Drugs used in Parkinsonism

Objectives: Ø Recognize the symptoms and pathophysiology of parkinsonism. Ø Understand the pharmacology of drugs used for treatment of parkinsonism. Ø Define pharmacokinetics, pharmacodynamics and side effects of different drugs used for the treatment of parkinsonism. color index: extra information and further explanation important doctors notes Drugs names Mnemonics

Check out the mnemonics file : https://docs.google.com/presentation/d/1Z0Vf9oEOJSXo4JIA0mTCk5jB- OU9LP5TFCwz8iBgNac/edit?usp=sharing Kindly check the editing file before studying this document https://docs.google.com/presentation/d/1_- g1vol4eBWPet5xVCkuTGFvvnhFF3PJmU0tWtEEw_o/edit?usp=sharing Parkinson’s Disease Pathophysiology

A progressive neurodegenerative diseases This movement disorder occurs mainly due to disorder that occurs mainly in the elderly ↓dopamine/↑acetylcholine imbalance in basal and can lead to disability unless effective ganglia (caudate nucleus, substantia nigra & corpus treatment is provided. striatum) that is involved in motor control.

Dopamine Pathway In Parkinson’s disease

Predominance of Ach + Deficiency of dopamine 1- Reward pathway 2-Motor pathway

DA is manufactured in Cell bodies in the nerve cell bodies substantia nigra that located within the manufacture and ventral tegmental release dopamine into area (VTA) and is the striatum. Treatment approach More discussed in page 3 released in the nucleus accumbens and the Main Or approach prefrontal cortex. Drugs to Drugs to block increase cholinergic dopaminergic activity activity

Causes Characters

It is idiopathic disease but some causes may be: • Genetic. Simplified by the acronym “ TRAP ”: • Toxins used to induce models of Parkinson • Tremors at rest. disease from animals • Rigidity of muscles. (MPTP = methyl phenyl tetrahydropyridine). • Akinesia or Bradykinesia (no movement or • Head trauma. slowness in initiating and carrying out voluntary • Cerebral anoxia. (hypoxia) movements). • Oxidative stress increase production of free • Postural and gait abnormalities. radicals due to e.g. environmental pollution, • Anxiety or depression. nicotine and sulfa medication • Drug-induced Parkinson's disease e.g. antipsychotics (as haloperidol) and Dopamine antagonists (as metoclopramide (antiemetic). Minor approach Main approach

Drugs to block cholinergic Drugs to increase dopaminergic activity. activity Increase Inhibition of DA releaser: Muscarinic Drugs that mimic DA receptor the effects of central DA DA antagonists: agonists amantadine D2&D3 receptor synthesis metabolism Benztropine, Trihexy- COMT Ergot phenidyl inhibitors: derivatives: *the non- (DA entacapone selective MAO bromocriptin inhibitors (A&B) precursors): e.g. e, pergolide L-dopa+ are used as Nitecapone Non ergot antidepressants carbidopa MAO-B and they derivatives: produce many inhibitors*: pramipexole ADRs. selegiline

Patients with Parkinson have deficiency of DA, to treat them we can’t give only DA. Why? Dopamine is a polar can not cross the blood brain barrier → can not produce action Also, Dopamine metabolized by COMT and MAO *L-dopa have catechol nucleus so, we prescribe it with one of the DA metabolism inhibitors to prolong the action

selegiline, amantadine or Mild cases anticholinergics

Main cases Levodopa and carbidopa disease Adjuncts to levodopa Other medications

Dopamine agonist →Bromocriptine

parkinson’s MAO-B inhibitors →Selegiline

Benzo is from Other useful drugs Enhance dopamine release benzene so it is lipid →Amantadine soluble à cross BBB. It is a minor treatment if the

treatment of Muscarinic receptor patient can’t take antagonist →Benztropine dopamine → give and trihexyphenidyl him anti-muscarinic drugs. COMT inhibitors entacapaone • DC: DOPA Decarboxylase • MAO: Monoamine Oxidase • COMT: Catechol-O-Methyl transferase

*L-dopa is an amino acid ( derivative from tyrosine)contain COOH and NH2 * Dopa decarboxylase enzyme convert L-dopa to dopamine by removal of COOH prescription P.D Limitation Pharmacokinetic Drug Dyskinesia and response fluctuations with L ------Limitation of ------Reduce Increase Lowers centrally Pathway of the disease. It is a precursor of dopamine. Benefit of → BBB peripheral conversion of L → L D1, D5 Dopamine of striatal dopamine nerve terminals. Wearing off effect and on T On frequency of administration and prolong the action potential. How can we improve wearing Wearing may then reappear. The dyskinesia can be reduced by lowering the dosage; however, the symptoms of parkinsonism levels Dyskinesia Short duration of action (t½ = High protein meal interferes with its absorption and transport into CNS. a protein meal → uptake process done by competition process between the amino acids & L Absorbed from the small intestine and taken up to CNS by Given orally (should be taken on 1 peripherally 99 Dopamine formed peripherally - 1 % dopa / Why? % 2 Why only peripherally? - . crosses BBB to form dopamine off phenomenon → L the effective - side effects of of dopa availability of → ↑ T1 is usually combined with → - levodopa . off effect Excitatory. L L (involuntary movements occurs in acts on dopaminergic receptors D1 because - - L dopa + DOPA is \ - 2 dopa decarboxylated . treatment levodopa : ( (not constant concentration) carbidopa duration of “on” states becomes shorter Carbidopa Is converted into dopamine via L - L * - - D2, D3, D4 dopa dopa (On= improved mobility & Off=Akinesia or hypomobility) - Levodopa (L - off phenomena occur due to dopa to dopamine. . to CNS. dose. (effective only for the first - L off effect? By combining to give dopamine combination 2 - is a peripheral dopa is a replacement therapy, it’s not prevent the progression of is metabolized by hs empty stomach carbidopa or → centrally. ) Inhibitory. → - DOPA (fluctuation of plasma concentration). : 40 dopa - → benserazide Because when it acts also centrally, we won’t take D5 (G produce dopamine + it is polar so can’t cross BBB the benefit because L in gut and liver to ( It acts only peripherally because it does not cross especially without proteins MAO on off phenomenon *Sudden transition from normal kinetic activity 90 decarboxylase inhibitor dopa - protein linked receptors) phenomenon % of patients) - it

→ 4 & COMT enzymes dopa) with MAO inhibitors - decarboxylase 5 progression active transport system (DC inhibitor). years) ) اﻟدم ﻓﻲ ﻋﺎﻟﻲ ﺗرﻛﯾزه ﻋﺎﻟﻲ ﻓﻲ اﻟدم (decrease in L to dyskinetic activity. by decarboxylase enzyme. = = drug in the therapeutic range → اﻟﺗرﻛﯾز ﯾﻘل اﻟﺗرﻛﯾز - dopa will not degraded to of the disease and the due to (DC) . → - dopa effect) peripherally and = ). inhibit = to decrease the fluctuating plasma = اﻷﺧﺿر اﻟﻣﺳﺗطﯾل ﻓوق اﻟﻣﺳﺗطﯾل اﻷﺧﺿر اﻷﺧﺿر اﻟﻣﺳﺗطﯾل ﺗﺣت اﻟﻣﺳﺗطﯾل اﻷﺧﺿر because of short اﻷﺧﺿر اﻟﻣﺳﺗطﯾل ﻓﻲ اﻟﻣﺳﺗطﯾل اﻷﺧﺿر . → GIT & other so if we take - dopa. loss

• • • • • • • Overview: Clinical use: Drug C.I ADRs Indications / Uses Drug interaction disease and may decrease the dose of levodopa in advanced Parkinson disease. Lippincott: Dopamine agonists may delay the need to use levodopa therapy in early Parkinson clinical improvement and reduce In advanced stages, initial therapy for early stages of the As monotherapy, the Non Ergot They are divided into ergot derivatives and non ergot depending on the density . likely to cause psychotic side effects Have longer duration of action than - - (Effective against all types of parkinsonism except those associated with antipsychotic drug therapy.) - - - ↑ ------Peripheral & B (metabolize DA)& non catecholamines malignant melanoma Patients with history of Glaucoma Psychotic patient. The best results of The most efficacious therapy Nonselective MAO inhibitors Adrenomimetic Pyridoxine High proteins meals. Should the disease. L CNS ergot derivatives - dopa derivatives: not ameliorates all signs of parkinsonism particularly (Vitamin B6). vivid dreams Mainly depression, delusions, confusion, sleep disturbances(insomnia), hallucinations, - - - - (due to be used in parkinsonism associated with orthostatic (postural) hypotension Mydriasis Cardiac arrhythmias. → Anorexia, nausea, vomiting bromocriptine, , MAO inhibitors are 3 types A (metabolize catechol amines: 5 aminees They are more common with combination of DC inhibitors. dopamine agonists : pramipexole dopamine agonists → mydriatic levodopa Levodopa (L (compensate on the same because it may exacerbate the mental disturbance - selective → melanoma → ↓ effect of L May occur and participate in acute glaucoma ( pergolide phenelzine, tranylcypromine) effect). . are obtained in the first few years of treatment. L , levodopa → - ropinirole dopa 1 disease, and it has longer duration of action. . Why?

st → are used as an adjunct to (less likely to cause line treatment.

are less effective than levodopa. - because of increased dopa due to ↑ peripheral metabolism by Vit.B6 dosage needs. (due to stimulation of chemoreceptor trigger zone CTZ). → . receptors ) L - dopa - → dopa) with higher doses is a precursor of melanin antipsychotic dyskinesias . bradykinesia → catecholamines Hypersensitivity crisis levodopa cont. than drug therapy. levodopa Thus can only be used as & - , they may contribute to . TH + NE ) . rigidity peripherally. → ) but more but does not cure due to so it may activate . Contraindications ADRs Indications Route of admin. Mech. of action Drug 3 under inhibitory control by dopamine. in women. Secretion of prolactin is serum prolactin Galactorrhea 2 1 Used for the treatment of: • • • • Absorbed to a variable extent from the . . Hyperprolactinemia ( . Parkinson’s disease GIT ; peak plasma levels are reached Infertility in women. within 1 But Longer than T½ = 6 antagonist D2 agonist, Excreted in the bile and feces. e.g:Bromocriptine • • Recent myocardial infarction. vasoconstriction and may cause gangrene with high dosage • Peripheral vascular disease (only ergot derivatives, • Psychosis L - dopa more effective. - – Active peptic ulceration (with Bromocriptine) 8 h. Ergot derivatives: 2 hours after an oral dose. Bromocriptine is a condition of elevated . and a partial D1 which induces infertility Levodopa Orally Similar to • • • • • galactorrhea , pergolide Nausea, vomiting, postural hypotension Somnolence Dyskinesias Confusion, hallucinations, delusions Cardiac (t½ =2 h) L - dopa - arrythmias : ) (less prominent). • • 40% increases the renal tubular secretion of organic bases, For example, scavenger. Has the advantage of being Renal insufficiency may necessitate dosage concentrations in approximately 2 hours, Rapidly absorbed, reaching peak plasma excreted largely unchanged in the urine combination D3 agonist Used excreted unchanged in urine. alone Non ergot derivatives: cimetidine halflife Pramipexole adjustment as initial therapy or in which cause severe with Orally of Ldopa ) pramipexole , which inhibits free radicals . by Notes ADRs C.I Uses Efficacy Route of admin. action - may induce acute toxic psychosis. Orthostatic hypotension, urinary retention, peripheral edema, inhibiting the N parkinsonism, including increasing the release of dopamine, blockading cholinergic receptors, and which is effective in the treatment of influenza has an Lippincott: It was accidentally discovered that the antiviral drug amantadine [a Of blood inside veins. *Discoloration of skin due to accumulation • Ankle edema, and neurotransmitter, antagonizing it will thus cause restlessness and hallucinations. NMDA is a type of glutamate receptors & glutamate is an excitatory • Restlessness and hallucinations (NMDA antagonist). → • Dry mouth, urinary Nausea, anxiety, insomnia, confusion, hallucinations ( - functioning. - caused by variation in response among patients) - months. - - - - 3. Antagonist at 2. Acts as an antagonist at 1. inhibit - tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia. develops more readily. However, amantadine has fewer side effects. The drug has little effect on and dry mouth also may occur. Amantadine is less efficacious than levodopa, and tolerance patients because it causes fluid retention. Amantadine is contraindicated with - - Anticholinergics. Useful in the The drug may cause restlessness, agitation, confusion, and hallucinations, and, at high doses, it Amantadine has several effects on a number of neurotransmitters implicated in causing Amantadine Its benefits last only for short period and only used for Tolerance Less efficacious than Most of the drug is excreted unchanged in the Given originally introduced as an orally (tolerance is after 3 s the reuptake of (decrease of response) (A muscarinic receptor antagonist effect - methyl with short half life and the early stages NMDA receptors - livedo reticularis D retention , - anticholinergics aspartate (NMDA) type of glutamate receptors. L - - In patients with a history of seizures or heart failure dopa DA muscarinic receptors of parkinsonism or as an adjunct to - antiviral 5 years for levodopa) → Increases (Modest effectiveness heart failure constipation = 2 (N develops to its therapeutic effect after 6 - - 4 h methyl . * Anti .(rare) may exert additive effects on mental dopamin - parkinsonism. - D (anticholinergic effects). - antiparkinsonism aspartate) urine ) e release and atropine like effect) dopamine L - ( dopa glutamate receptors action. levodopa resistance like side effects). - MAN - ta therapy. . - (which is deen - 8 ) ], Only slides Action/Mech. of Contra-indications ADRs Indications Mech. of action Drug ADRs Indications Drug

action in ! 4. 3. 2. 1. Co - increase the level of - At high doses: therapeutic range and that happens when levodopa. - - - Adjunctive to Metabolism so - - Selegiline - metabolism. It is a for stimulation

May cause insomnia when taking later during the day. Delay It may inhibit MAO Metabolized to girl - - - - Used as adjuvant to - - required for - A Reduce Has anti The blockade of administered with: level epically noradrenaline and causes hypertension ) of food with MAO B inhibitor (which indirectly increase noradrenaline) will increase the catecholamine (cheese effect)( increase in catecholamine Meperidine Prolong the ON Improve response Decrease fluctuations s monotherapy may be effective in newly diagnosed patients Food restriction “low Selective Tricyclic antidepressants. Acts Can’t cross BBB L carbidopa Usually given in combination with selective - the onset of dyskinesia and motor fluctuations that usually accompany long dopa. (the main goal is to prolong the effect of peripherally the required dose of may have - oxidant levodopa/carbidopa serotonin Orange discoloration of urine. * MAO L irreversible inhibitor of it slows the progression of the disease Mech to diminish - dopa desmethylselegiline cheese and banana are rich in tyramine which increase - catecholamines dopamine A - activity against TIME neuroprotective effects → . of its receptors. - to inhibit COMT enzyme reuptake A degradation. Enta (hypertensive crises) L tyramine → - dopa + carbidopa metabolize NE, 5 capone peripheral levodopa. metabolism makes more →Serotonin toxicity. inhibitors (may cause hyperpyrexia, agitation, delirium, coma). in l diet” is required . ater toxic free radicals , which is anti metabolism of - MAO we combine stage - L May ↑the adverse effects of levodopa. - dopa and L → - - to: - HT, DA dopa B parkinsonism to: Selegiline as a result, do not prescribe due to: , an important enzyme for L - . dopa → side effects L - increase release of E & NE →sever elevation in BP - apoptotic. dopa produced during without increase the dose and within the dopamine with - - - - Not all patients respond to anti More penetration into CNS. Peripheral and central More lipid soluble than Tole MAO & COMT inhibitors ) = Total = Central & peripheral available noradrenaline. So, taking this type dopamine selegiline dopamine Tole - term treatment with capone - with drugs that COMT inhibitor entacapone - cholinergic drugs due to . Benztropine Trihexphenidyl Drug of - Central muscarinic antagonist. (Efficacy is due to blockade of muscarinic receptors in the striatum)

action - It has modest anti-parkinsonian action. Action/Mech.

- Improve tremor & rigidity. (but have little effect on bradykinesia. - Provide benefit in drug-induced parkinsonism (due to antipsychotics). - Used during early stage of the disease

Indications - Used as an adjunct to levodopa therapy.

- Cycloplegia At high doses: - Mydriasis - Confusion - Dry mouth - Delirium

ADRs - Urinary retention - Hallucinations - Constipation - May cause withdrawal symptoms in pts receiving large dose - Prostatic hypertrophy - Glaucoma C.I - Intestinal obstruction (due to constipation)

Ø In mild cases, selegiline, amantadine or anticholinergics can be used.

Ø Levodopa and carbidopa is the main treatment

Ø All other medications are adjuncts to levodopa therapy

Ø Other useful drugs include bromocriptine (dopamine agonist), selegiline (monoamine oxidase-B inhibitor), amantadine (enhances dopamine release) and benztropine (muscarinic receptor antagonist), that is used for parkinsonism caused by antipsychotic drugs. قادة فريق علم الدوية : لي التميمي & عبدالرحمن ذكري الشكر موصول لعضاء الفريق التميزين : روان سعد القحطاني غادة الزروع رنا باراسي لينا الوكيل سمر القحطاني

References : 1- 436 doctors slides 2- 435 team’s work 3-Pharmacology (Lippincotts Illustrated Reviews Series), 5th edition.

[email protected] Your feedback: https://docs.google.com/forms/d/e/1FAIpQLSc57qjDXLPc @pharma436 QLYftI27W91gCKD2RgH0OzQDdDxsiLYmH9DKtw/viewform