Anticholinergics
Benztropine: tertiary antimuscarinic, CNS action, most commonly used anti-Ach for PD, most effective in
controlling tremor, peripheral ADRs-dry mouth/blurred vision/constipation/urinary
retention/tachycardia, central ADRs-delusions/hallucinations/sleepiness
Trihexyphenidyl: tertiary antimuscarinic, CNS action, treats PD, most effective for tremor
Procyclidine: tertiary antimuscarinic, CNS action, treats PD, most effective for tremor
Diphenhydramine (Benadryl!): tertiary antimuscarinic, CNS action, treats PD, most effective for tremor
Biperiden: tertiary antimuscarinic, CNS action, treats PD, most effective for tremor
Ethopropazine: phenothiazine, tertiary antimuscarinic, CNS action, treats PD, treats tremor
Increases Available Dopamine
L-DOPA: precursor for DA, used to treat PD, ADRs-nausea/vomiting/dyskinesia/hallucinations/increased
HR/decreased BP/inhibition of prolactin secretion, 1 isomer administered-preferred by AA pumps and
metabolizing enzymes (decarboxylating), crosses BBB
Carbidopa: peripherally acting DOPA decarboxylase inhibitor, hydrazine derivative, traps pyridoxal
phosphate cofactor used by DOPA decarboxylase, increases amt L-DOPA able to cross BBB, co-
administration w/ L-DOPA for PD, 1 isomer-selective for ability to inhibit enzyme, not good substrate for
AA uptake, doesn’t cross BBB
Amantidine: stimulates pre-synaptic DA release, low efficacy and dependence on the presence of pre-
synaptic DA stores, anticholinergic side effects, most effective L-DOPA>Amantidine>anti-Ach, benefit
sometimes seen when amantidine added to anti-Ach therapy, mild ADRs-nausea/dizziness/sleep
disturbances/lethargy, pKa 10.8, can still cross BBB due to lipophilic ring, acetylated form inactive
Dopamine Agonists
Ropinirole: DA agonist, selective at D2 (non-ergot), most selective DA agonist used to treat PD, extensive
metabolism, half life 6 hours, 30-40% PPB, 55% bioavailability, DA agonist titrated up most quickly,
hydrolysis/ring oxidation/OND, all metabolites inactive
Pramipexole: DA agonist (non-ergot), greatest affinity at D3, also affinity at D2, devoid of 5-HT activity,
some affinity at NE sites, ability to scavenge free radicals and offer neuroprotection, no metabolism, half
life 8-12 hours, 15% PPB, 90% bioavailability
Pergolide: DA agonist-D1 and D2 receptors, ergoline alkaloid derivative, alpha partial agonist, 5-HT
antagonist, ADRs- hallucinations/nausea/vomiting/L-DOPA like/rarely Reynaud’s and pulmonary fibrosis,
more potent than bromocriptine, extensive metabolism (S-oxidation/OND), half life 7-16 hours
Bromocriptine: DA agonist-D2 receptors, ergoline alkaloid derivative, alpha partial agonist, 5-HT
antagonist, ADRs- hallucinations/nausea/vomiting/L-DOPA like/rarely Reynaud’s and pulmonary fibrosis,
extensive metabolism(hydrolysis/ring oxidation), no active metabolites, half life 3-8 hours, C next to
carbonyl subject to epimerization (inactive)
Apomorphine: approved in 2004 for PD, DA agonist-primarily D4 w/ less affinity for D2/D3/D5, low
activity at alpha and 5-HT, derived from rearrangement reaction of morphine, little of analgesic
properties of morphine but does have ability to cause respiratory depression and is a strong emetic,
catechol precludes oral administration, low oral bioavailability, given SC/rectally/sublingually,
metabolized by glucuronidation (inactive) and eliminated extrahepatically, most selective
ropinirole/pramipexole>apomorphine>ergots
Rotigotine: DA agonist-greatest affinity for D3, 8-20 fold less affinity for D2/D4/D5,
agonist-D3/alpha-1/5-HT, antagonist-M2/alpha-2, approved in 2007 for PD, available as a transdermal
form to provide more consistent levels over 24 hour period, more “on” time and less “off” time, ADRs-
nausea/vomiting/psychiatric disturbances/drowsiness, 92% PPB, OND/ring oxidation/gluc, agent and
metabolites excreted in urine
Enzyme Inhibitors
Selegiline: MAO-B inhibitor, at high doses also inhibits MAO-A, inhibits catecholic destruction of DA,
adjunctive utility in management of PD, rapid uptake and elim of drug in brain (20-30 min), at high doses
intermediate formed from oxidative demethylation can be attacked in Michael fashion by cofactor
(flavin), high doses-suicide substrate inhibitor and covalent bond formation, some antiapoptotic and
antioxidant properties (the triple bond), R (-) enantiomer of an acetylenic phenethylamine derivative
related to amphetamines, (-) isomer metabolized to (-) methamphetamine which is less active than the
(+) isomer
Rasagiline: MAO-B inhibitor, inhibits catecholic destruction of DA, adjunctive utility in the management
of PD, more irreversible action than selegiline, more antiapoptotic and antioxidant properties (triple
bond) than selegiline, less amphetamine like
Entacapone: COMT inhibitor, prolong life of L-DOPA, decreases on-off effect, if carbidopa given then
COMT is preferred metabolism b/c DOPA decarboxylase is inhibited, entacapone more acidic than L-
DOPA, forms stable ionic interactions with COMT, nitro catechol is highly colored, shorter duration (2
hours), doesn’t cross BBB, metabolism-isomerization of DB and gluc of catechol
Tolcapone: COMT inhibitor, prolong life of L-DOPA, decreases on-off effect, when carbidopa given then
COMT is preferred metabolism b/c DOPA decarboxylase is inhibited, tolcapone more acidic than L-
DOPA, forms stable ionic interactions with COMT, nitro catechol is highly colored, longer duration (3-4
hours), hepatotoxicity-black box warning, metabolism-gluc and a small amt of methylation
Typical Antipsychotics (DA blockade)
Promazine: phenothiazine antipsychotic, aliphatic class
Chlorpromazine: phenothiazine antipsychotic, aliphatic class, used to treat schizophrenia/acute
bipolar/hiccups, high risk for seizures (decreases threshold), deposition in cornea and lens
Triflupromazine: phenothiazine antipsychotic, aliphatic class
Piperacetazine: phenothiazine antipsychotic, aliphatic class
Thioridazine: phenothiazine antipsychotic, piperidine class, causes retinal deposits
Mesoridazine: phenothiazine antipsychotic, piperidine class
Acetophenazine: phenothiazine antipsychotic, piperazine class
Fluphenazine: phenothiazine antipsychotic, piperazine class, low seizure risk
Perphenazine: phenothiazine antipsychotic, piperazine class, therapeutic use for schizophrenia
Trifluperazine: phenothiazine antipsychotic, piperazine class
Chlorprothixene: thioxanthene antipsychotic, aliphatic like
Thiothixene: thioxanthene antipsychotic, piperazine like
Enanthate: inactive prodrug converted to fluphenazine, IM depot
Decanoate: inactive prodrug converted to fluphenazine, IM depot
Haloperidol: typical piperazine like, only butyrophenone currently marketed in U.S., potent DA receptor
antagonist (D2 blockade), efficacious antipsychotic with low risk of sedation, little or no hypotension or
anti-Ach, ADRs-EPS/tardive dyskinesia, therapeutic use-schizophrenia, low seizure risk, precaution-for
pts with CVS disorder or PD, half life 24 hours (longer for depot formulation), OND forms inactive
metabolites, acts like MPTP-has hydroxyl group and loss of water produces double bond therefore
vulnerable to MAO and forms compounds like MPP+ and inhibits oxidative phosphorylation of NADH
Molindone: typical piperazine like, reduced indolone (dihydroindolone), among least potent typical
antipsychotic at D2 receptor, produces EPS (low antimuscarinic effect), low sedative and hypotensive
properties (decreased alpha-1 and H-1 blockade), extensive metabolism-36 metabolites, duration of
activity more than 24 hours, half life 2 hours
Pimozide: typical piperazine like, some selectivity w/ D2 postsynaptic receptors, used to treat
schizophrenia/Tourette’s, longer acting than haloperidol, side effects-Parkinsonism (EPS)/tardive
dyskinesia/less sedation/hypotension/anti-Ach effects, pimozide has more anti-Ach effects than
haloperidol and molindone but less than piperazines, low seizure risk, oral absorption slow and variable
(40-50%), half life 37-55 hours, metabolism via OND, lacks hydroxyl group sp no MPP+ effect
Loxapine: typical piperazine like, a dibenzoxapine-resembles TCAs but distance b/w the tricycle and
piperazine ring altered, weak D2 antagonist, less alpha-1 blockade, less anti-muscarinic activity, half life
4 hours, OND produces amoxipine (antidepressant), aromatic hydroxylation produces active metabolite
then gluc and elim
Atypical Antipsychotics (DA blockade)
Clozapine: atypical nonpiperazine like, weak D2 antagonist, lack neurotoxicity (EPS/TD), NH bioisostere
and 8-Cl regioisomer of loxapine (decreased interaction with DA receptors), greatest affinity for D4
(among DA group), more affinity for alpha-1/H-1/5-HT2 than D1/D2, little prolactin release,
agranulocytosis major problem-causes neutropenia and limits use to pts who don’t respond to other
therapy, sedation/orthostatic hypotension/antimuscarinic, H-1 blockade causes weight gain and
diabetes, therapeutic use-schizophrenia, high seizure potential (decreases threshold), OND yields major
metabolite (active), aromatic hydroxylation and N-oxidation produce inactive metabolites, approved for
prevention of suicide
Olanzapine: atypical nonpiperazine like, less EPS, doesn’t cause agranulocytosis, more potent D2 blocker
and 5-HT2 antagonist than clozapine, M1/H-1/alpha-1 antagonism-some side effects, therapeutic use-
schizophrenia/acute bipolar/mania /depression/maintenance treatment of bipolar I disorder, well
absorbed, significant 1st pass, extensively distributed, 93% PPB, inactive metabolites, elim in urine (57%)
and feces (30%)
Quetiapine: atypical nonpiperazine like, very little antagonism at D2, 5-HT (1a,2,6) antagonist, fairly
potent alpha-1 antagonist-may produce orthostatic hypotension, no significant anti-Ach, therapeutic
use-schizophrenia/acute bipolar/mania/depression , well absorbed orally, highly PPB (83%), extensive
metabolism (inactive sulfoxide and active desmethyl), metabolites primarily elim in urine (73%) and
secondarily in feces
Risperidone: atypical piperazine like, benzisoxazole derivative, potent D2 blockade with 5-HT2
antagonism, lacks anti-Ach/antihistaminic side effects, depending on dose may produce EPS, therapeutic
use-schizophrenia/acute bipolar/mania/mixed episodes, low seizure risk, less orthostatic hypotension,
popular drug b/c less ADRs, OND and ring oxidation, hydroxylated form is paliperidone (active), widely
distributed after oral administration, 90% PPB, elim in urine
Ziprasidone: atypical piperazine like, benzoisothiazole derivative, combines D2 and 5-HT2 antagonism,
capacity to induce arrhythmias, not 1st line, therapeutic use-schizophrenia/acute bipolar/mania/mixed
episodes, less histamine/muscarinic/alpha blockade, least likely to cause weight gain or diabetes,
oxidation at sulfur, OND, aldehyde oxidase then S methylation yields active metabolite
Aripiprazole: atypical piperazine like, D2 and 5-HT1a partial agonist, 5-Ht2 antagonist, high D3 affinity,
moderate alpha-1 /H-1 affinity, therapeutic use-schizophrenia/acute bipolar/manic/mixed
episodes/maintenance treatment of bipolar I disorder, less sedation, similar ADRs to risperidone,
dehydro metabolite has some activity, inactive metabolites produced by hydroxylation and OND