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49 Cards in this Set
- Front
- Back
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Describe the pathophysiology of Parkinson’s disease, including the dysfunction of the basal ganglia and the anatomical connections involved.
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SUBSTANTIA NIGRA PARS COMPACTA degenerates along with it’s ability to produce DOPAMINE. This leads to an OVERACTIVITY of the INDIRECT PATHWAY. Indirect pathway INCREASES the activity of GLOBUS PALLADUS and SUBSTANTIA NIGRA PARS RETICULAE. This leads to increased INHIBITION of the THALAMUS and REDUCED EXITATORY INPUT to the MOTOR CORTEX.
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MOA of levodopa
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A prodrug which is converted to dopamine, which interacts with dopamine D-2 receptors located on neuronal cell bodies in the striatum and on the presynaptic terminals of dopaminergic nigrostriatal axons. Peripheral effects from dopamine and other metabolites also occur.
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MOA of Sinemet
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same as levo-dopa
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carbidopa
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decarboxylase inhibitor
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amantadine
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Enhances the Dopamine release from neurons. Blocks dopamine reuptake.
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bromocriptine
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a STRONG AGONIST at D-2 R and a weak antagonist at D-1 R.
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pergolide
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Synthetic ergoline which is much more potent that bromocriptine. It appears to act at both D-1 and D-2 receptors
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selegiline
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inhibits MAO-B.
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entacapone
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SELECTIVE INHIBITORS of catechol-o-methyl-transferase (COMT), which BLOCKS primarily the PERIPHERAL CONVERSION OF LEVODOPA to 3-O-METHYL -DOPA-- L-DOPA
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anticholinergics
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blocks the central M-1 receptor. Decreases excititory cholinergic activity from striatal interneurons
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levo-dopa-pharmokinetics
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Dopamine is polar and does not cross the blood-brain barrier; therefore, administer levodopa, a precursor of dopamine which can cross BBB. Rapidly absorbed from the small intestine by active transport (aromatic amino acid transport); rate of absorption depends upon pH of gastric contents and rate of gastric emptying; food can delay absorption-- TAKEN IN EMPTY STOMACH; LARGE NEUTRAL AA (LEUCINE) COMPETES FOR AT. Undergoes extensive first-pass metabolism in the GI mucosa and liver---decarboxylated to dopamine. Only about 1% of administered dose enters CNS---unless a peripheral decarboxylase inhibitor is also administered.-- NEED LARGE DOSES. Half-life is short (1-3 hours). Major metabolites are 3, 4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyohenylacetic acid (homovanillic acid; HVA). Rapidly excreted in urine.
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levodopa-effects
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•CNS: Improve all major signs and symptoms of parkinsonism especially bradykinesia and rigidity.
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levodopa- side effects
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GI: Anorexia, nausea and vomiting (80%)
CV: Tachycardia and cardiac arrhythmias Postural hypotension Abnormal involuntary movements: Dyskinesias*** Behavioral disturbances: Hallucinations, paranoia, mania, euphoria, insomnia, anxiety, agitation, depression, excessive sexual behavior, vivid dreams |
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levodopa - contraindications
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Caution: Peptic ulcer, cardiac disease, open-angle glaucoma: madriasis. Caontraindications: angle-closure glaucoma, psychosis, malignant melanoma (L-Dopa, a precursor to melanin).
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levo-dopa- usefulness
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Best results are obtained in first 3 to 4 years of treatment; after that, general refractoriness may develop due to disease progression or increased side-effects due to drug-induced supersensitivity. Therefore, it has been suggested that levodopa therapy be reserved for more advanced parkinsonism with appreciable functional impairment; this concept continues to be debated. ABRUPT WITHDRAWL--SEVERE AKINESIA; GRADUAL WITHDRAW.
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sinemet - effects
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same as levodopa
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sinemet - side effects
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same as levodopa
Dyskinesias and psychiatric distrubances develop earlier and may be MORE SEVERE |
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sinemet- usefullness
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The combination is considered one of the most effective drug therapy for parkinson's. It is preferred to levo -DOPA because it: requires 75% less, less nausea and vomiting (2-5%). Less likelihood of tachycardia, hypertension. Greater efficacy with a smoother control: Sinemet CR may result in less fluctuation. Pyroxidine no longer antagonizes-Effect of L-DOPA.
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amantadine - effects
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increases the amount of dopamine
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amantadine - side effects
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mild and reversible. CNS: Dizziness, confusion, insomnia, anxiety, excitement, hallucinations. Livedo reticularis- from local release of catecholamines- vasospastic drugs, fishnet appearance in legs, arms. Edema; orthostatic hypotension.
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amantadine - usefulness
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good for mild cases: alone; <Levo-Dopa. Severe cases; adjuctive therapy with levo-dopa or anticholinergic drugs. The drug is orally effective; start low and increase gradually to 100 mg twice a day
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bromocriptine-effects
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Similar to levodopa, but less effective. Better effect when used in conbination with levodopa.
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bromocriptine- side effects
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GI: Anorexia, nausea, vomiting, constipation. Cardiovascular: orthostatic hypotension; cardiac arrythmias>L-Dopa.Dyskinesias; less than levo-dopa. Mental disturbances; confusion, hallucinations, delusions, nightmares, especially in elderly patients. > Levo-dopa. headache, nasal congestion, erythromelalgia, pericardial fibrosis
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bromocriptine- usefulness
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Combined with levodopa (Sinemet) in patients experiencing on-off phenomena, or becoming refractory. An alternative therapy to levo-dopa if the drug is contraindicated or not tolerated. Orally effective; start with low doses; increase gradually.
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selegiline - effects
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releases NE from neurons. Metabolized to amphetamine and methamp; antioxidant affect- decreases grugs progression.
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selegiline - side effects
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Dyskinesias and mental disturbances (e.g. confusion; hallucinations) from levodopa are increased in incidence and intensity. Anxiety, nausea, insomnia, hypotension.
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selegine - usefulness
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Adjunctive therapy in parkinsonism patients receiving levodopa: May prolong the effect of levodopa and reduce mild on-off or wearing off AKINESIA-- ¯ DOSE 20-30 %
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entacapone- effects
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inhibits COMT. Increases L-Dopa concentration
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entacapone- side effects
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Nausea, hypotension, orthostatic, vivid dreams, hallucinations, diarrhea. Hepatotoxicity: talocarpine only; monitor liver enzymes
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entacapone - usefulness
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Adjunct to levodopa / carbidopa in patients experiencing on-off phenomenon: may produce a smooth response and prolong “on-time”.
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levo-dopa: drug interactions
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pyridoxine-increases Levo -Dopa metabolism.
Antipsychotic drugs. Anticholinergic drugs. Non selective MAO inhibitors (phenylzine, tranycypromine, hypertensive crisis: increased catecholamine production. Other dopamine agonists |
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anticholinergics: drug interactions
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not good with catecholamines. Causes SLUDD side effects.
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amantidine
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causes release of catecholamines. So probably not good to be taking both.
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selegiline
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Meperidine: causes stupor, rigidity, agitation, hyperthermic
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entacapone
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prolongs usefulness of Levo-Dopa
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Identify the possible advantages of Sinemet CR.
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It is a slow release formula of Sinemet. It allows you to control the levels more easily. It has the same effect as Sinemet.
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Discuss the possible advantages of starting treatment with selegiline in the early stages of Parkinson’s disease.
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Selegine can be used as adjunctive therapy for patients on levo-Dopa. It may prolong its effects and reduce mild- on-off or wearing off.
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Describe the mechanism of local anesthetics and their effects on peripheral nerves
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Local anesthetics reversibly block nerve conduction when applied locally. They can act on every type of nerve fiber and also affect other excitable tissue. Optimal activity depends upon structural characteristics and a delicate balance between the lipophilic properties and hydrophilic properties. Amide linkages tend to be more stable than esters in the body. Blocks Na Channels in nerves & excitable cells; ß Na influx and conduction of AP. NA+ CHANNEL has 3 SUBUNITS: α, β-1, β-2. The α subunit is required for activity and β subunits anchor the channel in membrane. The α subunit contains 4 homologous DOMAINS that form the ION CHANNEL within the membrane. As the neuron depolarizes each DOMAIN will undergo conformational change in sequence causing the channel to open. After opening, the channel enters an INACTIVATED STATE in which is DESENSITIZED. LA : preferentially bind to Open and inactivated states. The cationic form has HIGHER affinity for the receptor at the intracellular side of the channel THAN NONIONIZED form. Increasing concentration of LA causes: Threshold for excitation increases: impulse conduction slows, rate of rise of action potential decreases, action potential amplitude decreases, complete block of conduction - - at high concentrations.
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List important differences in the pharmacology of ester vs. amide local anesthetics.
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The amide local anesthetics are rapidly and widely distributed (e.g. after I.V. administration); after a rapid initial distribution sequestration in tissues e.g. liver and heart. They cross BBB and placental barriers easily. Ester local anesthetics are hydrolyzed rapidly by plasma cholinesterases; amide local anesthetics are more slowly hydrolyzed by liver microsomal enzymes. Liver impairment prolongs the half-life of amide local anesthetic - - increases potential toxicity. Metabolites and small amount of unchanged drug excreted in urine.
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Recognize the differential sensitivity of nerve fibers to local anesthetics (i.e. myelinated vs. unmyelineated; size, and frequency and use-dependence).
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Samller unmyelinated fibers are more susceptible. Also if nerve fibers are of the same size, the myelinated one will be more sensitive. Three successive nodes need to be blocked to stop conduction. Degree of block depends on how much and recently the nerve has been stimulated. Resting nerve is much less sensitive to local anesthetic than one that has been recently and repetitively stimulated. High-frequency stimulation is blocked more readily than low-frequency stimulation. TYPE C & TYPE Ad BLOCKED FASTER THEN TYPE Aa.
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Describe the pharmacological/toxicological effects of local anesthetics on the central nervous system.
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CNS: All LA in high concentrations can elicit CNS stimulation with restlessness, dizziness, tremor and even convulsions; followed by depression, respiratory depression and death. Both the CNS depression and stimulation (inhibition of inhibitory neurons) probably result from blockade of central activity. Cocaine causes an intense CNS stimulation and euphoria by inhibiting NE reuptake; lidocaine may initially cause drowsiness and sedation.
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Describe the pharmacological/toxicological effects of local anesthetics on the cardiovascular system.
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Cardiovascular: Can decrease electrical excitability, conduction rate, and force of contraction of myocardium; may be useful in certain cardiac arrhythmias (e.g. AV conduction not affected by lidocaine). Arteriolar dilation and hypotension. Block the smooth muscle. EXCEPT: Cocaine - - Sympathomimetic effects due to blockade of NE reuptake.
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Describe the more common adverse reaction associated with local anesthetics
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Neuromuscular junction-- WEAK NM BLOCKING EFFECT
Autonomic ganglia-- BLOCK Smooth muscle-DECREASE CONTRACTILITY |
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Compare the unique features of the pharmacology of cocaine to other local anesthetics (e.g. procaine)
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Cocaine and procaine are both short acting when compared to others. Adverse reactions in the CNS with others includes restlessness, tremors, anxiety, light-headedness. Higher doses may lead to convulsions, followed by coma, respiratory depression, and death. In the CV, you see bradycardia, hypotension, heart block, shock, and cardiac arrest. Bupivacaine is more cardiotoxic and causes severe ventricular arrhythmias. Cocaine is a potent CNS stimulant and has peripheral sympathomimetic affects. It causes vaso constriction, hypertension and cardiac arrhythmias.
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Explain the role of epinephrine in local anesthetic solutions.
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It causes vaso constriction. This increases the concentration of the drug at the sight and increases its time of action. Overall, it increases the effectiveness of the drug.
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List the factors that determine the onset and duration of action of local anesthetics
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Degree of absorption is determined by dosage, vascularity of injected area, tissue protein binding and physicochemical properties of the drug. Addition of vasoconstrictor (e.g. epinephrine 1:200,00) slows rate of absorption by decreasing blood flow and enhances uptake by nerve. Application of local anesthetics to mucosal surfaces may result in very rapid and extensive absorption. Onset of action is determined by concentration of local anesthetic, lipid solubility, molecular size and quantity of nonionized species available.
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Explain the role of diazepam in the management of local anesthetic toxicity.
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Diazepam is given IV for convulsions. It supports respiration.
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List appropriate routes of administration for local anesthetics.
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Surface anesthesia (“topical”): Penetrates abraded skin and mucous membrane
Infiltration anesthesia: Extravascular; Intravascular (I.V.) Peripheral nerve block: Nerve block anesthesia, Field block anesthesia Central nerve block (peridural; caudal): Subarachnoid anesthesia (“spinal” or “intrathecal) |
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Explain the proposed mechanism of action of benzodiazepines.
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Mechanism of action is not fully known but they appear to act at many sites throughout the CNS to inhibit neuronal activity (cortex, hypothalamus, limbic system, etc) Because polysynaptic pathways are especially sensitive to these drugs we think they produce pre & post synaptic inhibition by facilitating the inhibitory effects of GABA.
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