Pharmacology Exam 2 PDF

A diagram of a human brain Description automatically generated Neuropharmacology (NP) Study of drugs that alter processes controlled by the nervous system These drugs are used to treat conditions that range from depression to epilepsy to hypertension to asthma NP agents are divided into two...

A diagram of a human brain Description automatically generated Neuropharmacology (NP) Study of drugs that alter processes controlled by the nervous system These drugs are used to treat conditions that range from depression to epilepsy to hypertension to asthma NP agents are divided into two broad categories 1\. Peripheral nervous system (PNS) drugs 2\. Central nervous system (CNS) drugs Neuropharmacology (NP) NP drugs can modify many diverse processes\ Skeletal muscle contraction Cardiac output Vascular tone\ Respiration\ Gastrointestinal function\ Uterine motility\ Glandular secretion\ Ideation, mood, and perception of pain Basic Principles of Neuropharmacology Neurons regulate physiologic processes in two ways 1. **AXONAL conduction** 2. **SYNAPTIC transmission** **Sites of action: Axons vs. synapses** **Axonal conduction** Action potential down the axon **Synaptic transmission** Information carried across the neuron gap and the postsynaptic cell NP Agents **Postsynaptic cell** Another neuron, muscle cell, or cell within a secretory gland Basic Mechanisms of NP Agents Steps in Synaptic Transmission 1\. Transmitter synthesis 2\. Transmitter storage 3\. Transmitter release 4\. Receptor binding 5\. Termination of transmission Basic Mechanisms of NP Agents **NP drugs affect specific steps in synaptic transmission** **Transmitter synthesis** Increase transmitter synthesis Decrease transmitter synthesis Cause synthesis of transmitter molecules that are more effective than natural transmitters **Transmitter storage\ ** If storage is decreased, there is less transmitter to cause effect **Transmitter release** **Receptor binding** Cause activation Block activation Enhance activation **Termination of transmission** Block transmitter reuptake Inhibit transmitter degradation Summary of Effects of Drugs on Synaptic Transmission and the Resulting Impact on Receptor Activation Multiple Receptor Types and Selectivity **Selectivity** As discussed in Module 01, selectivity is the most desirable quality a drug can have Drugs that are very selective can alter a disease process while leaving other physiologic processes largely unaffected **How to approach learning PNS drugs** Three types of information needed: **1. Type (or types) of receptor(s)** through which the drug acts (for example, alpha1, alpha2, beta1) **2. Normal response to the activation of those receptors** (agonist vs. antagonist -- module one follows you through the entire course) **3. What the drug in question does to receptor function** **For each PNS drug that you study**, you should **learn the identity of the receptors (β1, β2,** 𝝰**1,** 𝝰**2, etc)** at which the drug acts**,** the **normal responses** to activation of those receptors**,** and **whether the drug increases or decreases receptor activation.** The Nervous System **Divisions of the nervous system** **Central Nervous System (CNS) (discussed later)** **Peripheral Nervous System (PNS)** page5image37742960 **Autonomic Nervous System (ANS)** Sympathetic division -- "fight or flight"\ Parasympathetic division -- "rest and digest" **Three principal functions of the ANS** - Regulate the heart - Regulate the secretory glands salivary, gastric, sweat, and bronchial - Regulate the smooth muscles bronchi, blood vessels, urogenital system, and gastrointestinal tract **The Parasympathetic Nervous System** **Think of parasympathetic as "P"okey (slow) OR** *"**rest and digest**" or responsible for "**housekeeping**"* **Seven regulatory functions** 1\. Slowing heart rate\ 2. Increasing gastric and salivary secretions 3. Emptying bladder\ 4. Emptying of bowel\ 5. Focusing the eye for near vision\ 6. Constricting the pupil\ 7. Contracting bronchial smooth muscle **Parasympathomimetic drugs**  Parasympathomimetic drugs "MIMIC" the responses of the parasympathetic nervous system Parasympathetic nervous system drugs used primarily for **Digestion of food Excretion of waste Control of vision Conservation of energy** page9image51330928 **Think of the sympathetic nervous system ("S"peedy)** **Three main functions** **1. Regulation of the cardiovascular system** ü Maintaining blood flow to the brain ü Redistributing blood\ ü Compensating for the loss of blood 2. **Regulation of the body temperature** ü Regulates blood flow to the skin\ ü Promotes the secretion of sweat\ ü Induces piloerection (erection of hair) 3. **Implementation of the *"fight-or-flight"* reaction** ü Increasing heart rate and blood pressure ü Shunting blood away from skin and viscera ü Dilating bronchi\ ü Dilating pupils ü Mobilizing stored energy page10image53542656 Sympathomimetic Drugs Sympathomimetic drugs "MIMIC" responses of SNS Primarily used for effects on: § Heart and blood vessels § Lungs AUTONOMIC NERVOUS SYSTEM REGULATION MECHANISMS **Three basic patterns** - Innervation by ***both*** divisions of the ANS in which the effects of the two divisions are ***opposed*** (ex. heart rate) - Innervation by ***both*** divisions of the ANS in which the effects of the two divisions are ***complementary*** (ex. erection and ejaculation) - Innervation & regulation by ***only one*** division of ANS (ex. blood vessels controlled only by sympathetic system) **Autonomic Tone**: interaction b/t sympathetic & parasympathetic systems Most body structures are under control of both systems **Feedback regulation** Primarily **baroreceptors** (NUR 612); feedback loops; sensor and effector neurons Autonomic Tone Provides homeostasis **Reflex regulation is superimposed** When a system is innervated by both systems, one system generally predominates In most systems, **parasympathetic tone predominates** Anatomy of the Autonomic Nervous System N -- nicotinic; M -- muscarinic; ACh -- acetylcholine; NE -- norepinephrine; Epi - epinephrine  Anatomy of the Autonomic Nervous System (Cont.) Notice on the previous slide- **all preganglionic neurons use Ach** (both SNS and PNS) Parasympathetic postganglionic neurons only use Ach Sympathetic postganglionic neurons use Ach, Epi or NE Motor neurons use Ach as their neurotransmitter With the knowledge what might happen if you used a drug that non- specifically increased Ach in the synapse? The Neurotransmitters **Acetylcholine (ACh)** Synapses throughout the CNS; **pre**ganglionic neurons ending in the ganglia in both the **sympathetic and** **parasympathetic** nervous systems **(nicotinic)**; **post**ganglionic neurons ending in neuroeffector target tissues in the parasympathetic nervous system **(muscarinic)** **Norepinephrine (NE)** Throughout the CNS; most neuroeffector target junctions in the **sympathetic** nervous system **Epinephrine (Epi)** Major transmitter released by the adrenal medulla  Receptors of the Peripheral Nervous System **Cholinergic** (respond to ACh) Nicotinic and Muscarinic **Adrenergic** (respond to NE and Epi) Alpha and Beta Receptor Subtypes and Selectivity **Cholinergic** (respond to ACh) **Adrenergic** (respond to NE and Epi) Alpha (1,2) Beta (1,2) Cholinergic Receptors **Cholinergic** (responds to ACh)\ **Nicotinic (neuronal and muscle)** (**NN)**Stimulates ALL pre-ganglionic transmission (sympathetic and parasympathetic) **Muscarinic** § **Stimulates glandular secretions** - Pulmonary, gastric, intestinal, and sweat glands - Sweat glands are **SYMPATHETIC** -- ACh stimulation is the **EXCEPTION** for sympathetic transmitters. § **Stimulates SMOOTH muscle receptors** Bronchi and GI tract - Slows the heart - Meiosis (small pupils) - Dilation of blood vessels - Voiding page18image37465264 Adrenergic Receptors **Adrenergic** (responds to NE and Epi) Alpha 1 (Epi and NE) Male sex organs Prostatic capsule Bladder **Alpha 2 (Epi and NE)** On presynaptic nerve terminals - inhibits neurotransmitter release  **Adrenergic** (responds to NE and Epi) **Beta 1 (Epi and NE)** **Heart** § Increases force of contraction § Increases AV conduction **Kidney** Release of renin **Beta 2** (Epi only) **Arterioles dilate vessels in** Stimulates glycogenolysis in liver and skeletal muscle Relaxed uterus\ Enhances skeletal muscle contraction Life Cycle of Transmitters Acetylcholine -- stored in vesicles and available for immediate release - §  Effect terminated when ACh is broken down by acetylcholinesterase (AChE) - §  Byproducts are reabsorbed and reused to produce more ACh Life Cycle of Transmitters Norepinephrine -- stored in vesicles & available for immediate release  Effect is terminated by reuptake of NE into nerve terminal Inactivated by *monoamine oxidase* (MAO) **CHAPTER 16 & 17** **Muscarinic Agonists and Antagonists** **Cholinergic drugs** Most act directly at cholinergic receptors Mimic or inhibit actions of acetylcholine (ACh) May affect either pre- or post-ganglionic receptors OR both **For this module, only MUSCARINIC ANTAGONISTS are discussed** Muscarinic Antagonists: What's In a Name page5image37427088Muscarinic antagonists **competitively block the action of ACh at the muscarinic receptor** (review module 01 for competitive *vs* non-competitive receptor interaction) An often-confusing issue These drugs are interchangeable known as: Parasympatholytic drugs **[Atropine ]** Naturally occurring drug from the *Atropa belladonna* plant Atropine is also known as a *belladonna alkaloid* **Mechanism of action** **Competitive** blockade at the muscarinic receptor *(Where are they located?)* Atropine ***prevents receptor activation*** by endogenous ACh or drugs similar to ACh Atropine exerts influence on the ***heart, exocrine glands, smooth muscles***, and ***eyes*** Atropine: Pharmacologic Effects *(removes the parasympathetic tone)* **Heart\ ** **Increases** heart rate **Exocrine glands** **Decreases** secretion from salivary, bronchial, and sweat glands, and acid- secreting cells of the stomach **Smooth muscle** **CNS** Excitation at therapeutic doses Hallucinations and delirium at toxic doses  Atropine Pharmacologic Effects Pharmacologic effects are dose dependent Decreasing salivary secretions occurs at a much lower dose than decreasing sweating If stomach acid secretions are affected, all processes above are affected **[Atropine Therapeutic Uses: ]** **Anesthetic pre-medicatio**n **Eye disorders** - Useful to dilate the eye for ophthalmologic exam - Cycloplegia is helpful in refraction (this determines your glasses prescription) **Bradycardia** Often given in code situations (not as much as in previous times, however) **Intestinal hypertonicity and hypermobility** **[Atropine: Therapeutic Uses ]** **MUSCARINIC AGONIST POISONING** **Atropine is specific antidote** for poisoning caused by agents that activate muscarinic receptors **Muscarinic poisoning** - Medications (nerve agents)\ Mushrooms (muscarinic)\ Cholinesterase inhibitors *(anticholinesterases)* − **Sx associated w/anticholinesterase poisoning are: SLUDGE & KILLERB's** Salivation, Lacrimation, Urination, Diaphoresis/Diarrhea, GI cramping, and Emesis. This can progress to Bronchospasm, Bronchorrhea, Blurred vision, Bradycardia or tachycardia, hypotension, confusion, and shock. **[Atropine: Adverse Effects ]** Directly related to receptor blockade - Xerostomia (Dry as a bone) - Blurred vision/photophobia (Blind as a bat!) - Elevation of intraocular pressure - Urinary retention - Constipation - Anhidrosis (Hot as a hare) - Tachycardia - Asthma - Vasodilation (Red as a beet) Cholinesterase Inhibitors and Their Use in Myasthenia Gravis Chapter 18 Cholinesterase Inhibitors Two types\ **1. Reversible** inhibitors -- short to moderate duration of action **2. Irreversible** inhibitors -- long duration of action Pyridostigmine: The Prototype **REVERSIBLE** cholinesterase inhibitor Principally used for treatment of *myasthenia gravis* **Mechanism of action** - binds to and inhibits the action of cholinesterase - ACh is not broken down - Increased ACh becomes available at the synapse  **Kinetics** - Oral absorption is poor but therapeutic and toxic levels can occur - Does not cross the blood brain barrier except in **VERY HIGH DOSES** - Degraded by acetylcholinesterase Pyridostigmine: The Prototype **Pharmacologic effects** **\*Muscarinic stimulation\ ** Bradycardia, bronchial constriction, urinary urgency, increased glandular secretions, increased tone and motility of GI tract, meiosis, near vision **Neuromuscular effects:** Increased **OR** decrease ***force*** of contraction ***(dose dependent)*** **CNS stimulation** or depression (dose dependent) Pyridostigmine: The Prototype **Adverse effects** Excessive muscarinic stimulation **Muscarinic (AKA Cholinergic) Crisis** Neuromuscular blockade In toxic doses, may cause respiratory paralysis→**DEATH** **Drug interactions** - **Muscarinic antagonists-**Cholinesterase inhibitors oppose action of atropine; used to treat atropine toxicity - **Competitive neuromuscular (NM) blockers-**Accumulation of ACh reverses competitive NM blockers - **Depolarizing neuromuscular blockers**-Cholinesterase inhibitors **INTENSIFY NM** blockade cause by *succinylcholine* +-----------------------------------+-----------------------------------+ |  | | | | **Neuromuscular disorder** | | | | | | **Common symptoms** | | | | | | **Etiology** | +-----------------------------------+-----------------------------------+ Myasthenia Gravis - Reversible cholinesterase inhibitors are primary agent - Sufficient dose to provide muscle strength without - With initial treatment, "**START LOW, MOVE SLOW"** **Patient should record:** 1\. When is med taken\ 2. When fatigue occurs\ 3. Muscle strength before and after meds 4\. Signs of muscarinic stimulation Patients instructed to increase dose before exertion If serious muscarinic side effects occur *(cholinergic* **MEDIC ALERT** bracelet Myasthenia Gravis - **Myasthenic Crisis** is a result of **inadequate medication** ▪ Extreme weakness\ ▪ Possible paralysis - **Cholinergic Crisis** is caused by **overdose of cholinesterase inhibitor** - Note sx of both are similar. - How to differentiate? +-----------------------+-----------------------+-----------------------+ | | Myasthenia Gravis | **Cholinergic v/s | | | | Myasthenic Crisis** | | | | | | | | ▪Edrophonium | | | | (Tensilon) is | | | | ultrashort | | | | cholinesterase | | | | inhibitor used to | | | | confirm dx of | | | | myasthenia gravis | | | | (Tensilon test) | | | | | | | | ▪Tensilon given in | | | | environment where | | | | intubation/ventilator | | | | support available | | | | | | | |  | +=======================+=======================+=======================+ | Irreversible | Irreversible | | | Cholinesterase | cholinesterase | | | Inhibitors | inhibitors are not | | | | used clinically | | | | **WITH ONE | | | | EXCEPTION** | | | | | | | | Irreversible | | | | cholinesterase | | | | inhibitors are highly | | | | lipid soluble and can | | | | penetrate most | | | | membranes and the | | | | skin | | | | | | | | Irreversible | | | | cholinesterase | | | | inhibitors and are | | | | found in | | | | | | | | Notice the | | | | similarity in | | | | structure | | | | | | | | page12image37433952 | | +-----------------------+-----------------------+-----------------------+ Treatment of Irreversible Cholinesterase Inhibitors (Cholinergic Crisis) Organophosphate poisoning creates a **CHOLINERGIC CRISIS**→**SAFETY ALERT** Sx associated w/anticholinesterase poisoning are: **SLUDGE & the KILLER B's** Tx as soon as suspected **Overview of CNS Drugs** - **CNS drugs** act on the brain and spinal cord. - Used for **pain relief, seizure suppression, anesthesia, and mental health treatment**. - Understanding is limited due to **neurochemical complexity**. - Key concepts: **CNS neurotransmitters and the blood-brain barrier (BBB).** **Neurotransmitters of the CNS** - Neurons communicate via **neurotransmitters**. - Over **100 neurotransmitters** in the CNS, but **only 21** have established roles in drug therapy. - Unlike the peripheral nervous system, where neurotransmitter functions are well understood, **CNS neurotransmitter roles remain unclear**. **Selected CNS Neurotransmitters** - **Monoamines**: Dopamine, Epinephrine, Norepinephrine, Serotonin - **Amino Acids**: Aspartate, GABA, Glutamate, Glycine - **Purines**: Adenosine, AMP, ATP - **Opioid Peptides**: Dynorphins, Endorphins, Enkephalins - **Non-opioid Peptides**: Neurotensin, Oxytocin, Somatostatin, Substance P, Vasopressin - **Others**: Acetylcholine, Histamine **The Blood-Brain Barrier (BBB)** - **Restricts drug access to the brain** via tightly joined capillary cells. - Only **lipid-soluble drugs** or those with **specific transport systems** can cross. - **Protein-bound or highly ionized drugs cannot cross**. - The BBB protects against toxins but also **limits therapeutic drug access**. **Production of Therapeutic Effects** - **Exact mechanisms are often unknown**, relying on **hypotheses**. - Drug effects can change with **long-term use** due to **CNS adaptation**. **CNS Adaptation to Long-Term Drug Use** 1. **Increased Therapeutic Effects** - Some drugs (e.g., **antidepressants, antipsychotics**) require weeks to show full effects. - Delayed action results from **adaptive changes in the brain**. 2. **Decreased Side Effects** - Some drugs initially cause side effects (e.g., **phenobarbital sedation**) that diminish with continued use. - The brain adjusts to maintain therapeutic effects while reducing side effects. 3. **Tolerance and Physical Dependence** - **Tolerance**: Decreased drug response over time. - **Physical Dependence**: Withdrawal symptoms upon discontinuation due to CNS adaptation. **CNS Disorders and Neurotransmitter Involvement** -- -- -- -- **Challenges in Developing New Psychotherapeutic Drugs** 1. **Knowledge Deficit** - Many discoveries have been **serendipitous**. - Limited understanding of **neurochemical basis of mental disorders**. 2. **Research Challenges** - **No adequate animal models** for mental illness. - **Healthy individuals cannot be used** to test psychotherapeutic drugs. 3. **Drug Refinement Process** - New drugs are modified into **structural analogs**. - Candidates undergo **biochemical and toxicity screening**. - Goal: **Improve therapeutic effects and reduce side effects**. **Best Approach to Studying CNS Drugs** 1. Unlike **peripheral nervous system drugs**, CNS drugs **cannot be studied solely based on neurotransmitter function**. 2. Approach requires **simultaneous study of drugs and their effects on neurotransmitters**. **Key Takeaways** - **CNS drugs affect neurotransmitters and receptors in the brain and spinal cord**. - **BBB protects the brain but also limits drug therapy**. - **CNS adaptation to prolonged drug exposure alters effects and side effects**. - **Tolerance and physical dependence can develop with chronic use**. - **Psychotherapeutic drug development is challenging due to limited knowledge and research constraints**. - **CNS drug study relies on hypotheses rather than fully understood mechanisms**. **Drugs for Parkinson's Disease (PD) Chapter 24** +-----------------------------------------------------------------------+ | **Parkinson's Disease** | +=======================================================================+ | § Motor deficits arise from near total loss of dopaminergic cells in | | basal ganglia responsible for movement | | | | § **Cardinal symptoms** | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ Parkinson's Disease: Etiology §Dopamine/ACh Imbalance results from **degeneration of neurons** that supply dopamine §**Inadequate dopamine**à **ACh causes excessive release of gamma- aminobutyric acid (GABA)** Overactivity of gamma- aminobutyric acid neurons a- motor symptoms of PD Parkinson's Disease: Therapeutic Goals - **Goal: Improve patient's ability to carry out ADLs** - Drug selection and dosages are determined by the extent to which PD interferes with ADL Drug Therapy for Parkinson's Disease **Two major categories:** **1. Dopaminergic agents** Most commonly used drugs for PD Promote activation of dopamine receptors Levodopa \[Dopar\*\] **2. Anticholinergic agents** Prevent activation of cholinergic receptors Benztropine \[Cogentin\] The Basis for Symptomatic Drug Therapy of Motor Symptoms - **L-Aromatic Amino Acid Decarboxylase (LAAD)**: Converts levodopa to dopamine - **Catechol-O-methyl transferase (COMT)**: Converts levodopa to **3-hydroxymethyldopa (3-OMD)** - **Monoamine oxidase (MAO):** Converts dopamine into **dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide** PD: Drug Selection for Initial Treatment 1. **Mild symptoms**: Monoamine oxidase-B (MAOI-B) inhibitor 2. **More severe symptoms**: Levodopa *(combined with carbidopa) (Sinemet)* or dopamine agonist\ § Levodopa is more effective than dopamine agonists, *but long-term use has ↑ risk for disabling dyskinesias* 3. **Management of motor fluctuations** "Off" times ↓ with dopamine agonists, *catechol-O- methyltransferase (COMT) inhibitors, and MAO-B* *inhibitors* Drug-induced dyskinesias +-----------------------+-----------------------+-----------------------+ | | Drug Selection: | Symptomatic tx only | | | Initial Treatment | | +-----------------------+-----------------------+-----------------------+ Levodopa: Mechanism of Action Increases dopamine synthesis in the striatum Levodopa *(has no direct effects of its own)* is converted to dopamine Restores proper balance between dopamine and ACh\ **Enhanced by pyridoxine (vitamin B6) when used with carbidopa** **[Levodopa: Uses ]** **LEVODOPA\*** Promote activation of dopamine receptors - Levodopa \[Dopar\*\] - Levodopa/carbidopa \[Sinemet, Parcopa\] \*Although we will use only generics, know functional differences & advantages of *Sinemet and Parcopa* q **Diagnosis of PD questioned if levodopa fails** q **Several months of tx needed for full response** q Symptoms well controlled for first 2 -- 3 years q Return to pretreatment state at end of 5 years q Most troubling SE is dyskinesia **\*Always used with *carbidopa***  +-----------------------------------------------------------------------+ | **Levodopa: Acute Loss of Effect** | +=======================================================================+ | **Acute loss** of effect occurs in two ways | | | | 1\. Gradual loss---*"*wearing off*"*---**develops near the end of | | the dosing interval** and indicates that drug levels have declined | | to a subtherapeutic value | | | | 2\. Abrupt Loss of effect can occur at any time during the dosing | | interval | +-----------------------------------------------------------------------+ | | +-----------------------------------------------------------------------+ **[Levodopa: Kinetics ]** **Only given in combination with carbidopa or carbidopa/entacapone** Orally administered; rapidly absorbed from small intestine Food **delays** absorption Metabolized in the periphery by *decarboxylase enzymes* and catechol-O-methyl transferase (COMT)\ Only about 2% of levodopa (when used alone) is absorbed into brain **[Levodopa: Adverse Effects ]** **1. [ ] Nausea and vomiting** Activates dopamine receptors in chemoreceptor trigger zone **2. Dyskinesia** **3. Cardiovascular effects** Postural hypotension 4.**Psychosis** Hallucinations, vivid dreams, paranoid ideation **5.CNS effects** Anxiety/agitation, memory/cognitive impairment, impulse control Promiscuity, gambling, binge eating, and ETOH abuse **6. Other** **Levodopa: Drug Interactions** **Drug interactions** First-generation antipsychotic drugs (i.e., chlorpromazine, haloperidol) block receptors for dopamine in the striatum (↓ therapeutic effects of levodopa) **MAO inhibitors (MAOIs\*)** Levodopa: HTN crisis if administered concurrently with nonselective MAO inhibitor **Anticholinergic drugs** Excessive stimulation of cholinergic receptors → dyskinesias of PD; blocking these receptors = anticholinergic agents enhance levodopa response \*MAOIs used occasionally in psychotherapy. Generally, patients are highly educated to inform any provider about their use. **Drug-drug interactions with MAOIs can be FATAL** **[Levodopa: Drug Interactions ]** **Drug interactions (continued)** Pyridoxine (vitamin B6) - Stimulates decarboxylase activity - Acceleration of decarboxylation of levodopa in periphery Pyridoxine can decrease levodopa available to reach CNS - Therapeutic effects of levodopa can be ↓ - Levodopa is **always combined with carbidopa** **[Levodopa: Food interactions ]** Meals high in protein can ↓ therapeutic responses Neutral amino acids **compete** with levodopa for absorption from intestine for transport across BBB Recommend protein consumption evenly throughout day **[Levodopa/Carbidopa \[Sinemet and Parcopa\] ]** **Advantages\ ** Most effective therapy for PD Mechanism of action\ **Carbidopa** is used to enhance effects of levodopa Carbidopa has **no therapeutic effects of its own b/c unable to cross BBB\ ** Carbidopa inhibits the decarboxylation of levodopa in the intestine and peripheral tissues **More levodopa is available to the CNS at lower doses** Decreases side effects **[Levodopa/Carbidopa \[Sinemet & Parcopa\] ]** **Advantages\ ** By ↑ fraction of levodopa available, carbidopa allows dosage of levodopa to be ↓ by ***\~ 75%*** By ↓ dopamine in periphery, carbidopa ↓ CV response to levodopa & ↓ N/V **[Levodopa ]** **Disadvantages** § Carbidopa: no adverse effects § Adverse responses from carbidopa/levodopa are result of potentiating effects of levodopa § *When levodopa/carbidopa combined, abnormal movements/psychiatric disturbances can occur sooner* *& more intense than with levodopa alone* **[Dopamine Agonists ]** Direct activation of dopamine receptors **Comparison with levodopa** Does not compete with dietary proteins **Two types of dopamine agonists** Derivatives of ergot Nonergot derivatives **[Nonergot Dopamine Agonists ]** **Most common adverse effects:** *CNS & neuromuscular* (i.e., sleeping disorders, dizziness, headache, dose-related hallucinations, and dyskinesia) **Pramipexole** \[Mirapex\] Used **alone in early PD** and **with levodopa in advancing PD** *Maximal benefits take several weeks to develop* **Ropinirole** \[Requip\] Highly selective for D2 and D3 receptors; PD: Ropinirole can be used as monotherapy for early PD and as an adjunct to levodopa for advanced PD **[Nonergot Dopamine Agonists ]** **Apomorphine** \[Apokyn\] Acute tx of hypomobility during *"*off*"* episodes in patients with advanced PD - Not given by mouth - **Not indicated for routine PD management** Derivative of morphine but devoid of typical opioid effects Adverse effects **[Ergot Derivatives Bromocriptine & Cabergoline ]** **Bromocriptine \[Parlodel\]** Derivative of ergot Direct-acting dopamine agonist Beneficial effects derive from activating dopamine receptors in striatum Used alone for early PD and in combination with levodopa for advanced PD **Advantages** Can prolong therapeutic responses & reduce motor fluctuations when combined with LD **[Ergot Derivatives (Bromocriptine & Cabergoline) ]** **Bromocriptine** **Adverse effects** \*A rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. **[COMT inhibitors]** Inhibits metabolism of levodopa in periphery No direct therapeutic effects of their own Safer/more effective Tolcapone \[Tasmar\] \* Catechol-O-methyltransferase **[Entacapone \[Comtan\] ]** **Advantages** § Selective/reversible inhibitor of COMT § Indicated for use with levodopa § Inhibits metabolism of levodopa in intestines and peripheral tissues § Prolongs levodopa availability by inhibiting COMT **Adverse effects** § Dyskinesias § Orthostatic hypotension § Nausea § Hallucinations § Sleep disturbances § Impulse control disorders § Managed by decreasing levodopa dosage § Entacapone can cause vomiting, diarrhea, constipation, and yellow- orange discoloration of urine **[Entacapone \[Comtan\] ]** **Drug interactions** Isoproterenol (a beta-adrenergic agonist) **[Tolcapone \[Tasmar\] ]** - Used only in conjunction with levodopa - Benefits derived from inhibiting levodopa metabolism in the periphery, which prolongs levodopa availability - Improves motor function and may allow for a reduction in levodopa - Reduces *"*wearing-off*"* that can occur with levodopa, *thus extending "on" times by as much as 2.9 hours a day* - Deaths from liver failure have occurred - Treatment should be limited to 3 weeks in the absence of a beneficial response **[MAO-B Inhibitors ]** Considered first-line drugs even though benefits are modest Combination with levodopa can reduce wearing-off effect **Selegiline, Rasagiline and Safinamide** Benefits decline dramatically within 12 to 24 months **[Amantadine \[Symmetrel\] ]** - Developed as an antiviral agent; Later found effective for PD - Inhibition of dopamine uptake, stimulation of dopamine release, blockade of cholinergic receptors, and blockade of glutamate receptors - Responses within 2 to 3 days but are much less profound than with levodopa or dopamine agonists - Responses may begin to diminish within 3 to 6 months - Not considered a first- line agent - May be helpful for dyskinesias caused by levodopa +-----------------------------------+-----------------------------------+ | Amantadine \[Symmetrel\] | | | | | | **Adverse effects** | | | | | | - CNS: Confusion, | | | lightheadedness, and anxiety | | | | | | - Peripheral: Blurred vision, | | | urinary retention, dry mouth, | | | and constipation | | | | | | - Livedo reticularis: Condition | | | characterized by mottled skin | | | discoloration | | +-----------------------------------+-----------------------------------+ Centrally Acting Anticholinergic Drugs: Benztropine \[Cogentin**\]** **Benztropine (Cogentin)** - Reduces tremor & rigidity but not **bradykinesia** - Less effective than levodopa or dopamine agonists but better tolerated - **Used as second-line therapy for tremor** - Most appropriate for **younger patients with mild sx** - **Avoid in elderly** (intolerant of CNS side effects such as sedation, confusion, delusions, hallucinations) **[Nonmotor Symptoms and Their Management ]** **Autonomic\ ** Constipation, urinary incontinence, drooling, orthostatic hypotension, and cold intolerance **Sleep disturbance** Excessive daytime sleepiness Periodic limb movements of sleep Insomnia **Dementia** **Psychosis** **Depression** **Amitriptyline: only known effective drug** *(Tricyclics)* Main MOA of Drug Therapies in Parkinson's Disease +-------------+-------------+-------------+-------------+-------------+ | | ![page36ima | | | | | | ge54045632] | | | | | | (media/imag | | | | | | e33.png) | | | | +=============+=============+=============+=============+=============+ | Drugs | Promote | Activate | Prolong | Prolong | | | dopamine | specific | dopamine | levodopa | | page36image | synthesis | receptors | availabilit | bioavailabi | | 37363008 | | | y | lity | +-------------+-------------+-------------+-------------+-------------+ | Dopaminergi | Levodopa | Dopamine | MAO-B | COMT | | c | | Agonists | inhibitors | inhibitors | +-------------+-------------+-------------+-------------+-------------+ | Antiglutama | Amantadine | | | | | tergic | | | | | +-------------+-------------+-------------+-------------+-------------+ | Anticholine | | Trihexyphen | | | | rgic | | idyl | | | | | | Benztropine | | | +-------------+-------------+-------------+-------------+-------------+ **Drugs for Alzheimer's Disease Chapter 25** **Alzheimer's Disease** Characteristics \* **Inability to perform routine tasks of daily living** **Today, someone in the country develops Alzheimer\'s dementia every 66 seconds** **[Alzheimer's Disease]** ** Pathology** ** Degeneration of cholinergic neurons** ** Hippocampus** ** Cerebral atrophy** ** Later finding following neuronal degeneration** ** Presence of *neuritic plaques and neurofibrillary tangles*** ** *Degeneration may begin long before symptoms appear***  **Amyloid plaques** **Tau Neurofibrillary Tangles** +-----------------------------------+-----------------------------------+ | **Alzheimer's Disease** | **Hippocampus degeneration** | | | | | | - Important role in memory | | | | | | - As degeneration begins, | | | short-term memory fails | | | | | | **Cortical degeneration** | | | | | | - Difficulty with language | | | | | | - Loss of bladder and bowel | | | control | | | | | | - Inability for self care | | | | | | - Ultimately→death | +-----------------------------------+-----------------------------------+ **Alzheimer's Disease: Risk Factors** **Advancing age** **Family history** **Women greater than men** May be due to women living longer than men **Other possible factors (more ASSOCIATION v/s cause/effect)** **Pharmacological Intervention** **Cholinesterase inhibitors** Rivastigmine **Neuronal receptor blocker for *N-methyl- D-aspartate*** Memantine **NOTE** *No drug superior for symptom improvement* +-----------------------------------+-----------------------------------+ | **Pharmacological** | **[Cholinesterase inhibitors | | | ]** | | **Intervention** | | | | - Affects central neuronal | | | receptors | | | | | | - All approved for | | | mild-moderate symptoms | | | | | | | | | | | | - Do not stop progression→ | | | delays end result | | | | | | - Improvement in memory and | | | reasoning | | | | | | - | | | | | | **[ADVERSE EFFECTS | | | ]** | | | | | | - GI: nausea, vomiting | | | dyspepsia, diarrhea | | | | | | - Dizziness and headache | | | | | | - Bronchoconstriction | | | | | | Cardiac (often dose limiting) | | | | | | | | | Bradycardia→fainting→falls→fall- | | | related fractures | | | | | | May require pacemaker placement | +-----------------------------------+-----------------------------------+ **Pharmacological Intervention:DRUG-DRUG INTERACTIONS** ** Reduced cholinergic effects with:** 1. First-generation antihistamines 2. Tricyclic antidepressants 3. Conventional antipsychotics **THERAPEUTIC CONSIDERATIONS** +-----------------------------------+-----------------------------------+ | **Donepezil** | **[Donepezil (Aricept) | | | ]** | | page13image37543648 | | | | - Mild, moderate, or severe | | | disease | | | | | | - More selective for AChE found | | | in the CNS, less activity | | | peripherally | | | | | | - REVERSIBLE | | | | | | **KINETICS** | | | | | | - Well absorbed orally | | | | | | - Metabolized by CYP 450 (*be | | | aware of drugs with similar | | | metabolism)* | | | | | | - Excreted by kidney (urine) & | | | liver (bile) | | | | | | - *Remember issues | | | associated with renal and | | | hepatic disease* | +-----------------------------------+-----------------------------------+ **[Donepezil (Aricept) ]** **Oral Formulations:** 1. Oral tablets:5 mg, 10 mg, 23 mg 2. Orally disintegrating tablets: 5 and 10mg 3. Oral solution: 1mg/ml **ODT/oral solution** ✓ Useful for patients with swallowing difficulty **When initiating therapy** ✓ If symptoms not improved in 5-6 months, increase to 23 mg/day **[Memantine ]** **∆  Moderate to severe disease** **∆  No evidence to suggest better than donepezil** **THERAPEUTIC EFFECTS** ▪ May slow decline in function\ ▪ Symptoms may improve slightly **MECHANISM OF ACTION** ▪Neuronal receptor blocker for *N-methyl-D- aspartate* ▪Prevents the effects of constant leaking of glutamate from the presynaptic neuron Modulates glutamate (excitatory in the CNS) This mechanism may improve memory **[Memantine (Namenda) ]** **KINETICS** CAUTION with renal impairment **DRUG-DRUG INTERACTIONS** THE FOLLOWING MAY CAUSE UNDESIRED ADDITIVE EFFECTS Ketamine Amantadine Drugs that alkalinize urine can decrease renal excretion, increasing toxicity **[Memantine ]** ** ADVERSE EFFECTS** Dizziness ** DOSAGE AND ADMINISTRATION** Dosage and titration per recommended schedule **Drugs for Multiple Sclerosis (MS)** Chapter 26 **[Multiple Sclerosis (MS) ]** Chronic, inflammatory, autoimmune disease that damages myelin sheath of neurons in the CNS Characterized by exacerbations with episodes of complete or partial recovery Causes more disability in young adults than any other neurological disease **[Pathology ]** Presence of multifocal regions of inflammation and myelin destruction in the CNS **[Signs/Symptoms ]** Symptoms vary depending on location of demyelination Paresthesia Muscle/motor difficulty (weakness, clumsiness, tremors, cramps) Emotional lability Cognitive impairment The Kurtzke Expanded Disability Status Scale used to determine impact of MS on nine different functional systems **[Following attacks ]** Partial remyelination Functional axonal compensation Development of alternative neuronal circuits that bypass damage **[Four MS Subtypes ]** **1.Clinically Isolated Syndrome** - Refers to 1st Episode of MS - Neurologic Symptoms for at least 24 hours - MRI displays MS findings **2.Replapsing- Remittng** - Recurrent episodes separated by periods of remissions - 85 to 90% have this form initially **3.Primary Progressive** - Progressively intense disease from outset - occasional plateaus, no remission - 10% have this form **4. Secondary Progressive** - Patient with RRMS with Steadily worsening dysfunction - 50% will develop in 10-20 years of outset **[Drug Therapy Overview ]** Goals Modify disease process Disease Modifying Drugs **1. Immunomodulators** **2. Immunosuppressants** Treating Acute Episodes +-----------------------------------+-----------------------------------+ | Immune Modulators | **Adverse effects** | | | | | Prototype Interferon beta | 1\. Flu-like reactions | | | | | | 2\. Hepatotoxicity | | | | | | Follow periodic LFTs initially, | | | 1month, every3 months for 12 | | | months and then every | | | | | | 6 months | | | | | | 3\. Myelosuppression\ | | | Monitor CBCs same as LFTs | | | | | | 4\. Injection-site reactions | | | | | | *Moderate with antihistamines* | | | | | | 5\. Depression | | | | | | Some patients may experience | | | suicidal ideation and even | | | attempt suicide. | | | | | | 6\. Neutralizing antibodies | +-----------------------------------+-----------------------------------+ **[Immunosuppressants ]** **Mitoxantrone** Approved for decreasing neurologic disability and clinical relapses in patients with Worsening relapsing-remitting MS **MOA** Inhibits RNA and DNA synthesis Particularly toxic to Bone marrow Hair follicles GI mucosa **[Mitoxantrone: Pharmacokinetics ]** Mitoxantrone **[Mitoxantrone: Adverse Effects ]** § **Myelosuppression** § **Cardiotoxicity** **+** Irreversible L ventricular ejection fraction damage (LVEF) \--*heart failure* § **Fetal harm** -- **Pregnancy Cat D** § **Others** § GI issues § Rash, itching, hypotension, dyspnea § Skin discoloration **[SUMMARY OF TREATMENT OPTIONS]** **Clinically Isolated Syndrome** Immunomodulators (except Alemtuzumab) **Relapsing-Remitting** Immunomodulators Immunosuppressants **Primary Progressive** Immunomodulator (Ocrelizumab only) **Secondary Progressive** Immunomodulators Immunosuppressants [Symptom Management of MS Symptoms ] **Common symptoms** Bladder dysfunction Sexual dysfunction Neuropathic pain **Drugs for Epilepsy** Chapter 27 Definition of Epilepsy  Group of disorders characterized by **excessive excitability of neurons in the central nervous system** Can produce a **variety of symptoms** that range from brief periods of unconsciousness to violent convulsions May also cause problems with learning, memory, and mood Seizure: Generation Initiated by synchronous, high-frequency discharge from a group of hyperexcitable neurons (i.e., ***focus**)* **Focus** may result from 1. Congenital defects 2. Hypoxia at birth 3. Head trauma 4. Brain infection 5. Stroke 6. Cancer 7. Genetic disorders page5image54093664 Types of Seizures **Focal-onset (partial) seizures** Focal aware (Simple partial)\ Focal impaired awareness (Complex partial)\ Focal to bilateral tonic-clonic (Secondarily generalized) **Generalized-onset seizures** Tonic-clonic\ Absence (petit mal) Atonic\ Myoclonic\ Status epilepticus\ Febrile  Summary of Seizure Drugs page8image37483520 **Goals of Treatment** 1. REDUCE SEIZURES TO A LEVEL THAT ALLOWS THE PATIENT TO LIVE AS NORMAL A LIFE AS POSSIBLE 2. BALANCE THE DESIRE FOR COMPLETE SEIZURE CONTROL WITH ACCEPTABLE SIDE EFFECTS  **Epilepsy: Therapeutic Considerations** Drug evaluation\ 1. Antiepileptic drug **(AED)** trial period 2\. Dosage adjustment\ 3. Seizure frequency chart Monitoring plasma drug levels Therapeutic index often narrow Promoting patient adherence Withdrawing antiepileptic drugs **Suicide risk**: Antiepileptic drugs https://www.cms.gov/medicare-medicaid-coordination/fraud- prevention/medicaid-integrity-education/pharmacy-education- materials/downloads/ac-adult-dosingchart.pdf page9image53481408 **Antiepileptic Drugs (AEDs)** **Effects** **Mechanisms of action** **Simply**, AEDs control ion exchange and **modify glutamate and GABA**  **Classification of Antiepileptic Drugs and PROTOTYPES** page11image54076048 **Traditional AEDs** Phenytoin\ Carbamazepine\ Valproic acid\ Ethosuximide\ Phenobarbital\ Diazepam (IV) Discussed Later **Newer Generation AEDs** Oxcarbazepine Lamotrigine -------------------------------------------------------------- Traditional AEDs vs New AEDs page12image53541536 -------------------------------------------------------------- **[General principles of antiepileptic (AED) drugs ]** **AED selection** - Depends on type of seizures and epilepsy syndrome - **GOAL:** Seizure control with no side effects - Presence of other medical conditions - Titration rate and dosing - Special populations:\ Children\ Women of child-bearing age  **Teratogenicity** -All AEDs currently in use are labeled as pregnancy category C or D. Congenital malformations have been reported with of all AEDs mothers prescribed valproate and/or carbamazepine  **Lactation Principles** ▪ AEDs are found in breast milk in inverse proportion to protein-binding affinity ▪ Maternal use of AEDs is not an absolute contraindication ▪ Infants of mothers prescribed sedating AEDs monitored for sedation & poor feeding page15image53727840 **TRADITIONAL ANTIEPILEPTIC DRUGS** Phenytoin (Dilantin)\ Carbamazepine (Tegretol) **[Phenytoin \[Dilantin\] ]** **Mechanism of action**: ▪ Selective inhibition of sodium channels ▪ Stabilizes neuronal membrane\ ▪ Slows conduction velocity **Kinetics** Varied absorption based on formulation Hepatic metabolism capacity is limited\ Narrow therapeutic index Therapeutic level: 10 to 20 mcg/mL\ Average daily maintenance dose in adults is 300 to 400 mg **Therapeutic uses** Partial and tonic-clonic seizure Cardiac dysrhythmias **Adverse effects** 1. Nystagmus 2. Sedation 3. Ataxia 4. Diplopia 5. **Cognitive impairment** 6. Gingival hyperplasia 7. Skin rash 8. ↓ Vit K synthesis 9. **Cardiovascular effects** **PREGNANCY RISK CATEGORY D** Fetal hydantoin syndrome **Drug interactions** **↓ effects** of oral contraceptives and glucocorticoids Dosing: Highly individualized MANY drug interactions - Highly metabolized in liver (interacts with enzyme inhibitors or inducers) - Valproic acid competes for protein binding, which increases free phenytoin Administration: **With food** **Drugs with levels ↓ by phenytoin** -------------------------------------------- Drugs That Affect Phenytoin Concentrations  -------------------------------------------- **[Carbamazepine (Tegretol) ]** **Mechanism of action** Suppresses high-frequency neuronal discharge in/around seizure foci **Uses** Epilepsy Bipolar disorder\ Trigeminal and glossopharyngeal neuralgias **Adverse effects** - Neurologic: Nystagmus and ataxia - **Hematologic effects** **Birth defects** **Hyponatremia** **Dermatologic effects** **Drug-drug & drug-food interactions** - Hepatic drug-metabolizing enzymes increased - Decreases effectiveness of - **Warfarin** - **Carbamazepine level ↓ by Phenytoin** - **Grapefruit juice increases drug level** - **MANY drug interactions** **[Valproic Acid (Depakene, Depakote, Depacon) ]** **Mechanism of action** Suppresses high-frequency neuronal firing through blockade of sodium channels Suppresses calcium influx\ May augment inhibitory influence of GABA **Therapeutic uses** - First line drug for\ Seizure disorders - Migraine headache **Adverse effects** Gastrointestinal effects\ **Hepatotoxicity\ ** Pancreatitis\ **Teratogenic: PREGNANCY CATEGORY D** Hyperammonemia **Drug interactions** - Phenobarbital - Phenytoin - Topiramate - Carbapenem Antibiotics **Metabolism** - Extensive hepatic metabolism - **EXTREME CAUTION IN PATIENTS WITH LIVER DISEASE** **[Ethosuximide \[Zarontin\] ]** - Drug of choice for **absence seizures** - Suppresses neurons in the thalamus that are responsible for generating absence seizures - Generally devoid of significant adverse effects and interactions - Initially may cause drowsiness, dizziness, and lethargy - KINETICS\ Hepatic metabolism **[Phenobarbital ]** **Actions** ▪Reduces seizures without causing sedation **Uses** ▪Epilepsy (partial and generalized tonic-clonic seizures) ▪Sedation/Induction of sleep **Kinetics** ▪Very long half-life (\~4 days): 2-3 weeks to reach plateau **Adverse effects** - ❑ Neuropsychologic effects - ❑ Dependency - ❑ Exacerbation of intermittent porphyria - ❑ Rickets and osteomalacia - ❑ Nystagmus - ❑ Ataxia - ❑ decrease synthesis of vitamin K-- dependent clotting factors and can thereby cause *bleeding tendencies in newborns.* Phenobarbital Induces hepatic enzymes Drug interactions **Decreased** effectiveness Oral contraceptives Warfarin - Effects of CNS depressants are intensified - Valproic acid **INCREASES** phenobarbital by \~40% \*Drug withdrawal ↓ phenobarbital slowly  **[Primidone \[Mysoline\] ]** Active against all major seizure disorders except absence seizures Nearly identical in structure to phenobarbital Adverse effects similar to phenobarbital Drug interactions similar to phenobarbital page32image37420272 **[NEWER ANTIEPILEPTIC DRUGS ]** Oxcarbazepine (Trileptal) Lamotrigine (Lamictal) Gabapentin (Neurontin) Pregabalin (Lyrica)\ Levetiracetam (Keppra) Topiramate (Topamax) +-----------------------------------+-----------------------------------+ | Oxcarbazepine \[Oxtellar XR, | Indicated for monotherapy and | | Trileptal\] | adjunctive therapy of partial | | | seizures in **adults and | | | children** | | | | | | Antiseizure effects: | | | Voltage-sensitive sodium channels | | | in neuronal membranes blocked, | | | hyperexcitable neurons | | | stabilized, and seizures | | | suppressed | +-----------------------------------+-----------------------------------+ **[Oxcarbazepine \[Oxtellar XR, Trileptal\]]** **Adverse effects** Dizziness, drowsiness, double vision, nystagmus, headache, nausea, vomiting, and ataxia Clinically significant hyponatremia (\< 125 mmol/L) Stevens-Johnson syndrome (SJS)\ Toxic epidermal necrolysis **Drug interactions** - Induces some hepatic enzymes, inhibits others - ↓ effectiveness of **Oral contraceptive pills** - **Raises levels** of phenytoin (i.e., toxicity) - Alcohol intensifies effect of oxcarbazepine - **EXTREME caution with diuretics** **Lamotrigine (Lamictal)** +-----------------------------------------------------------------------+ | Therapeutic use | +=======================================================================+ | Broad spectrum of antiseizure activity | | | | Bipolar disorder | +-----------------------------------------------------------------------+ +-----------------------------------------------------------------------+ | Adverse effects | +=======================================================================+ | - dizziness, diplopia, blurred vision, nausea, vomiting, and | | headache | | | | - Severe skin reactions | | | | - Aseptic meningitis | | | | - Risk for suicide | | | | - Cleft Palate risk in pregnancy | +-----------------------------------------------------------------------+ **[Gabapentin (Neurontin, Gralise) ]** **Therapeutic use: Adjunctive therapy of partial seizures** **Off-label use:** Neuropathic pain, prophylaxis of migraine, treatment of fibromyalgia, & relief of postmenopausal hot flashes Drug interactions None described Adverse reactions **[Pregabalin \[Lyrica\] ]** - Adjunctive therapy of partial seizures - Analog of GABA - **Other Uses**:\ Neuropathic pain associated with diabetic neuropathy Postherpetic neuralgia Fibromyalgia - **Adverse effects**: Dizziness, somnolence, blurred vision, significant weight gain, difficulty thinking, headache, peripheral edema, and dry mouth - Hypersensitivity reactions: Life-threatening angioedema - Possible Rhabdomyolysis - Some Abuse potential/Physical dependency - Drug interactions\ alcohol, opioids, benzodiazepines and other CNS depressants may intensify effect +-----------------------------------+-----------------------------------+ | Levetiracetam | Unique agent that is chemically | | | and pharmacologically different | | (Keppra) | from all other AEDs | | | | | | Mechanism of action: not well | | | described | | | | | | Adverse effects: Mild to | | | moderate; notably mood changes | | | | | | Drug interaction: Does not | | | interact with other AEDs | +===================================+===================================+ | Topiramate | **Therapeutic use:** | | | | | \[Topamax\] | Seizures, bipolar disorder, | | | cluster headaches, neuropathic | | | pain, diabetic neuropathy, | | | infantile spasms, essential | | | tremor, binge-eating disorder, | | | bulimia nervosa, and alcohol and | | | cocaine dependence | | | | | | **Adverse effects:** | | | | | | Somnolence, dizziness, ataxia, | | | nervousness, diplopia, nausea, | | | anorexia, weight loss, memory | | | difficulties, altered thinking, | | | reduced concentration, kidney | | | stones, paresthesias, **metabolic | | | acidosis**, angle- closure | | | glaucoma, and risk for suicide | +-----------------------------------+-----------------------------------+ Management of Generalized Convulsive Status Epilepticus **Goals of treatment\ ** 1. Maintain ventilation 2. Correct hypoglycemia 3. Terminate seizures ❑ Diazepam may be used if lorazepam unavailable Initiate or continue long-term suppression drugs -------------------- Pregnancy and AEDs -------------------- **The risk to a fetus from uncontrolled seizures is greater (generally) than the risk from AEDs.** **Important considerations** Use lowest dose possible\ Use one drug when possible\ To reduce risk of neural tube defects→ supplement with folic acid\ To reduce the risk of bleeding, supplement with Vitamin K during last weeks of pregnancy\ Give infant Vit K immediately after delivery Drugs for Muscle Spasm and Spasticity - Chapter 28 Drugs for Muscle Spasm and Spasticity 1. Two groups of drugs that cause skeletal muscle relaxation ▪One group for localized muscle spasm ▪One group for spasticity 2. Most drugs (except dantrolene) produce effects through actions in CNS 3. **Groups are not interchangeable** +-----------------------------------+-----------------------------------+ | Muscle Spasm | **Muscle spasm**: **Involuntary | | | contraction of muscle** or muscle | | | group | | | | | | Causes | | | | | | | | | -------------- ---------------- | | | -- ------------------------------ | | | --------- ----------------------- | | | ----------------------- | | | **Epilepsy** **Hypocalcemia** | | | **Pain syndromes: acute and ch | | | ronic** **Trauma: Localized ske | | | letal muscle injury** | +===================================+===================================+ | Muscle | **Treatment of spasm\ | | | ** Physical measures | | Spasm | | | | Immobilization of affected | | | muscle | | | | | | Heat application for spasm \* | | | | | | Whirlpool baths\ | | | Physical therapy | | | | | | Drug therapy | | | | | | Analgesic, anti-inflammatory | | | | | | Acetaminophen, and NSAIDS | | | | | | Centrally Acting Muscle | | | relaxants | | | | | | cyclobenzaprine, tizanidine etc | | | | | | **\*Cold compress is used only to | | | reduce swelling following injury, | | | not to relieve spasm.** | +-----------------------------------+-----------------------------------+ **Centrally Acting Muscle Relaxants** **Therapeutic use** 1. Relief of localized spasm caused by muscle injury 2. Can decrease local pain and tenderness 3. Can increase range of motion **Adverse effects** 1\. Generalized CNS depression 2\. Hepatic toxicity Tizanidine \[Zanaflex\] and metaxalone Chlorzoxazone \[Paraflex\] can cause hepatitis and necrosis 3\. Serotonin Syndrome Cyclobenzaprine **Physical dependence** Abstinence syndrome +-----------------------------------+-----------------------------------+ | Spasticity | **Spasticity** | | | | | | **CNS movement disorders\ | | | ** Multiple sclerosis & | | | cerebral palsy most common | | | | | | **Characteristics\ | | | ** 1. Heightened muscle tone | | | | | | 2\. Spasm\ | | | 3. Loss of dexterity | | | | | | **Three Drugs for Spasticity\ | | | ** 1. Baclofen \[Lioresal\]: Acts | | | in the CNS | | | | | | 2\. Diazepam \[Valium\]: Acts in | | | the CNS\ | | | 3. Dantrolene \[Dantrium\]: | | | Acts on skeletal muscle | +-----------------------------------+-----------------------------------+ **[Baclofen (Lioresal) ]** **Mechanism** 1. Oral and intrathecal (instilled in the CSF) 2. **Acts in the spinal cord** 3. **Suppresses hyperactive reflexes** 4. Mechanism unknown 5. May mimic the action of GABA on spinal neurons **Therapeutic uses** Baclofen (Lioresal) - No antidote for overdose - Gradual withdrawal over 1 to 2 weeks - **Abrupt intrathecal withdrawal: Risk for rhabdomyolysis** **Adverse effects** **[Dantrolene (Dantrium) ]** +-----------------------------------------------------------------------+ | **Mechanism** | +=======================================================================+ | Acts directly on skeletal muscle | | | | Suppresses the release of calcium from the sarcoplasmic reticulum | +-----------------------------------------------------------------------+ **Therapeutic uses** **Spasticity** associated with multiple sclerosis, cerebral palsy, and spinal cord injury **Malignant hyperthermia** Potentially fatal condition caused by succinylcholine & general anesthetics **Adverse effects** 1. **Hepatic toxicity** 2. **Muscle weakness** **3. Drowsiness** **4. Diarrhea** page12image51335552 +-----------------------------------+-----------------------------------+ | **[Diazepam (Valium) | 13 | | ]** | | | | | | Benzodiazepine (Schedule IV)\ | | | ✓Only muscle relaxant labeled to | | | treat spasticity | | | | | | Mechanism\ | | | ✓Acts in CNS\ | | | ✓Mimics action of GABA | | | | | | Adverse effect | | | | | | ✓Sedation | | | | | |  | | +-----------------------------------+-----------------------------------+ **[CHAPTER 109 -- Drugs for the Eye Conditions and Diseases]** **GLAUCOMA** - Visual field loss secondary to optic nerve damage - Leading cause of preventable blindness in the United States - Of the 4 million Americans with glaucoma, only 50% are diagnosed - 90% could have saved their sight with timely treatment - Forms - Primary open-angle glaucoma (POAG) - Acute angle-closure glaucoma **AQUEOUS HUMOR** - Produced in ciliary body - Secreted into posterior chamber of the eye - Circulates around the iris into the anterior chamber - Exits the anterior chamber via the trabecular meshwork and the canal of Schlemm **PRIMARY OPEN-ANGLE GLAUCOMA** - Characteristics - Most common form of glaucoma in the United States - Progressive optic nerve damage, with eventual impairment of vision - Devoid of symptoms until significant and irreversible optic nerve injury has occurred - Treatment - Directed at reducing elevated IOP (the only modifiable risk factor) - Principal method: Chronic therapy with drugs **DRUG THERAPY FOR GLAUCOMA** - Drugs lower IOP by: - Facilitating aqueous humor outflow - Reducing aqueous humor production - Preferred route: Topical - Systemic effects relatively uncommon - Combined therapy more effective than monotherapy - If drugs are ineffective, surgical intervention is needed to promote outflow of aqueous humor - Laser trabeculoplasty - Trabeculectomy - First line - Beta-adrenergic blocking agents - Timolol - Alpha~2~-adrenergic agonists - Brimonidine \[Alphagan\] - Prostaglandin analogs - Latanoprost \[Xalatan\] - Second line - Cholinergic agonists - Carbonic anhydrase inhibitors - Beta blockers \[timolol\] - Alpha~2~ agonists \[brimonidine\] - Prostaglandin analogs \[latanoprost\] **ANGLE-CLOSURE GLAUCOMA** - Also known as *narrow-angle glaucoma* - Precipitated by displacement of the iris, which prevents the exit of aqueous humor - Develops suddenly and is extremely painful - No treatment; irreversible loss of vision in 1 to 2 days - Much less common than open-angle glaucoma - Treatment - Drug therapy - Corrective surgery - Laser iridotomy - Iridectomy **BETA-ADRENERGIC BLOCKING AGENTS** - Approved for use in glaucoma: Betaxolol, carteolol, levobunolol, metipranolol, and timolol - Lower IOP by reducing production of aqueous humor - Used primarily for open-angle glaucoma - Initial therapy and maintenance therapy - Adverse effects - Local: Usually minimal - Systemic: Heart and lungs if absorbed in sufficient amounts (bradycardia, bronchospasm) - Cardioselective agent (betaxolol) recommended for asthma patients **PROSTAGLANDIN ANALOGS** - Latanoprost - Travoprost - Bimatoprost - Tafluprost - Latanoprost - Lowers IOP by facilitating aqueous humor outflow - As effective as beta blockers, with fewer side effects - Can cause harmless brown pigmentation of the iris **ALPHA2-ADRENERGIC AGONISTS** - Two agents approved for use - Apraclonidine: Only for short-term therapy - Lowers IOP by reducing aqueous humor production and possibly by increasing outflow - Does not cross blood-brain barrier and therefore does not promote hypotension - Brimonidine \[Alphagan\]: First-line drug for long-term therapy - Common side effects - *Combigan*: 0.2% brimonidine and 0.5% timolol - Treatment: 1 drop applied to affected eye twice daily (about every 12 hours) - Benefits and adverse effects are about equal to those seen when the two drugs are applied separately **PILOCARPINE** - Direct-acting cholinergic agonist that causes: - Miosis - Contraction of the ciliary muscle - Now considered a second-line drug for open-angle glaucoma - Emergency treatment of acute angle-closure glaucoma - Adverse effects - Retinal detachment - Decreased visual acuity - Local irritation, brow pain, and eye pain - Systemic effects **CHOLINESTERASE INHIBITOR** - Echothiophate (phospholine iodide) - Long duration of action - Inhibits the breakdown of acetylcholine (ACh), promotes accumulation of ACh at muscarinic receptors - Effect on eye: Miosis, focusing of the lens for near vision, reduction of IOP - No longer a first-line drug - Adverse effects - Myopia: absorption into the system can cause parasympathomimetic responses - Cataracts - Dorzolamide \[Trusopt\] topical - Reduces IOP by decreasing production of aqueous humor - Generally well tolerated: Ocular stinging, bitter taste, allergic reaction in 10% to 15% of patients - Acetazolamide and methazolamide: Systemic CAIs - Adverse effects - Nervous system, teratogenic, acid-base disturbances, electrolyte imbalances - Netarsudil, a rho Kinase Inhibitor **CYCLOPLEGICS and MYDRIATICS** - Cycloplegics: Paralyze ciliary muscles - Mydriatics: Dilate the pupil - Uses - Adjunct to measurement of refraction - Intraocular examination - Intraocular surgery - Treatment of anterior uveitis - Adverse effects - Blurred vision and photophobia - Precipitation of angle-closure glaucoma - Systemic effects - Phenylephrine: Adrenergic agonist - Mydriatic agent (pupil dilation) - Does not cause cycloplegia - Adverse effects **ALLERGIC CONJUCTIVITIS** - Inflammation of the conjunctiva in response to an allergen - Seasonal or perennial - Itching; burning; thin, watery discharge - Results from biphasic immune response - Symptoms peak 20 minutes after allergen exposure, abate 20 minutes later, reappear after 6 hours - Mast-cell stabilizers - H~1~-receptor antagonists - Nonsteroidal anti-inflammatory drugs (NSAIDs) - Glucocorticoids (short term) - Ocular decongestants **AGE-RELATED MACULAR DEGENERATION** - Painless, progressive disease that blurs central vision and limits perception of fine detail - Dry ARMD: *Drusen* (yellow deposits under the retina) - Wet (neovascular) ARMD: Growth of new subretinal blood vessels, which are often fragile and leaky; fluid leakage lifts the macula from its normal place, which quickly causes permanent injury - Stages - Early - Intermediate - Advanced - Management of dry ARMD - Antioxidants and zinc, multiple vitamins - Management and treatment of wet ARMD - Laser therapy - Photodynamic therapy - Angiogenesis inhibitors **MANAGEMENT of AGE-RELATED MACULAR DEGENERATION** - Dry - High doses of antioxidants and zinc - Wet - Laser therapy - Photodynamic therapy (PDT) - Angiogenesis inhibitors - Ranibizumab \[Lucentis\] - Aflibercept \[Eylea\] - Bevacizumab \[Avastin\] - Laser therapy - Photodynamic therapy - Verteporfin \[Visudyne\] **ADDITIONAL OPHTHALMIC DRUGS** - Opthalmic demulcents \[Artificial Tears\] - Isotonic solutions: *Polyvinyl* alcohol, cellulose esters - Topical cyclosporine ophthalmic emulsions \[Restasis\]: Suppresses the immune response, promoting resumption of tear production - Ocular decongestants - Weak solutions of adrenergic agonists applied topically to constrict dilated conjunctival blood vessels - Phenylephrine, naphazoline, oxymetazoline, and tetrahydrozoline - Glucocorticoids - Dyes: Fluorescein, rose bengal, lissamine green - Antiviral agents: Trifluridine, vidarabine, ganciclovir, and idoxuridine