Chapter 41 Diuretics Drugs that increase urinary output Two major applications Treatment of hypertension Mobilization of edematous fluid to prevent renal failure Introduction to Diuretics Figure 41-1 How diuretics work – mechanism of action Blockade of sodium and chloride reabsorption Site of action Proximal tubule produces greatest diuresis Adverse effects Hypovolemia Acid-base imbalance Electrolyte imbalances Figure 41-2 Classification of diuretics Four major categories High-ceiling (loop) – furosemide Thiazide – hydrochlorothiazide Osmotic – mannitol Potassium-sparing: two subdivisions.
Aldosterone antagonists (spironolactone) Nonaldosterone antagonists (triamterene) Fifth group Carbonic anhydrase inhibitors High-Ceiling (Loop) Diuretics Furosemide (Lasix) – most frequently prescribed loop diuretic Mechanism of action Acts on ascending loop of Henle to block reabsorption Pharmacokinetics Rapid onset (oral 60 min; IV 5 min) Therapeutic uses Pulmonary edema Edematous states Hypertension Adverse effects Hypokalemia Hyponatremia, hypochloremia, and dehydration Hyperglycemia & Hyperuricemia Hypotension Loss of volume Relaxation of venous smooth muscle Ototoxicity Drug interactions.
Digoxin May cause imbalance in digoxin levels due to fluctuation in potassium levels Ototoxic drugs May cause tinnitus Potassium-sparing diuretics May help to prevent hypokalmia Lithium By lowering sodium levels can cause lithium accumulation and raise it to a toxic level Antihypertensive agents May reduce blood pressure to critical level Nonsteroidal anti-inflammatory drugs NSAIDs can blunt the diuretic effect of Lasix Potassium wasting May increase hypokalemia Preparations, dosage, and administration Oral Parenteral Thiazides and Related Diuretics Hydrochlorothiazide Also known as benzothiadiazides.
Effects similar to those of loop diuretics Increase renal excretion of sodium, chloride, potassium, and water Maximum diuresis is considerably lower than that produced by loop diuretics Not effective when urine flow is scant (unlike loop diuretics) Action – early segment distal convoluted tubule Peaks 4-6 hours Therapeutic uses Essential hypertension Edema Diabetes insipidus Adverse effects Hypokalemia Hyponatremia, hypochloremia, and dehydration Use in pregnancy and lactation Enters breast milk Hyperglycemia Hyperuricemia Drug interactions Digoxin May cause fluctuations in the potassium level.
Augments effects of hypertensive medications Can reduce renal excretion of lithium (leading to accumulation) Because of sodium fluctuations NSAIDs may blunt diuretic effect Can be combined with ototoxic agents without increased risk of hearing loss Potassium-Sparing Diuretics Aldosterone Antagonist (Spironolactone) Useful responses Modest increase in urine production Substantial decrease in potassium excretion Rarely used alone for therapy Aldosterone antagonist Spironolactone Nonaldosterone antagonists Triamterene Spironolactone (Aldactone) Mechanism of action Blocks aldosterone in the distal nephron.
Retention of potassium Increased excretion of sodium Therapeutic uses Hypertension Edematous states Heart failure (decrease mortality in severe failure) Less common uses Primary hyperaldosteronism Premenstrual syndrome Polycystic ovary syndrome Acne in young women Endocrine effects- spironolactone is a steroid derivative with a structure similar to that of steroid hormones (Progesterone, estradiol, & Testosterone) Adverse effects Hyperkalemia Benign and malignant tumors Endocrine effects Drug interactions Thiazide and loop diuretics Agents that raise potassium levels Osmotic Diuretic Mannitol (Osmitrol).
Promotes diuresis by creating osmotic force within lumen of the nephron Pharmacokinetics Drug must be given parenterally Therapeutic uses Prophylaxis of renal failure Reduction of intracranial pressure Reduction of intraocular pressure Adverse effects Hypovolemia Transient Edema May cause in all tissue except the brain Headache Nausea, Vomiting Fluid and electrolyte imbalance MUST be filtered before giving Check serum osmalality before giving If serum osmo is high then hold mannitol patient is too dehydrated Chapter 31 Antipsychotic Agents and Their Use in Schizophrenia Antipsychotic Agents.
Used for diverse spectrum of psychotic disorders Schizophrenia, delusional disorders, bipolar disorders, depressive psychoses, drug-induced psychoses Should not be used to treat dementia in the elderly Antipsychotic Agents First-generation antipsychotics (FGAs) or conventional antipsychotics Block receptors for dopamine in CNS Cause serious movement disorders (EPS) First-generation antipsychotics are thought to relieve symptoms of schizophrenia by blocking D2 receptors. First-generation antipsychotics improve positive symptoms of schizophrenia more effectively than negative symptoms or cognitive dysfunction.
Second-generation antipsychotics (SGAs) or atypical antipsychotics Only produce moderate blockade of dopamine receptors; stronger blockade for serotonin Fewer extrapyramidal symptoms (EPS) More metabolic side effects- weight gain, diabetes Therapeutic responses to antipsychotic drugs develop slowly, often taking several months to become maximal. Clinical Presentation Disordered thinking and reduced ability to comprehend reality Three types of symptoms Positive symptoms and negative symptoms Cognitive symptoms Positive symptoms include hallucinations, delusions, and agitation.
Negative symptoms include blunted affect, poverty of speech, and social withdrawal. Cognitive dysfunction manifests as disordered thinking, reduced ability to focus attention, plus learning and memory difficulties. Conventional Antipsychotic Agents I: Group Properties Classification by potency Low potency – chlorpromazine HCl (Thorazine) High potency – haloperidol (Haldol) Low-potency FGAs and high-potency FGAs produce equal therapeutic effects. Mechanism of Action Conventional antipsychotic drugs block a variety of receptors within and outside the CNS. They block dopamine2 (D2) receptors in the mesolimbic area of the brain.
Therapeutic Uses Schizophrenia Bipolar disorder (manic-depressive illness) Tourette’s syndrome Adverse Effects Extrapyramidal symptoms (EPS) (Know table 32-6) Acute dystonia- sustained muscle contractions cause twisting and repetitive motions Parkinsonism-tremor, hyperkinesia, and unstable gait Akathisia- restlessness (restless legs) Tardive dyskinesia- protrusion of tongue, lip smacking, puckering/pursing of lips First-generation antipsychotic drugs produce three types of early extrapyramidal symptoms (EPS): acute dystonia, parkinsonism, and akathisia. Acute dystonia and parkinsonism respond to anticholinergic drugs (eg, benztropine).
Akathisia is harder to treat, but may respond to anticholinergic drugs, benzodiazepines, or beta blockers. Tardive dyskinesia (TD), a late EPS, has no reliable treatment. For patients with severe TD, switching to an atypical agent may help. The risk of early EPS is much greater with high-potency FGAs than with low-potency FGAs, whereas the risk of TD is equal with both groups. Neuroleptic malignant syndrome Rare but serious reaction Risk of death without treatment Sweating, rigidity, sudden high fever, autonomic instability Dantrolene and bromocriptine are used for treatment.
Anticholinergic effects Orthostatic hypotension More prevalent with low potency FGA Sedation Usually subsides as tolerance to medication develops Neuroendocrine effects Galactorrhea & gynecomastia Seizures Does not cause seizures- reduces seizure threshold Sexual dysfunction Dermatologic effects Highest risk with phenothiazines (Chlorpromazine Thorazine) Increases the risk of sunburn Agranulocytosis Highest risk is with phenothiazines Need to report signs of sore throat, cold, not feeling well immediately Monitor CBC Severe dysrhythmias.
Prolonged QT interval, more common with Haloperidol (Haldol) Low potency has higher risk for sedation, orthostatic hypotension High potency has higher risk for early onset EPS Both are equal in the development of Tardive Dyskinesia Drug Interactions Anticholinergic drugs Intensify the anticholinergic effect CNS depressants Can intensify the depressant effect Levodopa and direct dopamine-receptor agonists May counteract the antipsychotic effects of neuroleptics Because levodopa activates dopamine receptors, whereas FGAs block dopamine receptors. Toxicity Conventional antipsychotic drugs are very safe.
Death by overdose is extremely rare. Overdose produces hypertension, CNS depression, and EPS. Treatment IV fluids, alpha-adrenergic agonist, gastric lavage Emetics not effective – neuroleptics block the antiemetic action Atypical Antipsychotic Agents Introduced in the 1990s Less risk of EPS than FGAs More risk of weight gain, diabetes, and dyslipidemia Examples: clozapine and other atypical antipsychotics Clozapine (Clozaril) The most effective antipsychotic drug available but because of side effects this drug is reserved for patients who have not responded to other SGAs or FGAs. Mechanism of action.
Blocks dopamine and serotonin Therapeutic use Schizophrenia Levodopa-induced psychosis Adverse effects and interactions Agranulocytosis Monitor CBC Seizures Diabetes the risk of metabolic effects is greatest with clozapine and olanzapine Weight gain Myocarditis Effects in elderly patients with dementia About double the mortality rate Depot Preparations Depot antipsychotics – long-acting, injectable formulations used for long-term maintenance therapy of schizophrenia No evidence that depot preparations pose an increased risk of side effects There are only 3 drugs available as a depot.
Schizophrenia Drug Therapy Three major objectives Suppression of acute episodes Prevention of acute exacerbations Maintenance of the highest possible level of functioning Most FGAs and SGAs are equally effective – except for clozapine, which is more effective than the rest FGAs – significant risk of EPS SGAs – risk of metabolic effects FGAs – cost 10 times less than SGAs SGAs differ from FGAs in three important ways: (1) they block receptors for serotonin in addition to receptors for dopamine; (2) they cause few or no EPS, including TD; and.
(3) they carry a higher risk of serious metabolic effects—weight gain, diabetes, and dyslipidemia—which can lead to adverse cardiovascular events and premature death. Schizophrenia Drug Therapy Dosing Highly individualized Elderly patients require relatively small doses Size and timing likely to be changed over course of therapy Promoting adherence Ensure that the medication is taken Encourage family members to oversee medication for outpatients Provide patients with instructions Inform patients and their families that antipsychotics must be taken on a regular schedule Inform patients about side effects of treatment.
Assure patients that antipsychotic drug use does not lead to addiction Establish a good therapeutic relationship with patient Chapter 32 Antidepressants Primarily used to relieve symptoms of depression Can also help patients with anxiety disorders Not indicated for uncomplicated bereavement Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (S/NRIs) Monoamine oxidase inhibitors (MAOIs) Atypical antidepressants Depression Treatment May increase suicidal tendency early in the treatment Suicide risk is greatest in children and young adults.
Patients should be observed closely for: Suicidality Worsening mood Changes in behavior Precautions Prescriptions should be written for the smallest number of doses consistent with good patient management Dosing of inpatients should be directly observed Tricyclic Antidepressants Amitriptyline (ELavil) Drugs of first choice for many patients with major depression Most common adverse effects – sedation, orthostatic hypotension, and anticholinergic effects Most dangerous adverse effect – cardiac toxicity This can be lethal if overdoses May increase risk of suicide early in treatment.
Mech Of Action: TCAs block reuptake of norepinephrine (NE) and 5-hydroxytryptamine (5-HT), and thereby intensify transmission at noradrenergic and serotonergic synapses. Drug Interactions TCAs can cause a hypertensive crisis if combined with an MAOI. Accordingly, the combination is generally avoided. TCAs intensify responses to direct-acting sympathomimetics (eg, epinephrine) and diminish responses to indirect-acting sympathomimetics (eg, amphetamine). Nucleus of the tricyclic antidepressants have three rings Similar to phenothiazine antipsychotics Produce varying degrees of: Sedation.
Orthostatic hypotension Anticholinergic effects Pharmacokinetics Long and variable half-lives Usually single daily dose Requires individualization of dosage Therapeutic uses Depression Bipolar disorder Other uses Neuropathic pain Panic disorder Obsessive-compulsive disorder Adverse Effects Orthostatic hypotension Anticholinergic effects Diaphoresis Sedation Cardiac toxicity Seizures Hypomania Yawngasm Toxicity: Clinical manifestations Primarily from anticholinergic and cardiotoxic actions Dysrhythmias Treatment Gastric lavage Ingestion of activated charcoal Physostigmine Propranolol, lidocaine, or phenytoin.
To help with dysrhthmias Selective Serotonin Reuptake Inhibitors Fluoxetine (Prozac) Introduced in 1987 Most commonly prescribed antidepressants As effective as TCAs – but do not cause hypotension, sedation, or anticholinergic effects Overdose does not cause cardiac toxicity Death by overdose is extremely rare SSRIs have two major advantages over TCAs: they cause fewer side effects and are safer when taken in overdose. Most SSRIs have stimulant properties, and hence can cause insomnia and agitation. This contrasts with TCAs, which cause sedation. Like most other antidepressants, SSRIs can cause weight gain.
Sexual dysfunction (eg, impotence, anorgasmia) is more common with SSRIs than with most other antidepressants. MOA: Produces selective inhibition of serotonin reuptake Produces CNS excitation Therapeutic Uses Primarily used to treat major depression Other uses Obsessive-compulsive disorder Bulimia nervosa Premenstrual dysphoric disorder Adverse Effects Serotonin syndrome 2-72 hours after treatment SSRIs can cause serotonin syndrome, especially when combined with MAOIs and other serotonergic drugs. Symptoms include agitation, confusion, hallucinations, hyperreflexia, tremor, and fever Withdrawal syndrome.
Neonatal effects when used in pregnancy Teratogenesis Sexual dysfunction Weight gain Serotonin/Norepinephrine Reuptake Inhibitors (S/NRIs) Venlafaxine (Effexor) Indications Major depression Generalized anxiety disorder Social anxiety disorder (social phobia) MOA: Blocks NE and serotonin uptake Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors Serious reactions if combined with MAOIs Side effects Nausea Headache Nervousness Sweating Insomnia Weight loss/anorexia Sexual dysfunction Hyponatremia (in elderly patients) Monoamine Oxidase Inhibitors (MAOIs).
2nd- or 3rd-choice antidepressants for most patients As effective as TCAs or SSRIs, but more dangerous Risk of triggering hypertensive crisis if patient eats foods rich in tyramine Drug of choice for atypical depression Like SSRIs (and unlike TCAs), MAOIs cause direct central nervous system (CNS) stimulation. Like TCAs (and unlike SSRIs), MAOIs cause orthostatic hypotension. Patients taking MAOIs must not eat tyramine-rich foods because hypertensive crisis can result. See table 32-6 Avocados, figs, bananas in large amounts, smoked or otherwise aged meats, fermented sausages: pepperoni, salami, bologna, etc.
smoked or dried fish, all hard cheeses, foods with yeast that have not been cooked, some beers; chianti wine, and soy sauce Mechanism of action Converts monoamine neurotransmitters (NE, serotonin, and dopamine) into inactive products Inactivates tyramine and other biogenic amines Two forms of MAO in the body MAO-A and MAO-B Affected by antidepressants Acts on MAO in two ways: reversible and irreversible Irreversible – lasts about 2 weeks All of the MAOIs in current use cause irreversible inhibition Therapeutic uses Depression Other uses Bulimia nervosa Obsessive-compulsive disorders Panic attacks Adverse effects.
CNS stimulation Orthostatic hypotension Hypertensive crisis from dietary tyramine Drug Interactions Do not mix with any medication without checking with pharmacist! Atypical Antidepressants Wellbutrin (Bupropion) Actions and uses Acts as stimulant and suppresses appetite Antidepressant effects begin in 1 to 3 weeks Does not affect serotonergic, cholinergic, or histaminergic transmission Does not cause weight gain Increases sexual desire and pleasure Adverse effects Can cause seizures Agitation Tremor Tachycardia Blurred vision Dizziness Headache Insomnia Dry mouth Constipation Weight loss Chapter 33 Drugs for Bipolar Disorder.
Mainstays of therapy Lithium, valproic acid Many also receive an antipsychotic Chronic condition that requires lifelong treatment Definition of bipolar disorder (BPD) Cyclic disorder Recurrent fluctuations in mood Episodes of mania and depression persist for months without treatment Treatment Drugs Psychotherapy Types of drugs employed Mood stabilizers Relieve symptoms during manic and depressive episodes Prevent recurrence of manic and depressive episodes Do not worsen symptoms of mania or depression; do not accelerate the rate of cycling Antipsychotics Given during severe manic episodes Antidepressants.
Given during depressive episodes Mood Stabilizing Lithium Antiepileptic drugs Therapeutic uses Bipolar disorder Mechanism of action Altered distribution of certain ions Altered synthesis and release of norepinephrine, serotonin, and dopamine Mediates intracellular responses to neurotransmitters Shown to facilitate regeneration of damaged optic nerves Can increase total gray matter in regions known to atrophy in BPD Pharmacokinetics Excretion Short half-life Excreted by the kidneys Sodium levels – lithium excretion reduced when sodium level low Plasma levels 0. 8 to 1. 4 mEq/L (normal therapeutic level).
Must be kept below 1. 5 mEq/L Must keep sodium in the normal range If sodium level goes down the kidneys will retain lithium and become toxic If sodium levels go up the kidneys will excrete more lithium and levels will go down Patient should have consistent intake of salt Adverse effects Excessive lithium levels Greater than 1. 5 mEq/L Monitor levels q 2-3 days at initiation of therapy and then q 2-3 months Therapeutic lithium levels Gastrointestinal Tremors Polyuria Renal toxicity Goiter and hypothyroidism Teratogenesis Leukocytosis Drug interactions Diuretics May cause sodium levels to fluctuate.
Nonsteroidal anti-inflammatory drugs (NSAIDs) Can increase lithium levels by up to 60% Chapter 34 Sedative-Hypnotic Drugs Benzodiazepines Midazolam (Versed) Responses result from actions on the CNS Reduce anxiety Promote sleep Muscle relaxation Alcohol withdrawals Seizures Does not normally cause respiratory depression if taken alone orally Has a ceiling effect when taken orally IV may lead to respiratory depression CNS depression Antergrade Amnesia Paradoxical effects Insomnia, tachycardia Abuse- schedule IV Orally- may cause drowsiness and impaired thinking Romazicom (Flumazenil) reversal agent Sleep Medications.
Zolpidem (Ambien) Falling Asleep; SR maintaining sleep Zaleplon (Sonata) Falling Asleep Eszopiclone (Lunesta) Falling Asleep and Staying Asleep Barbiturates Thiopental There is no ceiling to the effect so can cause death by overdose No antidote If OD then treat symptomatically Respiratory Depression Hypotension and possible shock May be used to keep a seizure patient in a coma Chapter 35 Management of Anxiety Disorders Types of Anxiety Disorders Generalized anxiety disorder Panic disorder Obsessive-compulsive disorder (OCD) Social anxiety disorder (social phobia) Post-traumatic stress disorder (PTSD) Drug therapy.
Benzodiazepines (Ativan Lorazepam) Buspirone (BuSpar) Non-CNS depressant Does not cause sedation Has no abuse potential Does not intensify the effects of CNS depressants Anxiolytic effects develop slowly So not good for acute attacks Adverse effects Dizziness Nausea Headache Nervousness Lightheadedness Excitement No withdrawal symptoms have been observed Chapter 36 CNS Stimulants and Attention Deficit Hyperactivity Disorder Amphetamines- CNS stimulants MOA: Promote release of norepinephrine and dopamine Works in the CNS and peripheral nerves Most results are from release of NE Pharm Effects CNS Effects mood and arousal.
Increases wakefulness and alertness Euphoria, talkativeness, and increased motor is likely Cardiovascular Increased heart rate Increased force of contraction Promotes vasoconstriction -> hypertension Tolerance May need to increase dose to keep getting the euphoric effect Physical Dependence Abrupt withdrawal may lead to abstinence syndrome Exhaustion Depression Prolonged sleep Excessive eating Craving for more amphetamine Because of the euphoria has a high potential for abuse!!! ALL AMPHETAMINES ARE A SCHEDULE II CNS stimulation Insomnia, restlessness Weight loss/ meth mouth Suppresses appetite Psychosis.
Can lead to paranoia (Psychosis) Does not cause schizophrenia but can lead to diagnosis CV Dysrhythmias (tachy), anginal pain, and hypertension Should be careful when starting on kids with congenital or known heart defects Therapeutic Uses ADHD Narcolepsy Obesity Not recommended because of high potential for abuse and the CV risks Methylxanthine Caffeine MOA Reversible blockade of adenosine receptors Effects CNS Decreases drowsiness and fatigue; can lead to nervousness, insomnia, and tremors CV Tachycardias, vasodilates in the periphery; vasoconstricts in the CNS Respiratory Relaxes smooth muscles of the bronchi.
Renal Diuretic Miscarriages >200 mg/day lead to spontaneous miscarriages Methylphenidate (Ritalin) Not structural the same as amphetamines but produces the same results Same MOA and same abuse potential ADHD low beta and high theta Medications work to equal out the waveforms Stimulants do NOT produce good behavior; they decrease undesirable behavior Patient Education with ADHD Medications Do not take a second dose after 1600 Do not combine with other stimulants caffeine Do not chew the long acting formulations If using the transdermal patch- remove after 9 hours or before 1600 Take dose after eating breakfast.
Monitor appetite, height, weight, and blood pressure Atmoxetine (Strattera) Nonstimulant medication used to treat ADHD May cause suicidal thinking in children and adolescents Usually only noticed during the first few months Should be monitored closely for mood swings and depression when starting Chapter 37 Drug Abuse Addiction Disease process characterized by the continued use of a specific psychoactive substance despite physical, psychologic, or social harm resulting in a failure to fulfill major role obligations at work, school, or home Drug abuse/addiction also has a cultural aspect.
Tolerance Physical dependence State in which an abstinence syndrome will occur if drug use is discontinued Controlled Substances Schedule I No medical purpose; NOT legal in the US Schedule II Must be typed or written by prescriber- no phone ins (unless in an emergency situation and written prescription must be turned in within 72 hours) Cannot write for refills but can write for 90 day supply Schdule III-V More lenient on refills and prescription- may be written or oral prescriptions, may have refills Chapter 38 Alcohol Abuse.
Alcohol causes general depression of the CNS by enhancing the depressant effects of GABA and reducing the excitatory effects of glutamate and activation of the reward circuit in the brain Drug Interactions with alcohol CNS depressants NSAIDs Acetaminophen Disulfiram Antihypertensive drugs Chronic use of alcohol causes vasoconstriction Acute Overdose/ Alcohol Poisoning Vomiting Coma Aspiration Respiratory depression Hypotension caused by vasodilation and may not be fixed with vasopressors Should always ask your patients about drinking disorders!!! Alcohol Withdrawal Can be mild or life threatening.
Will start to see in 24-72 hours of no drink Benzodiazepines Can help to prevent life threatening withdrawal Drugs used to maintain abstinence Antabuse (Disulfiram) Disrupts alcohol metabolism If drinks alcohol while taking Vomiting (may be severe) Flushing Headache Sweating Weakness Do NOT ingest any alcohol while taking (includes some medications, mouthwashes, cooking, colognes, liniments) for about 2 weeks after last dose of antabuse Administer the first dose at least 12 hours after their last drink Naltrexone (Revia) Pure opioid antagonist Decreases the feelings of euphoria received from alcohol.
Decreases craving for alcohol Blocks alcohol’s reinforcing effects Mechanism unclear Can be given by depot Adverse effects Nausea Headache Other Drugs Used in Treatment of Alcohol Abuse B vitamins Thiamine Folic acid Cyanocobalamin Vitamin supplements Fluid replacement therapy Chapter 39 Nicotine Nicotine through smoking causes nicotinic receptors to be activated May use the nicotine replacements during pregnancy Nicotine may cause physical dependence Nicotine replacements Used to wean a patient off of nicotine The patient should not smoke- can absorb too much nicotine May become addicted to the replacement.
Bupropion SR (Zyban) An Atypical antidepressant Causes CNS stimulation and suppresses appetite as well as the urge to smoke and some symptoms of nicotine withdrawal Should stop after 12 weeks Varenicline (Chantix) Partial agonist at nicotinic recpetors Is the most EFFECTIVE aid to smoking cessation Adverse effects Nausea most common Neuropsychiatric effects- mood changes, erratic behavior and suicidality Cardiovascular effects More pronounced in patients with already diagnosed cardiac issues Should stop after 12 weeks Chapter 40 Major Drugs of Abuse other than Alcohol Methadone.
May be given to patients who are physically dependent upon opioids in order to prevent withdrawal syndrome May be substituted for the opioid that the person is addicted to Taper off over 10 days Patient may still go through a withdrawal but it will be a lot less significant Buprenorphine (Subutex) An agonist-antagonist opioid Can be used for maintenance therapy and to facilitate detoxification Has a low potential for abuse because of the partial agonist Naltrexone Once the patient has been detoxified from opioids, naltrexone an opioid antagonist can be used to discourage renewed opioid use Blocks the euphoria from the opioid.
Chapter 14 Muscarinic Agonists and Antagonists Muscarinic Agonists and Antagonists Principal structures affected by muscarinic activation Work through direct activation of muscarinic cholinergic receptors Heart – bradycardia Exocrine glands – increase sweating, salivation, bronchial secretions, and secretion of gastric acid Smooth muscles Contraction in lung (constriction) GI tract (increased tone/motility) Bladder (contraction of detrusor) Vascular (relaxation, vasodilation, hypotension) Eye (pupillary constriction and ciliary contraction) Muscarinic Cholinergic Agonist Bethanechol.
Selective agonist at muscarinic cholinergic receptors Bethanechol, the prototype of the muscarinic agonists, is used primarily to relieve urinary retention. Muscarinic activation relaxes the trigone and sphincter muscles and increases voiding pressure Adverse effects Cardiovascular system Hypotension bradycardia Alimentary system Excessive salivation & increased gastric acid secretion Urinary tract Increases pressure within the urinary tract Should NOT be given to someone with urinary tract obstruction or weakness of the bladder wall Exacerbation of asthma bronchoconstriction.
Muscarinic agonist poisoning is characterized by Profuse salivation, tearing Visual disturbances Bronchospasm Bradycardia and hypotension diarrhea Treatment: atropine Muscarinic Antagonists (Anticholinergic Drugs) Competitively block the actions of acetylcholine at muscarinic receptors Most muscarinic receptors on structures innervated by parasympathetic nerves Anticholinergic drugs – produce selective blockade of muscarinic receptors – not all cholinergic receptors Certain drugs (antihistamines, tricyclic antidepressants, phenothiazine antipsychotics) have prominent anticholinergic actions.
Use with caution – or not at all – with patients receiving other muscarinic antagonists. Atropine Best known muscarinic antagonist Mechanism of action No direct effect of its own Muscarinic receptor blockade Therapeutic uses Preanesthetic medication Disorders of the eye Bradycardia Muscarinic agonist poisoning Pharmacologic effects (receptor blockade) Heart Increase heart rate Exocrine glands Decreases secretions Smooth muscle Relaxes muscles of the bronchi, urinary bladder, and GI tract Eye mydriasis Central nervous system (CNS) excitation Adverse effects Xerostomia (dry mouth).
Urinary retention Constipation Anhidrosis Blurred vision and photophobia Elevation of intraocular pressure Tachycardia Anticholinergic effects: Dry as a bone Hot as a firecracker Blind as a bat Mad as a hatter Red as a beet Drug interactions Avoid combining atropine with other drugs capable of causing muscarinic blockade. Anticholinergic Drugs for Overactive Bladder Oxybutynin (Ditropan, Oxytrol) Overactive bladder (OAB): Urge Incontinence MOA: Relaxes the bladder detrusor Specific anticholinergic drugs for OAB Toxicology of Muscarinic Antagonists Symptoms Dry mouth.
Blurred vision Photophobia Hyperthermia Hallucinations and delirium Hot, dry, and flushed skin Acute Poisoning of muscarinic antagonists Over Dose: Atropine, anthistamines, tricyclic antidepressants Symptoms: excessive muscarinic blockade Death results from respiratory depression secondary to blockade of cholinergic receptors in the brain Treatment Physostigmine Inhibitor of acetylcholinesterase Warning: Differentiate between poisoning and an actual psychotic episode! Chapter 15 Cholinesterase Inhibitors and Their Use in Myasthenia Gravis Cholinesterase Inhibitors.
Lack selectivity (muscarinic, ganglionic, and neuromuscular) Cholinesterase inhibitors prevent breakdown of acetylcholine (ACh) by acetylcholinesterase, causing ACh to accumulate in synapses, which in turn causes activation of muscarinic receptors, nicotinic receptors in ganglia and the neuromuscular junction (NMJ), and cholinergic receptors in the central nervous system (CNS). The major use of reversible cholinesterase inhibitors is treatment of myasthenia gravis. Benefits derive from accumulation of ACh at the NMJ. “Reversible” cholinesterase inhibitors Neostigmine “Irreversible” cholinesterase inhibitors.
Pesticides Can be used for glaucoma Reversible CI- Neostigmine (Prostigmin) Absorbed poorly with oral administration Can be given orally, IV or subcutaneous Can’t readily cross membranes Minimal effect on brain Poor substrate for ChE (Cholinesterase) ChE breaks down acetylcholine into choline and acetic acid Neuromuscular effects Therapeutic dose – increases force of contraction in skeletal muscle Usually evidenced by swallowing, muscle strength, and ptosis Toxic levels – decrease force of contraction Central nervous system Therapeutic levels – mild stimulation Toxic levels – depress the CNS.
Poisoning by reversible cholinesterase inhibitors is treated with atropine (to reverse muscarinic stimulation) plus mechanical ventilation. Adverse effects/acute toxicity Excessive muscarinic stimulation Neuromuscular blockade Myasthenia Gravis Treatment with cholinesterase inhibitors Beneficial effects Increased muscle strength Side effects Excessive muscarinic response Patient Education Dosage adjustment Start small and adjust to patient response May need to modify dosage in anticipation of exertion Signs of undermedication Ptosis, difficulty in swallowing Signs of o.