Pharm 2- FULL SET

Created by gsterling 

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heroin

Initial use: The first dose of heroin in healthy individuals is often aversive; nausea and emesis are
common. Most persons also experience some pleasurable effects, varying from mild euphoria to the
"rush,"
Tolerance is usually very marked - eventually a big reduction in effect of drug is seen:
• reduced effects of heroin
Characteristics of Opiate Withdrawal in Adults:16-96 hours: mydriasis, anorexia, gooseflesh, restlessness, irritability, tremor, weakness,
depression, nausea, vomiting, intestinal spasms (stomach cramps), diarrhea, muscle and back
pains, muscle spasms, CNS stimulation (ejaculationacid-base balance changes, dehydration, and ketosis

naloxone

facilitates diagnosis of heroine dependence- precipitates withdrawal syndrome

treatment with an opiate antagonist induces a severe but brief period of
withdrawal; i.v. midazolam may be given to induce a heavily sedated state.

methadone

i.v. heroin is replaced by oral methadone (cross-dependence) to
n mood experienced under heroin. Drug dose is then progressively
reduced on a pre-determined regimen (patient will attempt to delay dosage reductions).
Withdrawal is spread over 3-6 weeks, symptoms relatively mild, intense drug craving is reported.
Only approved for in-patient use or in licensed addiction treatment facilities.
-maintenance therapy- Why methadone? Long half-life gives stable levels of drug

clonidine

a centrally acting adrenergic α2-receptor agonist, reduces the
severity of withdrawal symptoms during withdrawal from low to moderate doses of opioids;
reduces the activity of noradrenergic neurons in the locus ceruleus whose firing rate is increased
during opioid withdrawal (these neurons express mu-opioid receptors); clonidine provides useful
but incomplete relief in mildly addicted subjects (probably most street addicts); less effective in
heavily dependent subjects. Side effects are dry mouth and sedation; euphoria is not observed

buprenorphine

a partial opiate agonist, may also assist in detoxification. Patients are
stabilized on buprenorphine which is then progressively withdrawn; withdrawal symptoms
are mild.

cocaine

The reinforcing effects of cocaine result from blockade of the re-uptake of
NE, DA, and serotonin (5HT) after they have been released by noradrenergic, dopaminergic, and
serotonergic nerves.
***increased levels of DA in nuc. accumbens.
There is no
available pharmacological treatment that reduces craving for cocaine and/or amphetamines and
reduces the probability of relapse to chronic use,

amphetamine

Amphetamines are indirectly acting sympathomimetic amines - they release
NE, DA (and 5-HT) from nerve terminals, both in the periphery and in CNS.

methamphetamine

Methamphetamine,
due to its extra methyl group, enters the brain more readily than D-amphetamine, and has a longer
half-life, but the mode of action of the two drugs is identical

MDMA

Drug related to amphetamine

tetrahydrocannabinol (THC)

Pharmacological effects of smoking one marijuana cigarette:
In roughly the following sequence:
• tachycardia -a result of increased sympathetic activity -blocked by propranolol.
• euphoria/"high" (elevation of mood) - usually associated with visual, auditory and
temporal perceptual distortions Frank hallucinations are absent at this dose level.
• relaxation and sedation - this distinguishes THC from LSD-like drugs.
• psychomotor impairment - impaired short term memory; simple motor tasks may be
unaffected, but more complex tasks involving several mental steps (driving, flying, etc.)
are usually performed less efficiently.
• dry mouth, hunger, peripheral vasodilation (e.g., pink conjunctiva), bronchodilation

LSD

HALLUCINOGEN
it is a partial agonist at 5HT2 receptors;
effects reversed by antagonists of 5HT2 receptors and partially by dopamine D2 antagonists.
Marked tolerance can occur; no evidence of physical dependence or compulsive drug use.
• somatic (1-2 hrs) - dizziness, pupil dilatation, weakness, tremor, nausea, paresthesias
• perceptual (2-6 hrs) - blurred vision, difficulty in focusing, altered awareness of shape
and color, micropsia, macropsia, hallucinations
• affective symptoms - elation, euphoria or dysphoria, depression, fear, paranoia, panic
(2-5 hrs); mood swings between these states; after 6 hrs, detachment

mescaline

HALLUCINOGEN
Drug related to LSD
(3,4,5 trimethoxy-ß-
found in peyote cactus, dimethyltryptamine, bufotenin

phenycyclidine (PCP)

Effects include analgesia, amnesia, poor muscle relaxation;
about 40% of patients experience dysphoric reactions, an violent psychotic behaviors.
PCP is a channel blocker at the NMDA receptor, blockingcation flux after NMDA receptor activation - non-competitive NMDA receptor antagonists
-in 2-5 minutes, blank stare, catatonic muscular rigidity, confusion, drowsiness,
hypersalivation,
High doses: stuporous, comatose state for 4-
6 hours; bizarre, unpredictable, aggressive behavior, paranoid psychoses (long duration, some-
times returning long after drug use), convulsive episodes, hypertensive crises

ketamine

drug related to PCP
widely used for animal anesthesia
Effects include analgesia, amnesia, poor muscle relaxation;
about 40% of patients experience dysphoric reactions, an violent psychotic behaviors.
ketamine is a channel blocker at the NMDA receptor, blockingcation flux after NMDA receptor activation - non-competitive NMDA receptor antagonists
-in 2-5 minutes, blank stare, catatonic muscular rigidity, confusion, drowsiness,
hypersalivation,
High doses: stuporous, comatose state for 4-
6 hours; bizarre, unpredictable, aggressive behavior, paranoid psychoses (long duration, some-
times returning long after drug use), convulsive episodes, hypertensive crises

Buprenorphine maintenance

retention rates are higher in
maintenance programs using this opiate partial agonist. Buprenorphine is available in a sublingual
tablet preparation combination with the opiate antagonist, naloxone, which has poor oral
bioavailability. After sublingual administration the naloxone has low bioavailability and
buprenorphine produces mild agonist effects. If the tablet is dissolved and injected i.v., the naloxone
has access to opiate receptors in brain, blocking the agonist effects of buprenorphine

Morphine

the major prototype opiate: given orally (first pass metab.), i.m. duration of action 3-4 hrs
may exert cardeioprotective effect

Codeine

- weaker than morphine; given orally; duration 3-4 hrs. also used as a
cough suppressant.

Heroin

- enters CNS more rapidly than morphine; metabolized to morphine in
liver; effects similar to morphine.

Hydromorphone

- more potent than morphine, otherwise very similar; duration 3-5 hours.

Methadone

- equipotent with morphine; orally active; duration of action 4-6 hours; used as an analgesic
and in treatment of heroin addiction.

Meperidine

- less potent and shorter duration of action than morphine (2-3 hours duration);
effects similar to morphine.

Oxycodone

- weaker drug, like codeine, used orally as analgesic for mild pain; duration of
action 3-4 hours.

Fentanyl

- very potent opiate short duration , approximately 1 hour; used as i.v. anesthetic agent
(similar drugs: sufentanil, alfentanil); also used as an analgesic by continuous transdermal (skin patch)
application.

Loperamide

- highly potent meperidine analog used to control diarrhea; does not enter brain
[rapidly removed by the multi-drug resistance transporter (MDR)] so does not produce analgesia,
respiratory depression; no abuse liability.

Naloxone

- antagonizes actions of all opiates; must be administered parenterally to be
active systemically; used to treat opiate drug overdose; short duration of action, 1-2 hours.

Naltrexone

- longer acting antagonist of opiate drugs; can be administered orally; used in
treatment of opiate addiction and alcoholism

Buprenorphine

- partial agonist at opiate receptors; weak analgesia, euphoria, antagonizes
action of morphine and heroin; used in treatment of opiate and other drug addictions.

Dextromethorphan

- dextroiosmer of an active opiate drug; has little or no effect on opiate
receptors; may act as antagonist on NMDA receptors in medulla; effective cough suppressant;
available in OTC preparations.

for moderate pain, consider combining NSAIDs with _________

codeine

Major cause of death subsequent to opiate OD

respiratory depression
reversed with naloxone

T/F: opiates do not cause diarrhea

TRUE

tranylcypromine

MAOI

imipramine,

TCA

desipramine,,

TCA

amitriptyline,,

TCA

nortriptyline,

TCA

fluoxetine,

SSRI

sertraline,,

SSRI

venlafaxine,,

SNRI

duloxetine,

SNRI

trazodone,

Miscellaneous antidepressant
• weak inhibition of 5-HT and NE reuptake,
• antagonists of post-synaptic 5-HT2A receptors
SE:relatively ***sedating, orthostatic hypotension, nausea, dizziness, few anti-cholinergic side effects
-can be used in combo with SSRI

bupropion,

Miscellaneous antidepressant
Antidepressant efficacy probably due to inhibition of dopamine and NE reuptake - (DAT and
NET),
Side effects: few - dry mouth, nausea; can act as stimulant - agitation, insomnia.
-can be used in combo with SSRI

mirtazapine

Miscellaneous antidepressant
• antagonism of presynaptic α2 adrenergic receptors; this causes increase in noradrenergic (&
serotonergic) transmission
• has little effect on reuptake systems (possibly some NE reuptake block)
• also is antagonist at 5-HT2 and 5-HT3 receptors
Side effects caused by blockade of various other receptors, both in CNS & periphery:
• very potent H1 histamine receptor antagonist (therefore is sedating and can lead to weight
gain and increased appetite)
• less potency at blocking muscarinic and α1 adrenergic receptors
**Sedation
-can be used in combo with SSRI

lithium,

anti-seizure- Bipolar tx
a. interferes with metabolism of inositol phosphates (intracellular "second messengers")
b. inhibits glycogen synthase kinase 3
->Note that lithium is generally not effective alone in abating an acute manic episode
->Lithium has a very narrow therapeutic window. Levels must be monitored
SEs:edema, polydipsia, polyuria, GI irritation
***sodium-depleting diuretics (esp. thiazides; also furosemide, ethacrynic acid); also, ACE
inhibitors, NSAIDs can increase chance of lithium toxicity

valproic acid,

anti-seizure- Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable

carbamazepine,

anti-seizure- Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable

lamotrigine

Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable

D-amphetamine,

ADHD tx
These formulations aim to reduce the abuse potential by achieving
steady blood levels of amphetamine. Adderall® is a cocktail of amphetamine isomers and salts
that have different pharmacokinetics.
Black box warning: increased risk of heart attack, stroke, or sudden death

methylphenidate,

ADHD tx
Methylphenidate inhibits NE, DA, and 5HT uptake like cocaine,
but is less reinforcing. It is administered orally, in a variety of formulations with different
durations of action. The pharmacology of methylphenidate overlaps significantly with that of
amphetamines, and the two drugs have approximately the same efficacy in treating ADHD (70%). The abuse potential of methylphenidate is less than for amphetamines,

atomoxetine

ADHD tx
NE-selective re-uptake inhibitor. Atomoxetine is an FDA-
approved alternative to stimulants, but not all cases respond to this drug. This drug is not
reinforcing, and has a low potential for abuse/addiction; major side effect is drowsiness; other
effects sexual dysfunction, inhib. of CYP2D6, suicidal thoughts in a small percent of patients.

Monamine oxidase inhibitors (MAOIs)

2. MAOIs: neurochemical effects -block oxidative metabolism of biogenic amines by irreversibly inhibiting MAO-A & MAO-B in
nerve terminals
3. MAOIs: general behavioral / clinical effects
- acute (1st several days at least):
• CNS stimulation, agitation, possibly euphoria
- chronic (2-6 weeks):
• improvement of most or all clinical symptoms of depression
• CNS activation remains, may be lessened
5. MAOIs: adverse effects/toxicities
• orthostatic hypotension
• CNS stimulation (insomnia, hypomania, agitation, convulsions, REM suppression)
• GI distress; some weight loss
• some sexual dysfunction
7. MAOIs: Interactions:
Avoid indirectly acting sympathomimetics, including food containing high concentrations of
tyramine (cheese, red wine), amphetamines, bupropion, L-DOPA etc. Can lead to hypertensive
crisis, agitation and seizures.
Should not be taken together with SSRIs as may cause serotonin syndrome

Tricyclic antidepressants (TCAs)

• blockade of neuronal reuptake of NE and/or 5HT, raising synaptic level of these
biogenic amines; this effect correlates with therapeutic effects
TCA side effects often lead to serious problems with patient acceptance & compliance: sedation, seizures, ***orthostatic hypotension, dry mouth, urinary retention,urinary retention, increased appetite, weight gain
low therapeutic index
Because patients taking these drugs may be suicidal, it is critical to dispense in small
amounts
TCAs are highly metabolized by CYP450 enzymes. Their low therapeutic index increases the
probability of adverse drug interactions.

Serotonin-Selective Reuptake Inhibitors (SSRIs)

first-line antidepressant
• selectively block neuronal reuptake of 5-
HT; effect is to raise synaptic levels of 5-
HT
SSRIs are much more specific than tricyclic antidepressants, without significant effect at
neurotransmitter receptors so have less side-effects:
• headache
• GI upset, nausea, weight loss
• ***sexual dysfunction: ↓libido, anorgasmia
High therapeutic index
*** fluoxetine & paroxetine inhibit CYP450 enzymes, and can slow metabolism of various drugs
(most important with drugs with low therapeutic index - TCAs, lithium, warfarin, theophylline).

Best pharmtx for atypical depression

MAOI

Treatment of acute mania

a. antipsychotics
classic treatment: chlorpromazine, haloperidol, related drugs
more recently: olanzapine (Zyprexa®), an atypical antipsychotic with fewer side effects,
quetiapine (Seroquel), risperidone or aripiprazole
b. sedatives
- classic treatment: benzodiazepines; typically, lorazepam, clonazepam or diazepam
c. antiseizure drugs (either alone or in combination with atypical antipsychotic)
- more recently, valproic acid, carbamazepine, lamotrigine

Treatment of bipolar depression

Breakthrough depression may occur despite maintenance treatment. Care must be taken with
antidepressant treatment, not to push patient into mania. Recent trial suggest that addition of
antidepressant to mood stabilizer does not increase efficacy. These combinations have recently
been shown to be efficacious in treating bipolar patients suffering depression

Maintenance therapy with bipolar patients

a. lithium carbonate
b. antiseizure drugs - given alone or with lithium
• valproic acid (also called divalproex sodium) [Depakote®]
• carbamazepine [Tegretol®]
• lamotrigine [Lamictal] (better than lithium at preventing depressive episode).
c. atypical neuroleptic plus lithium or valproic acid - olanzapine, quetiapine or
aripiprazole

Intoxication gradients of Lithium

Acute intoxication - vomiting, profuse diarrhea, coarse tremor, ataxia, seizures and coma

Milder toxicity - look closely for signs:
Nausea, vomiting, diarrhea, abdominal pain, mental confusion, aphasia, ataxia,
motor hyperactivity, bizarre motor movements, hypotension

Treatment of lithium overdose - mainly supportive; osmotic diuretic, dialysis

T/F: NSAIDs can increase chance of lithium toxicity

TRUE

ethanol

One of the most widely used centrally acting drug known to man and a widely used
industrial solvent. Formed in the fermentation of sugars by yeasts; the concentration of ethyeast ferments can rise to about 15%; higher concentrations can be obtained by distillation
Over 90% of ingested ethanol is eliminated by metabolism in the liver

methanol

Methanol is sometimes consumed accidentally, or as a substitute for ethanol, or as a contaminant
in moonshine; effects are qualitatively similar to ethanol, although it is even less potent as a CNS
depressant. Extremely toxic, causes metabolic acidosis, blindness, and death when taken in large
quantities because toxic products are formed. Methanol is metabolized via the same enzymes as
ethanol:
Blindness is a result of the toxicity of formaldehyde
TX: admin of ETOH/fomepizole

ethylene glycol

antifreeze
potent CNS depressant; oxidation product, glycoaldehyde,
is toxic to the kidney, causes renal failure and death from uremia. A secondary product, glycolic
acid, causes metabolic acidosis
TX- fomepizole is also used to delay ethylene glycol metabolism

fomepizole

ADH inhibitor
delay the metabolism of toxic alcohols such as methanol or ethylene glycol that generate severely
toxic metabolites. Since the availability of NAD+ is rate-limiting, metabolism of one alcohol by
ADH can also be inhibited by giving a different alcohol

disulfiram

inhibitor of aldehyde dehydrogenase; leads to accumulation of acetalde-
hyde after ethanol ingestion (or even use of aftershave etc); causes very unpleasant symptoms:
• cutaneous vasodilatation, nausea and vomiting, syncope due to hypotension, overall misery
• hepatitis, with jaundice, fatigue, fever, abdominal pain (in severe cases).
This is an example of aversion therapy - negative reinforcement of undesirable behavior.
Use only with counseling; effectiveness may decline with time (non-compliance with dosing)

naltrexone

an opiate antagonist, reduces reinforcing effects of ethanol; decreased relapse to
alcohol drinking has been demonstrated in double-blind clinical trials of naltrexone in
alcoholics

acamprosate

an analog of GABA, thought to impair NMDA receptor function - reduces
neuronal hyperexcitability during abstinence; reduces craving, voluntary alcohol intake and
relapse, effectiveness comparable to naltrexone in clinical trials; combined treatment may be
better.

Primary metabolizers of ETOH

alcohol dehydrogenase (ADH) +
aldehyde dehydrogenase

Rate of Metabolism: ETOH

Maximum rate of ethanol oxidation by alcohol dehydrogenase is limited
by the availability of NAD+. Oxidation exhibits zero-order kinetics since reaction proceeds at maximum rate when blood alcohol levels are in excess of about 0.1 mg/ml. A constant amount of
ethanol is eliminated per unit time (rather than a constant fraction); t1/2 (half-time) increases with
dose. Average metabolic rate in adults is approx. 7 grams/hour and nothing can effectively increase
this rate (acutely); a single shot (1.5 oz of 80 proof alcohol; approx 14 g ethanol) requires about 2
hours plus to be cleared.

Effects of EOTH on Liver

Ethanol is a weak drug; many grams must be taken to induce an effect; this places a heavy
burden on the elimination system. A large fraction of available NAD+ in liver is consumed in the
metabolism of ethanol by ADH, and then in the metabolism of acetaldehyde by aldehyde
dehydrogenase - this results in an altered redox potential from the increased NADH:NAD+ ratio.
Effects of reduced NAD+: fatty acid synthesis increased, fatty acid oxidation decreased; plasma free
fatty acid levels increased; triglycerides accumulate in the liver; all at low, non-intoxicating doses

ETOH- ____________ of a glutamate (NMDA)-activated cation current, reducing synaptic transmission at some synapses

inhibition

ETOH- ____________ of GABA-mediated increase in Cl- conductance through action at an allosteric site in
the GABA-receptor-Cl- channel complex;

potentiation

SXS of withdrawal from ETOH (signs of dependence)

• tremors (often severe), hyper-reflexia, sweating, muscle cramps, vomiting
• visual hallucinations, delirium tremens or DTs (about day 3-4)
• hyperthermia, cardiovascular collapse
• generalized tonic-clonic seizures

albuterol,

BRONCHODILATOR
β-adrenergic agonists
tx sxs of asthma, not underlying condition
inhaled or oral, short acting β2
agonists (SABA); these are used for rapid relief—not for long-term prophylaxis; albuterol is
the primary medication for exercise-induced asthma
β adrenergic receptor agonists stimulate adenylyl cyclase → increased cAMP in airway
tissues and, therefore, relaxation of smooth muscle

tiotropium,

BRONCHODILATOR
muscarinic antagonists
tx sxs of asthma, not underlying condition
valuable for patients intolerant of inhaled β agonists
• block action of acetylcholine released from parasympathetic (vagal) neurons in bronchi by
competitively binding muscarinic receptors on the bronchial smooth muscle cells

theophylline,

BRONCHODILATOR
methylxanthines
tx sxs of asthma, not underlying condition
• most importantly antagonism of adenosine receptors
• inhibition of phosphodiesterases - elevation of cAMP (at high concentrations)

fluticasone,

ANTI-INFLAMMATORY AGENT
corticosteroids
Drugs that treat underlying cause of asthma- inhaled
FIRST LINE FOR LONG-TERM CONTROL
2. Mechanism of Action
• act through soluble nuclear glucocorticoid receptors to regulate gene expression
• inhibit eosinophil-induced inflammation of airway mucosa—mechanism unknown
• inhibit cytokine production
• inhibit activity of Phospholipase A2 and thereby inhibit release of arachidonic acid from cell
membranes - decrease prostaglandin and leukotriene synthesis

montelukast,

ANTI-INFLAMMATORY AGENT
leukotriene pathway modifiers
Drugs that treat underlying cause of asthma
2. Mechanism of action:
• leukotrienes are made by a variety of inflammatory cells in airways (e.g. eosinophils, mast
cells, macrophages, and basophils)
• LTB4 is a neutrophil chemo-attractant; LTC4 and LTD4 → bronchoconstriction, increased
bronchial reactivity, mucosal edema, and mucus hypersecretion
• leukotriene synthesis requires 5-lipoxygenase activit

cromolyn,

ANTI-INFLAMMATORY AGENT
release inhibitors
Drugs that treat underlying cause of asthma
Mechanism of Action
• inhibit delayed chloride channels in cell membrane - reduced accumulation of antigen-
induced intracellular calcium in sensitized mast cells
• reduce mast cell degranulation (i.e., release of histamine/autacoids) (mast cell stabilizer)
• inhibit release of inflammatory mediators from several cell types
• block activating effects of chemotactic peptides - reduction in burden of infiltrating cells
• inhibit IgE production by B lymphocytes

omalizumab

ANTI-INFLAMMATORY AGENT
anti-IgE therapy
Drugs that treat underlying cause of asthma
Blocks IgE-dependent mast cell
activation by removing unbound circulating IgE, preventing its interaction with mast cell surface
receptor. Administered iv or by subcutaneous injection every 2-4 weeks

Adverse Effects/Toxicity of ANTI-INFLAMMATORY AGENT
corticosteroids

Inhaled:
minimal (low oral bioavailability!)
• cataracts
• decreased bone density (fractures)
• oral candidiasis (less with ciclesonide
since it is activated only in the lung)

Oral:
• severe weight gain
• bone loss
• iatrogenic Cushing's syndrome
• adrenal suppression

L-dopa®

L-dopa, the direct precursor of
dopamine, does permeate the striatal tissue where it is taken up by the few remaining dopaminergic
neurons via dopamine transporters (DAT) and is decarboxylated to dopamine.
Large doses of L-dopa are required because more than 95% of the ingested L-dopa is
decarboxylated to dopamine in the peripheral tissues
The drug must be increased very gradually to minimize the many side effects and toxicity of the
large doses of L-dopa required for the desired therapeutic efficacy. L-dopa is effective in reducing
bradykinesia and rigidity, but is less effective in reducing tremor. All symptoms improve over a
period of weeks to months.

carbidopa,

co-administration of a
decarboxylase inhibitor (such as carbidopa) that does not enter the brain, allows lower doses of L-
dopa to be given, since a higher percentage of the administered dose of L-dopa is unmodified and
can enter the brain. Therapeutic effectiveness can be achieved with 75% less L-dopa when it is
combined with carbidopa.

Sinemet®,

Carbidopa is widely used in the US in a fixed combination with L-dopa at a ratio of 1 part
carbidopa to 10 parts L-dopa. This combination is known as Sinemet® and is presently the most
widely used medication in the treatment of Parkinson's disease. A controlled-release formulation,
Sinemet CR-Du Pont, is also available for treatment of Parkinson's disease.

bromocriptine,

DOPAMINE AGONISTS
ergot derivative with dopaminergic agonist properties, is used to treat
Parkinson's disease.
The combination of bromocriptine with L-dopa (and carbidopa)
substantially reduces the incidence of the 'on-off' phenomenon

ropinirole,

DOPAMINE AGONISTS dopaminergic agonists
(non-ergots)

pramipexole,

DOPAMINE AGONISTS dopaminergic agonists
(non-ergots)

rotigotine,

DOPAMINE AGONISTS a transdermal dopamine agonist, was introduced for treatment of PD

amantadine,

Initially introduced as an antiviral drug, amantadine was serendipitously found to improve the
symptoms of Parkinson's disease. The drug is believed to act as a dopamine-releasing agent (by
displacing dopamine from nerve terminals). Although the side effects are mild, amantadine is not as
effective as L-dopa; it is more effective than antimuscarinics alone. It is sometimes used in the
initial treatment of Parkinson's disease.

rasagiline,

COMBINATION OF L-DOPA WITH RASAGILINE - A SELECTIVE MAO B
INHIBITOR
MAO B predominates in the
brain, and is specifically inhibited by the MAO B inhibitor, rasagiline. Rasagiline decreases
dopamine breakdown in the brain but does not cause catecholamine build-up in the peripheral
tissues. Therefore, rasagiline does not cause hypertensive crisis. Rasagiline was approved for the
treatment of PD in 2006.

selegiline,

COMBINATION OF L-DOPA WITH RASAGILINE - A SELECTIVE MAO B
INHIBITOR
Selegiline is an older MAO B inhibitor that is still used

propranolol,

TX cardiac SE of L-dopa
• cardiac arrhythmias due to dopamine stimulation of beta receptors on the heart.
Arrhythmias are more likely to occur in patients with coronary artery disease, and can
be controlled by the administration of the beta blocker, propranolol.

benztropine,

CENTRALLY ACTING ANTIMUSCARINIC AGENTS
For more than a century prior to the introduction of L-dopa, anticholinergic drugs were the drugs
of choice in the treatment of Parkinson's disease because they reduced tremor. It is thought that
their therapeutic efficacy results from their blockage of muscarinic receptors within the striatum.
Use of anticholinergic drugs has greatly diminished, but they are still quite useful in combination
with L-dopa.
Side effects include dry mouth, blurred vision, and occasionally, urinary retention

trihexyphenidyl,

CENTRALLY ACTING ANTIMUSCARINIC AGENTS
For more than a century prior to the introduction of L-dopa, anticholinergic drugs were the drugs
of choice in the treatment of Parkinson's disease because they reduced tremor. It is thought that
their therapeutic efficacy results from their blockage of muscarinic receptors within the striatum.
Use of anticholinergic drugs has greatly diminished, but they are still quite useful in combination
with L-dopa.
Side effects include dry mouth, blurred vision, and occasionally, urinary retention

entacapone

COMT INHIBITORS
catechol O-methyltransferase inhibitors. These COMT inhibitors
prevent the breakdown of L-dopa by COMT primarily in peripheral tissues. Therefore, less L-dopa
needs to be administered and the "off" time is decreased.

donepezil,

acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia

rivastigmine,

acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia

galantamime,

acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia

memantine

an NMDA receptor antagonist, may have neuroprotective properties and therefore
may slow the progression of the disease. Memantine has been used in Germany since 1982; it was
approved for use in the US in the fall of 2003

RECOMMENDATIONS
FOR SELECTING DRUGS FOR THE TREATMENT OF PARKINSON'S DISEASE:

1. In early stages, start patients off with dopamine AGONISTS such as pramipexole or ropinirole
or transdermal rotigotine. These drugs are less likely to cause motor problems seen with L- dopa and may be neuroprotective.
2. When dopamine agonists no longer provide enough symptomatic relief, add L-dopa and carbidopa. L-dopa is the most effective drug for the treatment of Parkinson's disease.
3. COMT inhibitors, such as entacapone, can be used with L-dopa to prolong the effectiveness of
L-dopa and to reduce 'wearing off' periods.
4. The addition of an 'atypical antipsychotic' (such as risperidone, olanzapine, or quetiapine) will
help control hallucinations caused by L-dopa without worsening parkinsonian symptoms.
5. Rasagiline may delay the onset of symptoms in newly diagnosed patients, but it is still unknown if rasagiline is neuroprotective.

In general, increasing the hydrophobicity __________ the anesthetic potency and duration of action,
but toxic side effects also are increased

increases

Local anesthetics

• selectively block the transient rise in sodium permeability that is responsible for conduction
in excitable membranes.
• progressively: 1) increase the threshold and decrease the rate of rise and amplitude of the
action potential; and 2) decrease the conduction velocity and finally block action potential
generation and nerve conduction.
• do not significantly alter the resting membrane potential, except at high concentrations,
which affect K+ channels.
• binding site is located in the intracellular region of the Na+ channel pore.
• degree of block is voltage and frequency dependent. This is because the charged form gains
access to the binding site in the channel pore only in the open state and local anesthetics bind
more tightly and stabilize the inactivated state of the Na+ channel.

T/F • do not significantly alter the resting membrane potential, except at high concentrations,
which affect K+ channels.

TRUE

T/F Cocaine
itself produces vasoconstriction

TRUE

Local Anesthetics- Metabolism:

• Ester-type local anesthetics (e.g. procaine) are hydrolyzed very rapidly by plasma
cholinesterase (pseudocholinesterase).
****Exception: Cocaine is metabolized in liver and plasma and
partially excreted unchanged in urine.
• Amide-type local anesthetics (e.g. lidocaine) are metabolized by liver microsomal CyP450.

Local Anesthetics- Cardio effect:

Local anesthetics decrease myocardial electrical excitability and conduction rate
and decrease blood pressure via reduced myocardial contraction strength and arteriolar dilation. This
occurs because of direct effects on myocardium and smooth muscle and indirect effects via actions
on autonomic neurons.
***Exception: Cocaine increases heart rate and blood pressure due to its
intrinsic sympathomimetic and vasoconstrictor properties. Cocaine is the
only local anesthetic that inhibits catecholamine uptake.
***

T/F Cocaine also produces mood and behavioral alterations

TRUE

Cocaine

When abused, cocaine is snorted, smoked, injected or ingested
orally. Cocaine will block re-uptake of NE, DA, and serotonin (5HT), but the reinforcing effects of
cocaine are due to increased activation of mesolimbic pathways by DA. Chronic cocaine users
become sensitized to the pleasurable effects of cocaine, but repeated acute use produces tolerance,
leading to increased doses to achieve the high. Chronic use of high doses may result in cardiac
damage (enlarged heart), paranoia and psychotic behavior. Chronic intranasal use can result in
damage to the nasal septum from repeated local vasoconstriction. Withdrawal is associated with
ahedonia (and associated craving for more cocaine), along with increased appetite, lethargy, and
chronic depression. Despite the acute aphrodisiac qualities of cocaine, sexual dysfunction is
common among heavy users
**oral ingestion route increases risk of OD

Desirable properties of local anesthetics:

1. Short time of onset
2. Appropriate duration of action
3. Fairly quick recovery
4. Non-irritating to tissue
5. Produces no permanent damage to nervous tissue
6. Low systemic toxicity (i.e., high therapeutic index)

cocaine

ESTER
Nerve conduction blockade
Vasoconstriction due to inhibition of NE uptake
Toxicity & abuse potential due to inhibition of catecholamine (particularly dopamine) uptake
Primary clinical use is topical anesthesia in upper respiratory tract

procaine

ESTER
Prototype ester local anesthetic
Low potency, short duration
Decreased use; used for infiltration anesthesia &
occasionally diagnostic nerve blocks
Hydrolyzed to Psulfonamides
local anesthetic suitable for injection

benzocaine

ESTER
Topical use only, often directly to wounds / ulcers
Widely used in OTC topical preparations
Long duration due to low solubility in water
local anethetic suitable for mucous membranes and skin

lidocaine

AMIDE
Greater potency, longer duration than procaine
Still one of the most widely used local anesthetics -
can be used for most clinical applications where
intermediate duration local anesthetic is needed
Also used as an antiarrythmic agent
local anethetic suitable for mucous membranes and skin and injection

bupivacaine

AMIDE
Greater potency, longer duration than lidocaine
More cardiotoxic than lidocaine
**most lipophilic- can cause CV depression before convulsion

proparacaine

local anesthetic suitable for opthalmological use

Tetrodotoxin

TTX; from puffer fish, some poisonous newts and frogs
reversibly block sodium permeability, but the binding site
is the outer mouth of the Na+ channel pore and thus is not use-dependent. Both toxins are extremely
potent and can cause fatal poisoning in humans.

saxitoxin

from
dinoflagellates that cause "red tide"
reversibly block sodium permeability, but the binding site
is the outer mouth of the Na+ channel pore and thus is not use-dependent. Both toxins are extremely
potent and can cause fatal poisoning in humans

Nonselective COX inhibitors

Asprin
Indomethacin
ibuprofen
naproxen
phenylbutazone
acetaminophen

COX-2 Selective inhibitor

Celecoxib

methotrexate (MTX)

DMARD
most widely used DMARD to date;
mg given as a single weekly oral dose may produce an anti-inflammatory
effect within 4 to 6 weeks (side effects: anorexia, vomiting, abdominal cramps, increased hepatic
enzyme activity, immuno-suppresion leading to infections, bone marrow suppression, lympho- mas); combinations of MTX with cyclosporine or infliximab are more effective that MTX alone

leflunomide

DMARDs often given together with MTX
taken orally; active metabolite is an immunosuppressant, inhibits dyhydroorotate
dehydrogenase (important in lymphocyte proliferation); slows joint destruction

etanercept

DMARDs often given together with MTX
a TNF-α antagonist - a dimeric protein composed of the TNF-α binding domains of
p75 TNF receptor coupled to Fc fragments of immunoglobulin; binds to TNF-α, preventing it
from stimulating TNF-α receptors. Given by s.c. injection twice weeklyinflammation evident in 2 weeks to 3 months. Can be given with MTX.

infliximab

DMARDs often given together with MTX
TNF-α chimeric monoclonal antibody (human Fc region of IgG + Fab sequences of
mouse anti-TNF-α antibody); binds to free TNF-α; reduces joint swelling and damage. Given i.v. Adalimumab is a humanized version of infliximab

abatacept

DMARDs often given together with MTX
selectively modulates a co-stimulatory signal required for full T-cell activation.
Reduces production of TNF-α. Recombinant chimera of CTLA-4 extracellular domain fused to
the Fc portion of human IgG1

rituximab

DMARDs often given together with MTX
chimeric mouse/human anti-CD20 monoclonal antibody that causes depletion of
CD20 positive B lymphocytes. FDA approved for RA. May be useful in TNF-α inhibitor resistant
RA.

anakinra

DMARDs often given together with MTX
naturally occuring IL-1 receptor antagonist- competitively inhibits pro-inflammatory
actions of IL-1. Should not be given together with TNF-α antagonists, as increases risk of adverse
effects.

Asprin

an irreversible non-selective inhibitor of COX enzymes; it acetylates the enzyme. New enzyme synthesis required for recovery of COX activity

Indications for NSAIDs

Treatment of mild-to-moderate pain
Treatment of primary dysmenorrhea
Treatment of inflammatory conditions
The irreversible inhibition of COX induced by aspirin, specifically, has 2 important uses:
• Aspirin in low dose (~80 mg) has been shown to reduce the incideninfarction by 32% in men, and of ischemic stroke in women by 24%
Patent ductus arteriosus:
Bartter's syndrom

Schizophrenia tx

it has been proposed that the antipsychotics may exert their beneficial actions in schizophrenia by
blocking dopamine receptors in mesolimbic areas of the brain, such as the nucleus accumbens

Typical antipsychotics

chlorpromazine
haloperidol.

Nonneurological SEs of typical antipsychotics (chlorpromazin, haloperidol)

Orthostatic Hypotension
Altered sexual fx
Increased Prolactin secretion (hyperprolactinemia, gynecomastia)
Weight gain
Sedation
Seizures
Anticholinergic effects- nasal congestion, dry mouth
Phototoxicity

neurological (extrapyramidal) SEs of typical antipsychotics (chlorpromazin, haloperidol)

Parkinsonism syndrome- akinesia, rigidity- controlled with anticholingergic (benztropine, trihexphenidyl)
Dystonia- spastic movements- tx with antichol benztropine or antihist diphenhydramine
Akathisia- restlessness- tx with antichol benztropine
Tardive dyskinesia- involuntary facial movements- NO TX

Atypical antipsychotics

Risperidone, clozapine, olanzapine, quetiapine, and ziprasidone
In addition to blocking D2-type dopamine receptors,
these compounds also block serotonin 5HT2A receptors.
Aatypical' antipsychotics cause
more severe weight gain than the older antipsychotic

Risperidone

Atypical antipsychotics
causes some elevation of prolactin, and, at higher concentrations, causes
extrapyramidal side effects

Clozapine

Atypical antipsychotics
does not cause prolactin elevation and causes only very mild extrapyramidal side
effects. Tardive dyskinesia has never developed in patients treated with clozapine. However,
clozapine is associated with the development of ***agranulocytosis, a potentially fatal blood
dyscrasia in which the number of white cells plummets. The potential development of
agranulocytosis limits its use. Patients treated with clozapine must have white cell counts done
every week

Olanzapine

structurally similar to clozapine and binds to many of the same receptors, including
the 5HT2A and the D4, although it also binds with a moderately high affinity to the D2 dopamine
receptor. Olanzapine is at least as effective as risperidone in relieving symptoms, has a lower
incidence of extrapyramidal effects, and is less likely to elevate serum prolactin concentrations.
Neither tardive dyskinesia nor hematologic abnormalities (such as agranulocytosis) have been
attributable to olanzapine.

improve cognitive function of schizophrenic patients

clozapine & olanzapine

Quetiapine and ziprasidone

atypical antipsychotic
greater affinity for
5HT2A serotonin receptors than for D2 dopamine receptors. They also antagonize H1 histamine
receptors (causing some sedation) and 1 adrenergic receptors (causing some hypotension). High
doses of quetiapine or ziprasidone cause less hyperprolactinemia and fewer extrapyramidal
symptoms than high doses of risperidone or olanzapin

Dopaminergic pathway

dopamine containing neurons project from the Ventral Tegmental Area (VTA) to the mesolimbic system (Nuc. Accumb, olfactory bulb, PFC, amygdala, and cortical regions)

Aripiprazole

DOPAMINE SYSTEM STABILIZER
a partial agonist at D2 dopamine and
5HT1A serotonin receptors & an antagonist at 5HT2A receptors. It seems to be as good as atypical
antipsychotics and may be safer. It causes little or no sedation, extrapyramidal side effects,
hyperprolactinemia, or hypotension.

Prostaglandin analogues

aloprostadil, misoprostol, iloprost

cGMP phosphodiesterase inhibitor

cGMP phosphodiesterase inhibitor: sildenafil

anti histamine - 1st generation:

diphenhydramine, dimenhydrinate, meclizine, promethazine

anti histamine - 2nd generation

loratadine, fexofenadine

antimigraine drugs

sumatriptan, ergotamine, dihydroergotamine

NITRIC OXIDE

• is a gas.
• diffuses through membranes to act on surrounding cells.
• has a very short half life- usually a few seconds.
• is inactivated by interaction with O2 and converted to nitrite or nitrate.
• interacts with other radicals, thiols, or metals to exert many of its effects.
• activates guanylate cyclase through binding to iron in heme group.
• increases levels of cGMP, may activate cGMP-dependent protein kinase, relaxing smooth
muscle.
• causes vasodilation.
Inhalation of NO is used to produce selective pulmonary vasodilation and to improve
oxygenation in persistent pulmonary hypertension of the newborn and in adult respiratory
distress syndrome.

Neuronal NO

• NO may couple brain activity to cerebral blood flow.
• Glutamate-induced increases in NO, mediated by Ca2+ entry through NMDA receptors, may be
involved in diverse processes ranging from excitotoxic cell death to memory (LTP).
• In the peripheral autonomic nervous system, it is one of the neurotransmitters in nonadrenergic,
noncholinergic neurotransmission (NANC) in the GI, urogenital, and vascular systems.
• In the GI tract as a regulator of sphincter contraction, and intestinal motility. Children with
pyloric stenosis have been shown to have deficient NOS myenteric nerves at the pylorus.
• In the urogenital system NO is thought to be the major neurotransmitter in penile erection.
Lack of NO may account for some forms of erectile dysfunction, and this may be another
potential therapeutic avenue.
• NO may play a role in the etiology of migraine (see below).

Endothelial NO

NO plays a major role in vascular function and it is probable that alterations in NO synthesis will
contribute to vascular disease.

NO acts
• as a vasodilator and mediator of the vasodilatory effects of acetylcholine, substance P,
bradykinin, ATP, histamine and other signaling molecules.
• to prevent platelet adherence and aggregation and neutrophil aggregation.
• to prevent smooth muscle proliferation.

Inducible NO

Inducible NOS expression is part of an adaptive response during inflammation or injury. NO kills
the foreign body, probably through the formation of damaging radicals and peroxynitrite ions.
These large amounts of NO can be detrimental in septic shock.

Prostaglandins

• are eicosanoids from the fatty acid arachidonic acid.
• are not stored but are synthesized in response to diverse stimuli.
• are released in bursts into the extracellular space.
• act through specific G protein linked cell surface receptors (EP1-4).
• generally act locally.
• circulate at low levels in the normal state.
• are targets for pharmaceutical intervention, either by inhibition of their synthesis (see anti-
inflammatory lecture) or by using stable analogues to enhance/mimic their effects.

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