Mechanism, clinical use, and toxicity of: Motion sickness drugs

Drug	Mechanism	Clinical Use	Toxicity
Scopolamine P 150, Goodman Gilman P 45-48 Lippincotts Illustrated Review Pharm 2^nd Ed.	Scopolamine is in the same family of antimuscarinic drugs as atropine and the belladonna alkaloids. Scopolamine has a few extra effects though, it has greater action on the CNS than atropine does, and it also blocks short term memory. Scopolamine acts to selectively block the muscarinic synapses of the parasympathetic nerves. Generally antimuscarinics act to: - dilate pupils (mydriasis- don’t use with glaucoma) - reduce activity of GI tract - reduce hypermotility of bladder - dose dependent effects on cardiovascular system ranging from slight bradycardia at low doses, to tachycardia at medium doses, to coma at high doses - decrease secretions; reduce salivation, tearing and sweating	Biggest use is to prevent motion sickness, and must be taken BEFORE symptoms start. -also used in obstetrics along with morphine to produce amnesia with sedation	Dose dependent; high doses can cause dry mouth, blurry vision, tachycardia, constipation. Effects on the CNS include restlessness, confusion, hallucination, delirium, which may progress to depression, and collapse of the CV and respiratory systems and death. Don’t use with glaucoma patients.
H1 Antagonists P 586, Goodman Gilman	H1 antagonist antihistamines have actions at the following sites: Smooth muscle-antagonism of the constrictor action of histamine on respiratory smooth muscle Capillaries- inhibition of histamine stimulated capillary permeability CNS- certain H1 antagonists have profound sedative effects, however antihistamines can also cause exitability, nervousness and insomnia. CNS excitation is a sign of H1 antagonist toxicity, especially in infants. Anticholinergic- inhibition of responses to ACH that are mediated by muscarinic receptors (atropine like effect) The anticholinergic properties of most H1 antagonists are probably responsible for the anti-nausea (anti motion sickness) effect. (note that second generation H1 antagonists do not tend to have anticholinergic effects)	Dimenhydrinate- is a combination of diphendydramine and 8-cholortheophylline (Dramamine) Piperazines, meclizine and clyclizine (meclizine is Antivert) Promethazine-most potent anti-muscarinic, and best motion sickness drug of this class, but has pronounced sedative effects, which may not be desired. These H1 antagonists are useful for milder motion sickness and have fewer side effects than Scopolamine. Use: these should be administered 1 hour before anticipated motion, dosing after onset of nausea and vomiting is not helpful.	The greatest danger with acute poisoning with H1 antagonists is due to the effects on the CNS. Hallucinations, excitement, ataxia, incoordination, athetosis and convulsions progressing to coma and death may occur. Fixed dilated pupils, flushed face, sinus tachycardia, urinary retention, dry mouth and fever are also signs of toxicity, and make signs of H1 antagonist poisoning remarkably similar to those of atropine poisoning.

Opiates

Class	Drug	Mechanism	Clinical Use	Toxicity (side effects)
Analgesic	Morphine- prototype for m receptor agonist Codeine is less potent- similar actions	Morphine and Codeine both act strongly at m, less at k and d and weakly at s. Actions include: -analgesia -euphoria -respiratory depression -depression of cough reflex -miosis -emesis -GI tract slowing -Hypotension and bradycardia at high doses -releases histamine -inhibits gonadotropin releasing hormone	Analgesia mostly. Morphine can also be used in treatment of diarrhea, and for cough, although codeine is a more potent antitussive.	Dose dependent respiratory depression, may progress to respiratory arrest if dose increased. Also causes -miosis -emesis -reduced GI motility (constipation) -hypotension and bradycardia at high doses -bronchoconsriction -urticaria -urinary retention -elevation of ICP Toxic effects (depressant actions) of morphine are enhanced by phenothiazines, MAO-inhibitors, and tricyclic antidepressants.
	Meperidine	Synthetic opioid unrelated to morphine -favors k receptors -causes respiratory depression similar to morphine -no CV effects if given orally -contracts smooth muscle -increases ICP (intra cranial pressure) -may cause tachycardia and hypotension if given IV	Used for acute pain	Large doses cause: -tremors -muscle twitches -convulsions (rarely) *Important difference from other opioids: -causes pupil dilation (others cause miosis) -also different: causes hyperactive reflexes Severe reactions may occur if taken with MAO- inhibitors, such as hyperthermia and convulsions
	Methadone	Synthetic opioid, approximately equal to morphine in potency, but less euphoria and longer duration of action. -greatest action at m receptors	Controlled withdrawal of addicts from heroin and morphine.	Similar to morphine
	Fentanyl	Meperidine relation Primarily m agonist	80 x analgesic potency of morphine, used in anesthesia -also available in transdermal patches for severe refractory pain	High doses produce muscle rigidity
	Heroin	Is converted to morphine in the body	No medical use	See morphine
	Propoxyphene	Derivative of methadone	-dextro isomer is used as an analgesic -levo isomer is used as antitussive Weaker analgesic than codeine, but is often used in combination with acetaminophen or aspirin for greater analgesia than with either alone	-Toxic doses cause respiratory depression, convulsions, hallucinations and confusion. -Severe reaction may occur in some people with cardiotoxicity and pulmonary edema -respiratory depression may be antagonized by naloxone but the cardiotoxicity cannot. Also may cause: -nausea -anorexia -constipation -hallucinations, confusion
Antidiarrheal	Loperamide and Diphenoxlate	Meperidine analogues, act at k receptors, activating presynaptic opioid receptors in the enteric nervous system to inhibit ACH release and decrease peristalsis.	Anti motility agents in treatment for diarrhea	Dizziness Toxic megacolon Don’t use in young children or people with severe colitis.
Antitussive	Codeine	At lower doses than required for analgesia, decreases the sensitivity of CNS cough centers to peripheral stimuli, and decreases mucosal secretion	Prescription use for cough suppression.	At very high doses could mimic morphine
	Dextromethorpan	Derivative of morphine, suppresses response of cough center	Over the counter antitussive, less constipating than codeine	No analgesic or addictive potential.
Mixed Agonist/antag
	Pentazocine	k agonist, weak m, d, s agonist. -activates receptors in spinal cord causing analgesia	Used to relieve moderate pain -note that in opiate-tolerant/dependent people Pentazocine will act to induce withdrawl, but will not antagonize sedation or respiratory depressive effects.	At high doses causes respiratory depression and reduces motility of GI tract. Also: -high blood pressure -tachycardia -hallucinations -dizziness -increases work of the heart- don’t give to folks with CAD
Antagonists
	Naloxone	-rapidly displaces bound opioid molecules as a competitive antagonist at m, d, and k receptors.	Used to reverse coma and respiratory depression of opioid (heroin) overdose.	None listed (except precipitating withdrawl in opiate dependent people)
	Naltrexone	-similar to Naloxone, but has longer duration of action	-used in opiate dependence maintenance programs and may be used in treating chronic alcoholism

4. Drugs for Myasthenia Gravis

Drug	Mechanism	Use	Toxicity
Neostigmine	Reversible acetylcholinesterase inhibitor; effectively allows ACH to remain in postsynaptic cleft for longer, resulting in increased response of myasthenic muscle to repetitive nerve impulses. Duration 2-4 hours.	Treatment of MG Antidote to tubocurarine	Toxic doses result in cholinergic crisis: -bradycardia and decrease in CO -hypotension -bronchospasm -nausea -ab pain -Salivation -Lacrimation -Urination -Diarrhea (SLUD)
Pyridostigmine	Longer acting than neostigmine (3-6 hours)	Treatment of MG	See above
Edrophonium	Shortest acting acetylcholinesterase inhibitor (10-20 min), not useful for treatment.	Diagnosis of MG	Excess may cause cholinergic crisis; atropine is antidote

All information came from Lippincotts Pharm Review p 43-44 and Goodman Gilman p 173

5. Hormonal treatments of cancer

Drug	Mechanism	Therapeutic use	Resistance	Toxicity	Other
Tamoxifen/raloxifene	Estrogen receptor mixed antagonist/agonist blocks estrogen binding	Breast cancer (best in patients with tumors expressing estrogen receptors)	Decreased affinity for receptor, decreased number of receptors, dysfunctional receptor	Hot flashes, n/v, menstrual irregularities, vulvar pruritis, vaginal bleeding & discharge	No effective in pre-menopausal women, may also protect against heart disease and osteoporosis
Estrogens	Block production of LH à decrease androgen synth	Prostate cancer		General: thromboemboli, MI, strokes, hyperCa, HTN Women: loss of libido Men: gynecomastia, impotence
Leuprolide/goserelin	Analogs of LHRH & GnRH à inhibit FSH and LH à decrease androgen and estrogen synth	Advanced prostate or breast cancer à chemical castration (loss of GnRH pulsatility)	Increased LH receptors, mutation in receptor	Impotence, hot flashes, tumor flare	Also used to treat endometriosis
Flutamide	Nonsteroidal antiandrogen à blocks inhibition of testosterone by inc LH and testos levels	Prostate cancer		Gynecomastia, GI distress	ALWAYS administered with leuprolide or gosrelin
Aminoglutethimide	Inhibits adrenal synthesis of pregnenolone from cholesterol and extra-aromatase synth of estrogen	Metastatic breast cancer (second line Tx)	Increased metabolism when given with dex, theophylline, digoxin	Transient CNS depression, maculopapular rash	Induces and metabolized by P450 system
Prednisone	Triggers apoptosis, esp in dividing cells, blocks prolif of activated T cells, inhibits inflam mediators and Ab production	CLL, Hodgkin’s lymphomas (part of MOPP regimen), immunosuppressant in autoimmune dz	Absence of receptor protein, mutation à lowers receptor affinity	Cushing-like symptoms, immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia	Abrupt withdrawal leads to adrenal insufficiency à TAPER!!

6. New oral hypoglycemic agents

Drug	Action	Side effects/CI	Hypoglycemia	GI SE	Lactic acidosis
Sulfonylureas (Glyburide)	Increase insulin secretion		Yes, especially dec renal fxn	No	No
Metformin	Inhibits hepactic glucose output à increases insulin sensitivity	Appetite suppression, additive effect with sulfonylureas	No (when used alone)	Yes	Yes, especially with renal, liver impairment
Glitazones	Insulin sensitizer (targets insulin resistance)	Troglitazone à hepatic dysfunction, liver failure (now d/c)	No	Yes	No
Acarbose	Inhibits carbohydrate absorption	Bloating, flatulence, diarrhea	No	Yes	No