment of psoriasis; it is most effective with pustular and erythrodermic forms of the disease

2. Adverse effects include hair loss and liver enzyme abnormalities

3. Etretinate is teratogenic

Antifungal Agents (for more details, look in Lippincott and BRS Pharmacology)

Amphotericin B (Fungizone) (given IV)

Mechanism of Action

1. It’s an antibiotic that binds to ergosterol, a major component of fungal cell membranes, alters membrane stability and allows leakage of cellular contents

2. Binds to mammalian cholesterol with much less affinity, explaining some of its adverse effects

Clinical Uses

1. Treats systemic and/or severe fungal infections, including those caused by Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, Aspergillus species, and Sporothrix schenckii, especially in immunocompromised patients

2. Liposome-encapsulated amphotericin B is under investigation and is less toxic

3. Resistance occurs from decreased membrane ergosterol content or ¯ binding affinity

4. Combination tx with flucytosine is advantangeous, esp. with Candida, crypotococcal meningitis, and systemic candidiasis

Adverse Effects – significant – low TI

1. Chills and fever in 50%

2. Impaired renal function in 80% of patients

3. Anaphylaxis, thrombocytopenia, severe pain, and seizures

4. Hypotension

5. Anemia

6. Neurologic effects - seizures

Ketoconazole (azole family)

Mechanism of Action

1. Interacts with a cytochrome p450 enzyme (C-14 a-demethylase) to block demethylation of lanosterol to ergosterol – disrupts membrane function and increases permeability

2. Acts in additive manner with flucytosine against Candida, but antagonizes amphotericin B’s antifungal activity

Clinical Uses

1. Broad spectrum, same as amphotericin B, but most useful in tx of histoplasmosis

2. Also effective against nonmeningeal coccidiomycosis and blastomycosis

3. Candida and others resistant to griseofulvin are also susceptible

Adverse Effects

1. GI most common

2. Endocrine effects – blocks androgen and adrenal steroid synthesis – gynecomastia, decreased libido, impotence, and menstrual irregularities

3. Hepatic dysfunction – low incidence, but very serious when happens

4. Contraindicated with amphotericin B

Fluconazole

Mechanism of Action – same as Ketoconazole, but…

1. Lacks endocrine side effects of ketoconazole

2. Has best penetrability into the CSF

Clinical Uses

1. Drug of choice for Cryptococcus neoformans, candidemia and for coccidioidomycosis

2. Also useful in tx of blastomycosis, candidiasis, and histoplasmosis – good for chronic use

Adverse Effects – Fewer than ketoconazole

1. N/V, rashes

2. Potent teratogen

3. Rare hepatitis

Itraconazole

Mechanism of Action

1. Also lacks endocrine SE of ketoconazole

2. Same mode of action

3. Does not penetrate CSF

Clinical Uses

1. Tx of choice for blastomycosis

2. Effective in AIDS-associated histoplasmosis, also aspergillosis, candidemia, coccidioidomycosis and cryptococcosis

Adverse Effects

1. NV, rash

2. Hypokalemia

3. Hypertension, edema

4. Headache

Miconazole, clotrimazole and econazole

Mechanism of Action – same as ketoconazole

Clinical Uses – topical only due to systemic toxicity

Adverse Effects – none if used topically

Flucytosine (5-FC)

Mechanism of Action

1. Enters fungal cell via cytosine-specific permease (not in mammalians)

2. 5-FC then converted to 5-FdUMP which inhibits thymidylate synthetase, thus depriving the organism of thymidylic acid, an essential DNA component

3. Also metabolized into 5-FUTP and disrupts nucleic acid and protein synthesis

4. Amphotericin B allows more flucytosine to penetrate the cell – synergistic

5. Synthetic pyrimidine antimetabolite used only in combo with ampho due to quick buildup of resistance when used alone

Clinical Uses

1. Fungistatic – chromoblastomycosis alone (no resistance buildup)

2. In combination with ampho for candidiasis and cryptococcosis

Adverse Effects

1. Hematologic toxicity – reversible

2. Hepatic dysfunction – reversible

3. GI disturbances

Griseofulvin

Mechanism of Action

1. Inhibits mitosis (disrupts the mitotic spindle, microtubules)

2. Accumulates in affected tissues making them unsuitable for growth of fungi

3. Tx must be continued for weeks or months, until new tissue replaces infected tissue

Clinical Uses

1. Fungistatic only against dermatophytes – trichophyton, microsporum, and epidermophyton

2. Used in tx of severe tinea infections that do not respond to other antifungal agents

Adverse Effects

1. Not considered toxic, but allergic reaction possible and headache and nausea

2. May cause hepatotoxicity

3. Contraindicated in patients with acute intermittent porphyria

4. Potentiates intoxicating effects of alcohol

5. Teratogenic

Nystatin

Mechanism of Action - Polyene antibiotic – action similar to Amphotericin B

Clinical Uses – restricted to topical tx of Candida infections due to systemic toxicity

Adverse Effects – rare when used topically, some N/V

New Drugs (per Lippincott, but we’ve seen many of these already)

Erythropoietin wasn’t listed as a new drug, nor was RU486, but I’ll give more info on them anyway since First Aid says to

Erythropoeitin

MOA – Glycoprotein usually made by kidney that regulates red cell proliferation and differentiation in bone marrow

Clinical – Tx of anemia caused by end-stage renal disease (give IV), HIV-infected patients (give SQ), and some cancer patients (give SQ) – need to supplement with iron to get adequate response

Adverse - BP may occur, iron deficiency

RU486 – Mifepristone

MOA – progestin antagonist with partial agonist activity, also potent antiglucocorticoid

Clinical – termination of pregnancy in 85%, adding PgE1 or misoprostol will effectively terminate gestation, can also be used as a contraceptive once a month

Adverse – significant uterine bleeding and possibility of incompletely abortion

Tx of Parkinson’s Disease

Pramipexole and ropinirole – first line therapy

MOA – dopamine receptor agonist

Clinical – may delay need for levodopa

Adverse – no peripheral vasospasm, nausea, hallucinations, insomnia, dizziness, constipation, orthostatic hypotension, greatly dependent on renal function

Tolcapone

MOA – selectively and reversibly inhibits peripheral and central COMT

Clinical – use as an adjunct to levodopa/carbidopa

Adverse – diarrhea, increased levodopa SE

Tx of Epilepsy

Tiagabine

MOA – blocks GABA uptake into presynaptic neurons

Clinical – decreases number of seizures in refractory patients with focal epileptic disorders

Adverse – Tiredness, dizziness and GI upset

Topiramate – chemical relative to fructose

MOA

1. Blocks Na channels

2. GABA activity at GABA receptors

3. Blockade of some glutamate receptors

Clinical – when added to conventional tx in refractory patients, causes 50% or greater reduction in number of partial seizures in approximately 50% of patients

Adverse – CNS and GI disturbances, renal stones, teratogenic

Vigabatrin

MOA – reversibly inhibits GABA transaminase – decreases levels of GABA in brain

Clinical – reduces partial seizures in refractory patients

Adverse – drowsiness, dizziness, weight gain.

There are too many drugs listed to continue to give all these details, so I’m going to list just the drugs and its main purpose, and you can look them up in Lippincott’s Pharmacology if you want more details – again, we’ve actually learned about most of these anyway.

Drugs affecting blood

Abciximab, eptifibatide and tirofiban – platelet aggregation inhibitors

Lepirudin – thrombin inhibitor

Antihyperlipidemic drugs

Atorvastatin – HMG-CoA reductase inhibitors

Drugs affecting the respiratory system

Zileuton, Zafirlukast and montelukast - anti-leukotriene drugs – asthma

Insulin and Oral Hypoglycemic drugs

Lispro insulin

Sulfonylureas – Glimepiride

Repaglinide – similar to sulfonylureas

Troglitazone and Rosiglitazone – reduces increased hepatic output of glucose

Steroid Hormones

Raloxifene – SERM similar to tamoxifen

Quinolones and Urinary Tract Antiseptics

Trovafloxacin – longer half life allowing for once-a-day dosing, serious liver injury, no longer than 14 days use

Antiviral Drugs

Penciclovir – Herpes

Cidofovir – CMV retinitis in patients with AIDS

Treatment of AIDS

HIV protease inhibitors – Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir

Adverse Effects discovered – Inhibition of cyt p450-dependent oxidations and lipodystrophy and hyperglycemia

Non-nucleoside reverse transcriptase inhibitors – Nevirapine, Delavirdine, Efavirenz

Other reverse transcriptase inhibitors – Abacavir, Adefovir

Anticancer Drugs

Antimetabolites

Capecitabine – metastatic breast cancer, colorectal cancer

Gemcitabine – pancreatic cancer

Other chemotherapeutic agents

Topotecan – Metastic ovarian cancer

Monoclonal antibodies

Trastuzumab – metastatic breast cancer

Rituximab – B cell non-Hodgkin’s lymphomas

NSAIDS

Celecoxib – COX-2 only

Slow-acting Anti-Inflammatory Agents – use for rheumatic disorders

Leflunomide – cell arrest of autoimmune lymphocytes

Etanercept (soluble TNF-receptor), Infliximab (IgG monoclonal Ab) – both decrease activity of TNF

Antihistamines

Fexofenadine – allergic rhinitis

Immunosuppressants

Non-selective immunosuppressants

Mycophenolate mofetil – beginning to replace Azathioprine, blocks GMP

Antibodies

Antilymphocyte and antithymocyte globulin

Muromonab-CD3

Obesity

Anorexic agents

Phentermine and sibutramine – interfere with reuptake of serotonin and NE

Lipase inhibitors – Orlistat

Osteoporosis

Bisphosphonates – etidronate, risedronate, alendronate, pamidronate

Erectile Dysfunction

Sildenafil – first oral drug – increases blood flow