Exam 1 Pharm.pdf

Exam 1 Module 1 1. Bonds → the stronger the bond the more effective the medication is Hydrogen – Hydrogen atoms bound to nitrogen or oxygen become more positively polarized allowing them to more negatively polarized atoms such as oxygen, nitrogen, or s...

Exam 1 Module 1 1. Bonds → the stronger the bond the more effective the medication is Hydrogen – Hydrogen atoms bound to nitrogen or oxygen become more positively polarized allowing them to more negatively polarized atoms such as oxygen, nitrogen, or sulfur ++ Covalent – Two bonding atoms share electrons → irreversible bond, if we break the bond, we need energy (other drug, something with effort) Strongest Ionic – Atoms with an excess of electrons (imparting an overall negative charge on the atom) are attracted to atoms with a deficiency of electrons (impairing an overall positive charge on the atom) +++ Van der Waals – Shift electron density in areas of molecule, or in a molecule, results in the generation of transient positive or negative charges – these areas interact with transient areas of opposite charge on another molecule → Weakest, 2 electrons shifting in the same space 2. Pharmacodynamics – What the drug does to the body Pharmacokinetics – What the body does to the drug (ADME) 3. Pharmacodynamics Therapeutic window – The range of drug dosages which can treat disease effectively without having toxic effectives Effective window (ED 50) – Effective dose at which 50% of population experiences the therapeutic effects Toxic Dose (TD 50) – Toxic dose at which 50% of the population experiences the toxic effect Lethal Dose (LD 50) – Lethal Low TI = small therapeutic – TD is not much greater than 50 Therapeutic Index (TI) – Numerical ratio that compares the dose of a drug that produce a therapeutic effect (ED 50) to the dose that causes toxicity (TD 50) → A higher TI indicates a safer drug. TI = TD50/ED50 Want a higher TI for low toxicity and high efficacy → large window High TD and low ED we will get a narrow window High TI = wide therapeutic window – TD is much greater than ED 4. Full agonist – A substance that binds to a receptor causing maximal change in cellular activity of a target and stabilize DR* (receptor in its active conformation → promotes continuing signaling and cellular responses) Partial agonist – Activates a receptor without maximal efficacy and stabilizes DR and DR* (stabilize both the inactive and active state – they can balance the activity of the receptor) 5. Inverse Agonist – Inactivates free active receptors and stabilizes DR in the case of R* (stabilizes the active conformation of the receptor (DR), shifting the balance away from the active state (DR*) leading to decreased signaling through the receptor)  Competitive Antagonist – Reversible binding that blocks agonist at active or allosteric site and stabilize DR, preventing DR* (only stabilize the inactive state by preventing activation) Noncompetitive Antagonist – Irreversible binding blocks agonist at active or allosteric site and stabilizes DR and prevents DR* 6. Hydrophilic drugs: “Water loving”/water soluble Polar, usually ionized Renal excretion Requires transport mechanism to cross cell membranes and BBB Forms H+ bonds Hydrophobic drugs: “Fat-loving”/water insoluble Lipophilic Passively diffuses across cell membrane and BBB Non-polar, usually not ionized 7. Ion channel Linked to intracellular G protein Enzyme within cytosolic domain Extracellular (Intra/extra) All this impact how the medication affects that receptor or that cell. And what is required to have molecules do its work with that medication *LOOK AT OMOSIS* 8. Absorption: Concentration: Higher concentration = greater absorption Circulation at the side of absorption Increased blood flow, local massage, local application of heat enhances absorption Decrease blood flow, vasoconstrictor agents, shock, or other disease factors slow absorption Drug solubility Drug Solubility → If its not soluble and it doesn’t break up, it’s not going to where it needs to go Extent of dissolution Rate of dissolution Surface area → Different types of types of those body systems are going to affect the absorption of the drug, e.g. thin skin = altered absorption of drug (faster) Pulmonary alveolar epithelium – max. gas exchange due to alveoli as they go through the blood stream due to the thinness and rich blood supply Intestinal mucosa – Have microvilli, the pH, food intake, formulation of a drug  Extensive application to skin Distribution: Blood flow Protein binding → Drugs tend to bind to plasma proteins (albumin), changes in the protein levels or binding affinity can affect free (active) drug concentrations Tissue barriers Volume of distribution (Vd) → Factors that alter body composition (obesity, edema, dehydration) can influence Vd, e.g. a larger Vd can lead to lower plasma concentration of a drug as this is crucial for relationship for dosing considerations as it influences the effectiveness and safety of drug therapy pH and ionization → The degree of ionization of a drug at physiological pH can affect its ability to cross membranes. Weak acids and bases may become trapped in compartments where pH favors their ionized forms Drug interactions Pathological conditions Metabolism: CYP405 induction → Drug A is metabolized by CYP450 as Drug B induces CYP450 = increases metabolisms of Drug A and be quickly excreted Increased transcription or translation Decreased degradation Induction by another drug or autoinduction CYP450 inhibition → Drug A is metabolized by CYP450, but Drug B inhibits the enzyme, whatever subgroup it might be and therefore you get a buildup of Drug A Incidental or deliberate – We want to have more of Drug A available as this can be due to giving another drug with knowledge that is going to inhibit the metabolization of the other drug we are giving, adverse effect Competitive inhibition Irreversible inhibition Genetics “Slow-acetylator” phenotype Race and ethnicity CYP450 2D6 is nonfunctional in 8% of Caucasians Age and gender Lack of UDPGT in neonates Diet Grapefruit juice – Affects CIP45 enzymes Disease states Liver disease, cardiac disease Excretion: Renal Impairment  Hepatic Impairment Altered Urinary pH → pH of urine can affect the ionization of drugs, influencing their reabsorption or excretion, e.g., acidic drugs are more likely to be reabsorbed in acidic urine while basic drugs may be more effectively excreted Drug interactions → Certain drugs can inhibit renal transporters responsible for drug secretion, leading to increased plasma concentrations of affect drug Physiological Factors Genetic Factors Pathological conditions 9. First-pass metabolism is the process by which a drug is metabolized in the liver after it is absorbed from the GI tract but before it reaches systemic circulation → Can reduce the bioavailability (the extent and rate at which the active moiety (drug or metabolite) enters the systematic circulation). When a drug is taken orally, it is absorbed into the portal circulation and transported to the liver, where enzymes may metabolize it. As a result, a portion of the drug may be inactivated before it reaches the systemic circulation. Reduced bioavailability and dosing considerations (we might need higher doses to achieve therapeutic levels) Administration for High First-Pass effects: Sublingual/Buccal – Avoid the liver and go directly to the blood stream IV Transdermal Rectal 10. Volume of distribution → Volume of fluid required to contain the total amount of drug absorbed in the body at uniform concentrations equal to that in the plasma steady state Low Vd = retained within vascular compartment = high protein binding High Vd = highly distributed into nonvascular compartment = low protein binding Factors that influence Vd: Physicochemical properties Plasma protein binding → Drugs that bind extensively to plasma proteins will have a lower Vd as less free drug is available to distribute to tissues Tissue binding Physiological factors Drug formulation 11. Cholinergic Agents – Drugs that stimulate PNS by mimicking the action of ACh or increasing its availability. They can directly activate cholinergic receptors (muscarinic or nicotinic) or inhibit the enzyme acetylcholinesterase, leading to increased levels of ACh. Anticholinergic Agents – Drugs that block the action of ACh at muscarinic or nicotinic, inhibiting the PNS.  Effects Cholinergic Agents Anticholinergic Agents Heart Rate Decreased (bradycardia) Increased (tachycardia) Bronchial Effects Bronchoconstriction Broncho vasodilation GI Increased motility, Decreased motility, secretions secretions Urinary Increased urinary Decreased urinary urination urination = RENTENTATION Ocular Miosis (constriction) Mydriasis (dilation) Neuromuscular Increased muscle Reduced contractions contraction 12. Alpha agonists – Drugs that stimulate alpha-adrenergic receptors, primarily found in the SNS Alpha 1 - Agonists: Activates alpha-1 receptors leading to vasoconstriction Alpha 2 - Agonists: Activates alpha-2 receptors, often leading to decreased norepinephrine release and reduced sympathetic outflow Beta agonists - Drugs that stimulate beta-adrenergic receptors, which are also part of the SNS Beta - 1 Agonists: Primarily stimulate beta -1 receptors in heart = increasing HR and contractility Beta – 2 Agonists: Primarily stimulate beta -2 receptors = smooth muscle relaxations (e.g. bronchi) Feature Alpha Agonists Beta Agonists Receptor targets Alpha 1 and 2 Beta 1 and 2 Primary Effects Vasoconstriction, Increased HR and increased BP (alpha -1), contractility (beta -1) and sedation (alpha -2) bronchodilation (beta-2) Cardiovascular Increased BP, possible Tachycardia (beta -1) bradycardia (alpha-1) Respiratory Minimal effects Bronchodilation (beta -2) Metabolic Minimal Increased glycogenolysis lipolysis (beta-2) CNS Effects Sedation (alpha-2) Typically, minimal CNS effects Clinical Use Hypotension, nasal Asthma/COPD (albuterol, congestion dobutamine for HF) (phenylephrine, clonidine) 13. Direct-acting sympathomimetics are drugs that directly stimulate adrenergic receptors, which are part of the SNS. These receptors include Alpha 1 and 2 and Beta 1, 2, and 3. Module 2 1. Pharmacogenetics – the study of variability of a drug response due to genetic factors comparing to pharmacogenomics which is the study of effects of the genetic differences among people and the impact that these differences have on the update, effectiveness toxicity, and metabolism of drugs 2. Polymorphisms – Chemical compound crystallizes into different forms with different internal structure. This affects the drugs properties. It can result in ultrarapid metabolizers (think about if you were to give 2 drugs together & drug B causes drug A to be more quickly metabolized), extensive (normal) metabolizers, and poor metabolizers (think if drug B inhibited the metabolism of drug A). We are not taking about drugs interacting with each other, we are talking about the physical enzymes that pt has because of SNP and polymorphism. 3. Ultrarapid metabolizers – Have increased enzyme activity, leading to faster drug clearance. This may reduce drug levels, leading to therapeutic failure as the drug may be eliminated before it can exert its effects → require a higher dosage Poor metabolizers – Have reduced or absent enzyme activity, leading to slower drug clearance. This can cause drug accumulation, increasing the risk of toxicity and ADRs → require a lower dosage Extensive (normal) metabolizers – Have normal enzyme activity due to the presence of functional alleles in genes responsible for drug metabolism → process drugs at a normal rate, which means drug levels in the body typically fall within the expected therapeutic range when given standard doses 4. FDA has retired the A, B, C, D, X system and have come up with the system of Pregnancy and Lactation Labeling Rule (PLLR). It is divided into 3 sections (Pregnancy, lactation, and Females and Males of Reproductive potential). Within the pregnancy section, it provides potential effects of the drug such as, fetal risk summary, clinical considerations and data. With the lactation section, it provides information on the use of a drug during breastfeeding including, the amount of drug that is excreted in BM, potential effects on the infant that is breastfeeding, and any precautions or recommendations for breastfeeding mothers (avoidance of certain drugs and adjusted doses). With the females and males of the reproductive potential, it includes information on pregnancy testing, contraception, and fertility considerations for individuals of reproductive age who may be exposed to the drug and highlights any effects of the drug on fertility or risks related to reproductive health. 5. Pediatric Calculations: Convert pounds to kg Calculate the total daily dose in mg Divide the dose by the daily frequency Convert the mg dose to mL 6. Drug Burden Index (DBI) – A risk assessment tool that measures the drug burden of anticholinergic and sedative medications. It measures the effect of dose-related cumulative exposure to both anticholinergic and sedative medications on physical and cognitive function. The scoring is 0-1. 𝐷 𝐷𝐵𝐼 = 𝑀𝑖𝑛𝐸𝐷+𝐷 D= daily dose of the medication Min ED= the minimum effective dose of the drug for its indication The totally DBI is the sum of the individual DBIs for each drug a pt is taking  Pts who has a high of DBI (elderly) have an increased risk for: Cognitive Decline Increased falls and fractures Functional decline Increased hospitalizations Delirium Reduced quality of life Mortality To lower DBI it is important to do medication review deprescribe, and use non- pharmacologic interventions 7. The process of describing is: Review current medications Identify potentially inappropriate medications Prioritize medications for discontinuation (start with the one that has highest adverse effects) Develop a plan for discontinuation (tapering) Monitor for withdrawal or adverse effects Communicate with the patient 8. Obesity WHO Classification of BMI BMI (𝒌𝒈/𝒎𝟐) Underweight 500) Reporting and documenting High Risk of: Agranulocytosis Anticholinergic, sedatives, cardiac and hypotensive properties Bone marrow suppression Seizures Many drug interactions, mostly with CYP1A2 and CYP3A4 Also interacts with cigarette smoking – Reduce dose by 30-40% in pts who quit or are forced to be in nonsmoking environments, to account for that lack of drug interactions 5. Benzodiazepines – class of psychoactive drugs used for their sedative, anxiolytic (anti- anxiety), muscle relaxant, and anticonvulsant properties. They act on the CNS by enhancing the effect of the neurotransmitter GABA, which inhibits neuronal activity, leading to a calming effect MOA: Bind to GABA-A receptors in the brain which increases the effect of GABA, the major inhibitory neurotransmitter which results in reduced neuronal excitability, sedation and relaxation, anxiolysis, muscle relaxation, and anticonvulsant effects. Time frame: 48 hrs for short acting and 3 weeks for long acting Typical symptoms of benzodiazepine withdrawal are: Anxiety  Confusion Insomnia Irritability N/V Seizures 6. Nonbenzodiazepines hypnotics – Known as Z-drugs, which are a class of medications that is used primarily to tx insomnia. They act on the same GABA-A receptors in the brain as benzodiazepines, their chemical structure is different, and they are often preferred due to their perceived lower risk of dependence and fewer SE. Three categories: GABA MOA: Reduce the neuronal excitability throughout the nervous system by binding to GABA receptors, A and B. When GABA binds to GABA – A receptors, it causes an opening of chloride channels, the influx of this ion into the neuron causes hyperpolarization of the cell membrane, making the neuron less likely to fire an AP AE: Sedation, cognitive impairment, motor impairment, respiratory depression, dependance and tolerance, withdrawal symptoms, paradoxical reactions Melatonin receptors agonists MOA: Work by binding to MT1 and MT2 receptors in the brain, particularly the suprachiasmatic nucleus (SCN) of the hypothalamus, which is involved in regulating circadian rhythms. MT1 promotes sleep onset by reducing the neuronal activity associated with wakefulness and MT2 helps synchronize circadian rhythms and plays a role in timing of sleep and wake cycles AE: Drowsiness, dizziness, HA, nausea, hormonal effects, vivid dreams or nightmares, allergic reactions Orexin receptor antagonists MOA: Orexin is a neuropeptide that promotes wakefulness and arousal by binding to OX1 and OX2 in the brain. OX1 regulates reward and arousal and OX2 is directly linked to promoting wakefulness. Orexin receptor antagonists block the binding of orexin to these receptors,  preventing the wake-promoting effects of orexin. This results in increased sleepiness and helps with the initiation and maintenance of sleep. AE: Daytime drowsiness, HA, abnormal dreams, sleep paralysis, nightmares, complex sleep behaviors, worsening depression, dependence and bise potential PK: rapidly absorbed and have a short half- life → making them ideal to take before bed knowing they will wear off in the morning 7. Triptans – Used to abort and stop migraines that started and cluster headaches. MOA: Acts as a 5HT receptor, specially at 5-HT1B and 5-HT1D receptors found in blood vessels and nerve terminals in the brain. They vasoconstriction of dilated blood vessels in the brain, which is believed to relieve migraine pain. During a migraine, the dilation of blood vessels may trigger pain pathways. They also, inhibit the release of pro-inflammatory neuropeptides, such as, substance P and calcitonin gene-related peptide (CRGP) which plays a major role in migraine pathology. They also, block the transmission of pain signals along the trigeminal nerve, which is involved in migraine attacks. Indications: cluster of headaches and acute migraine attacks Contraindications: CAD → risk of coronary artery vasospasm Cerebrovascular disease Basilar or hemiplegic migraine Ischemic bowel Pregnancy PVD Uncontrolled HTN Do not use: Within 24 hrs of taking ergotamine derivatives → increased vasospasm risk Within 2 weeks of taking a MAOI AE: Serious: Coronary vasospasm MI Ventricular arrhythmias Subarachnoid hemorrhage Serotonin Syndrome Common: Dizziness Nausea Jaw or neck pain Hot or cold sensation  Dry mouth Chest pain Diaphoresis Vertigo Ergots – Class of medication derived from the fungus Claviceps purpurea. They are primarily used for acute treatment of migraine and cluster HA MOA: Binds to 5Ht-1b/d receptors o Vasoconstricts and decreases amplitude or pulsatility in the extracranial arteries o Does NOT alter perfusion in the basilar artery distribution or hemispheric blood flow Indications: o Acute migraine attacks o Cluster HA o PP Hemorrhage o Vasospastic disorders Contradictions: o CAD o HTN o PVD o Pregnancy o Lactation o Severe renal or hepatic disease o Caution: ▪ Elderly ▪ Cardiac disease risk ▪ Valvular heart disease Do Not Use: o Within 24 hrs of taking ergotamine derivatives → Increased vasospasm risk o Within 2 weeks of taking an MAOI CAUTION: SERIOUS OR LIFE-THREATENING PERIPHERAL ISCHEMIA CAN OCCUR WHEN TAKEN IN COMBINATION WITH POTENT 3A4 INHIBITORS → can increase ergotamine levels and increase risk for vasospasm and are contraindicated in pts taking ergotamine AE: o Serious: ▪ Coronary vasospasm ▪ MI ▪ Ventricular arrhythmias ▪ Subarachnoid hemorrhage ▪ Stroke ▪ Gangrene  ▪ Intestinal Ischemia o Common: ▪ Dizziness ▪ N/V, diarrhea ▪ Flushing ▪ Dyspnea ▪ Paresthesia ▪ Diaphoresis ▪ Rash ▪ HTN 8. Hydantoins – First line tx for tonic-clonic and partial complex seizure. It is the least sedating and hypersensitive. SODIUM CHANNEL INHIBITOR MOA: Inhibiting the sodium channels in neuronal membranes. This stabilization of the neuronal membrane prevents the rapid firing of neurons that can lead to seizures. It prevents the spread of seizure activity in the brain. BBW: Severe cardiovascular events → Faster you give the med, the more likely to cause life-threatening hypotension (with phosphatidines, you can avoid that) Indications: Tonic-clonic and partial complex seizure Contraindications: Hypersensitive, Heart block, pregnancy AE: Common: Gingival hyperplasia dizziness and drowsiness N/V Rash Serious: SJS Toxicity CV effects Succinimides – treat absence seizures, a type of generalized seizure that is characterized brief episodes of staring and unresponsiveness MOA: Reduce the activity of T-Type calcium channels in thalamic neurons. These channels play a role in the generation of the abnormal electrical activity seen in absence seizure. They reduce calcium influx to prevent the hyperexcitability of the neurons. They decrease nerve impulses and transmission to motor cortex Indications: Absence seizures Contraindications: Hypersensitivity and Sever liver or kidney damage AE: o Common: ▪ GI distress ▪ drowsiness and fatigue ▪ Dizziness and HA  ▪ Weight loss o Serious: ▪ Blood dyscrasias → cause bone marrow suppression leading to leukopenia and thrombocytopenia ▪ SLE ▪ Psychiatric effects o Caution: Can interact with other seizure medications = altering their serum levels and may affect or be affected by other drugs processed through the CYP450 enzyme system o Monitor CBC and hepatic/renal function tests Carbamazepine - Anticonvulsant and mood-stabilizing drug used to tx various types of seizures as well as certain psychiatric and neurological conditions. They work by stabilizing overactive nerve activity. SODIUM CHANNEL BLOCKER MOA: Inhibiting voltage-gated sodium channels. They stabilize hyperexcited nerve membranes, reducing repetitive neuronal firing, and decreases the propagation of abnormal electrical discharges in the brain. By doing this it indirectly affects the neurotransmitter release, which helps prevent seizures and stabilize mood in psychiatric disorders. Indications: Focal (partial) seizures, generalized tonic-clonic seizures, bipolar disorder, trigeminal neuralgia, neuropathic pain Contraindications: Hypersensitivity, bone marrow suppression, HLA-B*1502 alle (Asian descent) Caution: Induces CYP450 enzymes (CYP3A4 and CYP1A2), interaction with other anticonvulsants and grapefruit juice Monitor Serum levels, CBC, Hepatic and Liver function test GABA Agents – Primary inhibitory neurotransmitter system in CNS. GABA reduces neuronal excitability, leading to calming effects on the brain and body. MOA: Acts through different mechanisms. o GABA-A receptor agonism or modulation: Enhance GABA’s action at the GABA-A receptor, leading to increased chloride ion influx, which hyperpolarizes the neuron and decreases its excitability o GABA Reuptake Inhibition: Inhibit the reuptake of GAA into neurons, increasing the availability in the synaptic cleft o GABA Metabolism Inhibition: Inhibit the enzyme GABA transaminase, which is responsible for breaking down GABA, leading to higher levels of GABA in brain o GABA Analogues: Structural analogues of GABA, although they don’t bind directly to GABA receptors but instead modulate calcium channels and indirectly affect GABAergic activity Indications: Seizure disorders, anxiety/panic disorders, sleep disorders, muscle relaxation, alcohol withdrawal, neuropathic pain, movement disorders  Contraindications: Respiratory depression/disorders, alcohol intoxication, severe liver disease, substance abuse, myasthenia gravis, depression, SI, narrow glaucoma, pregnancy and breastfeeding, severe hypotension, CV instability, acute porphyria, hypersensitivity Excreted relatively unchanged in the urine Caution in pts with impaired renal function as they can also develop that Sodium Channel Blockers – Inhibit the influx of sodium ions through sodium channels in neurons and cardic cells. Essential for initiation and propagation of electrical impulses in CNS. These drugs act on neurons to reduce the excitability and are used in tx of seizures and neuropathic pain. MOA: Block the rapid influx of sodium into excitable cells, thus stabilizing the cell membrane and reducing excitability. They reduce the frequency of AP, making them effective in txing seizures and neuropathic pain by inhibiting excessive neuronal firing Indications: Tx various types of epilepsy and neuropathic pain Contraindications: Severe heart disease, liver disease severe bradycardia or heart block, hypersensitivity AE: Cardiac effects (arrhythmias, hypotension, heart block, bradycardia), CNS effects (dizziness, ataxia, drowsiness, tremor, nystagmus, seizure), GI (n/v, constipation, rashes, liver and blood toxicity 9. Parkinson’s disease – Progressive loss of dopaminergic neurons in the substantia nigra. It causes tremors, bradykinesia, motor complications. Lewy body formation in surviving neurons affecting the neurotransmitters in the brain. Drugs that slow down the progression: o Dopaminergic – increases levels of dopamine, stimulate dopamine receptors, or inhibit dopamine degradation in CNS ▪ Types of dopaminergic drugs: Levodopa – Precursor that crosses the BBB and converts to dopamine in nigrostriatal system o Dopamine agonist o Improving motor symptoms o Increased dyskinesias with long term use o SE: N/V, orthostatic hypotension, hallucinations and impulse control disorders Carbidopa – DOPA decarboxylase inhibitor; decreases peripheral conversion of levodopa to dopamine → increases levodopa transported into the brain, decreases the N/V levodopa induced. NO PHARMACOLOGY ACTIVITY IF GIVEN ALONE o Dopamine agonist o Improving motor symptoms o Increased dyskinesias with long term use  o SE: N/V, orthostatic hypotension, hallucinations and impulse control disorders Dopamine Agonists – directly stimulate dopamine receptors in the brain = increasing dopamine levels o E.g. Pramipexole, ropinirole COMT inhibitors – inhibition leads to decrease in conversion of levodopa to 3-O methyldopa in the periphery leading to increased bioavailability and prolonged effects of levodopa, as well as increasing the amount of levodopa that reaches the brain o NO PHARMACOLOGIC ACTIVITY IF GIVEN ALONE o Prolonges the duration of action of levodopa, helping to smooth out motor fluctuations o SE: Abdominal pain, diarrhea (delayed & more common with tolcapone), dyskinesia/hyperkinesia, brown-orange urine discoloration, increased daytime sleepiness, sleep attacks, orthostatic hypotension, rhabdomyolysis o E.g. Entacapone, Tolcapone (associated with liver failure; avoid if ALT/AST > 2 ULN) MAO-B inhibitors – Selective, irreversible MAO-B inhibition leads to decreased dopamine degradation in the brain leading to prolonged effect of levodopa o Monotherapy o Less likely to cause dyskinesia o With L-DOPA, it may need to decrease the L-DOPA dosage o With L-DOPA, may delay motor complications and improve “on” time without troublesome dyskinesia o AE: N/V, HA, orthostatic hypotension, Insomnia (Selegiline) o E.g. Rasagiline, Selegiline (Eldepryl capsule), Selegiline (Zelapar ODT), Safiamide o Anticholinergic – Decrease ACh thus restoring the ACh: dopamine balance as with Parkinson’s disease when dopamine is low, ACh goes up, so this drug balances them ▪ Minimize resting tremors and drooling ▪ Limited use in older pts due to anticholinergic SE ▪ SE: dry mouth, blurred vision, urinary retention, constipation, cognitive impairment, confusion, memory issues ▪ E.g. Benztropine (Cogentin), Trihexyphenidyl (Artane) 10. Alzheimer’s disease – Accumulation of abnormal neuritic plaques and neurofibrillary tangles in the brain. Beta amyloid plaque formation in between neurons, neurofibrillary tangle formation that formed within neuron cells → Tau protein breakdown causes more damage, degeneration of cholinergic neurons, excess glutamate transmission, and cortical atrophy. Cholinesterase inhibitor – used to tx Alzheimer’s disease and other forms of dementia. They work by inhibiting the enzyme, acetylcholinesterase, which breaks down ACh, that plays a role in memory, learning, and cognition MOA: Increase cholinergic concentrations and neurotransmission through inhibition of acetylcholinesterase (think: KEEPING THINGS ROUND BY SHUTTING THAT ENZYME DOWN) Effects are dose-dependent and doses should be titrated to maximum- tolerated dose Warning/Precautions: Dizziness, syncope Bradycardia, arrhythmias PUD, GI bleed N/V, diarrhea, anorexia, weight loss Insomnia, vivid/abnormal dreams, nightmares Drug interactions: Anticholinergic medications – They fight with each other, counteracting leading to a decrease efficacy of cholinesterase inhibitor Amiodarone, beta-blockers, diltiazem, verapamil – may worsen bradycardia Cholinergic medications – may have synergistic effects that will worsen SE and won’t increase efficacy or improvement NSAIDs – Increase risk of GI bleed Examples: Donepezil (Aricept) o Mild to serve dementia due to AD o DO NOT CRUSH 23 mg TABLET AS IT WILL INCREASE RATE OF ABSORPTION Rivastigmine (Exelon, Exelon patch) Mild to severe dementia due to AD (pill and patch) Patch → Hepatic impairment, LBW (