albuterol

• (Proventil HFA, Ventolin HFA, ProAir HFA)
• Beta­₂ agonist                          
•  Asthma

• Treatment with beta-2 receptor agonists

  1.         Specificity of products a.         Selective agonists (beta-2 > beta-1 effects)

   1)         Albuterol (Proventil HFA, Ventolin HFA, ProAir HFA)2)         Selectivity is relative; high doses produce cardiacstimulation

   -           Direct beta-1 stimulation

            -           Reflex response to beta-2 vasodilation

  3)         Most common side effect is skeletal muscle tremor    (beta-2)

  4)         Oral, inhalational and parenteral products are available

    -           inhalation route improves selectivity and provides                                                                             more rapid onset

      -           oral or parenteral routes may provide deeper                                                                                      penetration

  5)         Levalbuterol (Xopenex) is the active isomer from racemic

                                                              mixture (albuterol)

2.    Older mechanism:  releases DA

B.   Unique side effect:  patches of skin discoloration

Elavil

Tricyclic antidepressants (TCA) 

classic tricyclics

Prototypes:  amitriptyline (Elavil)/nortriptyline (Aventyl)

a.    Administer amitriptyline (parent) à two active drugs circulate

b.    Active metabolite (nortriptyline) also marketed separately

aripiprazole

Abilify

Third generation atypical antipsychotic:

atropine

Muscarinic antagonist

Ophthalmology, motion sickness, GI and genitourinary spasms, etc.

A.        Natural alkaloids found in atropa belladonna and hyoscyamus niger

                        1.         Prototypes of competitive muscarinic receptor antagonists

                        2.         Indications rely on their ability to antagonize the actions of ACh in the and various peripheral organs

                        3.         Block all subtypes of muscarinic receptors

                        4.         Well absorbed and widely distributed

                        5.         Dose-related effects (atropine)

B.        Organ effects with significant indications

CNS-parkinsons, motion sickness

GI and GU tracts: peptic ulcers, hypermolbility

Asthma and COPD

eye-Opthalmologic exam-dilate pupils-relax pupillary sphincter

C.        Side effects - many predictable from mechanism

                        1.         Dry mouth

                        2.         Fever:  inhibition of sweating

                                                children especially sensitive

                        3.         Dry eyes, blurred vision

                        4.         Urinary retention, constipation

                        5.         Tachycardia

                        6.         Psychiatric:  confusion, disorientation, delirium

                        7.         Atropine poisoning description - "dry as a bone, blind as a bat, red as a  beet, mad as a hatter"

   D.        Drug interactions

                       1.         Cholinergic agonists (direct and indirect acting)

                                    a.         Atropine used as an antidote for overdose of drugs, chemical   warfare agents, and overexposure to pesticides (approx. 120 AChE inhibitors are available for this use)

                                    b.         Atropine does not block AChE inhibitor action at the NMJ

                        2.         Drugs with anticholinergic side effects (additive)

baclofen

(Lioresal)

muscle relaxant

Drugs used to treat spasticity:(this , Dantrolene, Tizanidine )

1.    Structure similar to GABA

2.    Mechanism

b.    Muscle weakness

c.    Withdrawal syndrome

5.    Intrathecal administration

a.  Injection in subarachnoid space surrounding spinal cord

b.   Programmable pump system c.   maximize benefit (including analgesia), minimize side

effects

d.    Drawbacks

1)    Malfunction of pump system

2)   Tolerance requires dose increase over time

benztropine

Anticholinergic drugs (M receptor antagonists)

Antimuscarinic drugs-correct cholerinergic hyperactivity, restore ACh/DA balance

(Cogentin)

A.   Prototype: benztropine (Cogentin)

B.   Mechanism

1.Inhibits cholinergic activity in the corpus striatum

2.    Restores DA/ACh balance

C.   Drawbacks:  anticholinergic side effects

D.   Often used in combination

E.   Effective for antipsychotic drug-induced Parkinson's

botulinum toxin

(Type A, ona-prefix, BoTox: Type B, rima-prefix,Myobloc)

Mechanism:  binds to presynaptic vesicles and inhibits release ofACh

2.Uses

a.Indicated for dystonias and other specific muscle spasms;local injection paralyzes specific muscles

b.Approved Oct 2010 for chronic migraine

3 Drawbacks

a.Effect wears off in 2-3 months

b.Limited number of muscles may be treated in a givensession

4.Caution:  may spread from injection site.

a.Medwatch Feb 08 reported systemic effects, suggestive of

botulism (respiratory failure and death).  Most occurred in

children with cerebral palsy, treated for limb spasticity (not

an FDA-approved use).

b.Update Apr 09

1)FDA now requires a Boxed Warning for all products

2)Labels must be clarified to highlight dose (units)

differences amongst the products

bupropion

Wellbutrin

2nd/3rd generation drug antidepressant( Venlafaxine is also one)

1.    No significant effects on NE or 5HT reuptake.                          2.   Mechanism may be inhibition of DA reuptake (structural similarity to

amphetamine)

3. Anxiety, restlessness, insomnia, seizures may occur, no classic tricyclic

side effects

4.    Aids in smoking cessation (Zyban)

carbamazepine

Tegretol

Antiseizure

A.   Mechanism - prolongs sodium channel inactivation                          1.   Is used as an adjunct for depression/mania; structurally similar to tricyclic

antidepressants

2.Also indicated for trigeminal neuralgia and other neuropathic pain

B.   Advantages - broad spectrum, little sedation

C.   Drug interactions P450 related:  an inducer

D.   Has an active 10-11 epoxide metabolite

cevimeline

Evomax

ACh analog that is selective for M1 and M3 receptors

-           has a longer t ½ than pilocarpine with fewer cardiac   effects           -           indicated for Sjogren’s syndrome

chlorpromazine

Thorazine antipyshchotic Phenothiazines and related drugs (older, classic, typical, traditional):

D2 receptor antagonists

A.   Chlorpromazine (Thorazine): prototype

1.    Advantages:  generic, inexpensive, familiar 

2.    Disadvantages:  significant autonomic and sedative actions 

B.   Fluphenazine (Prolixin)

1.    Most potent of the phenothiazine group

2.    Advantages

a.    Low incidence of sedation and autonomic effects

b.    Long-acting form used im for non-compliant patients

3.    Disadvantages:  high incidence extrapyramidal

dantrolene

Dantrium

Drugs used to treat spasticity:skeletal muscle relaxant( Baclofen also one) 

1.   Mechanism of dantrolene action

a.   Inhibits calcium release from sarcoplasmic reticulum in

skeletal muscle cells

b.   Inhibits muscle contraction

2.    Use

a.   Severe spasticity regardless of cause (po): cerebrovascular

accident (CVA), cerebral palsy, spinal cord lesions,

multiple sclerosis

b.   Malignant hyperthermia (iv) 

3.    Serious adverse effects

a.  Generalized muscle weakness

b.    Hepatotoxicity

diazepam

Valium

sedative-hypnotic, antianxiety

used to treat Tardive dyskinesia 

Benzodiazepines (BZD): 

has three active compounds in the body

1.   More "selective" in the suppression of anxiety than barbiturates 2.    Have shallower dose-response curves

 a.   Most rapidly and completely absorbed of BZD (po)

b.   Variable bioavailability im

c.   Rapid and complete distribution into the CNS and other tissues

1)   Rapid onset of therapeutic effect

2)   Rapid termination of CNS action (after single iv dose) due to redistribution in fat

d.    Long acting (with repeated doses)e. Widest range of indications:  anxiety disorders, status epilepticus,

skeletal muscle spasms, anesthetic premedication, drug withdrawal

syndromes

Mechanism:  enhance GABA binding to its receptor

Diazepam(Valium)hasalonghalflife(20-100hours)andis metabolizedtodesmethyldiazepam(halflife>40hours).

donepezil

(Aricept), one of the four AChE inhibitors approved for  treatment of mild to moderate Alzheimers

b.         Cholinergic neurons are critical in memory, cognition, etc.

c.         Alzheimers is characterized by a degeneration in cholinergic   neurons

 d.         AChE inhibitors indicated for Alzheimers

   1)         Cross the BBB (no (+) charge)

   2)      Increase any remaining cholinergic activity, thus partially                                                                 restoring function

entacapone

Comtan

COMT inhibitors (also Tolcapone (Tasmar):  hepatotoxin)

PROTOTYPE: only active in the periphery

D.   Drug interactions (EPI)

NE release          

   Asthma, shock, nasal congestion  

 DRUGS AFFECTING ADRENERGIC SYNAPSES: ADRENOMIMETIC DRUGS

A.        Long history as herbal medicine, found in Ma-huang (ephedra), sold as a dietary  supplement to "increase energy".

            B.        Releases endogenous catecholamines plus nonspecific agonist actions mimic EPI   in spectrum

            C.        Non-catechol structure - high bioavailability and long duration of action

            D.        Serious side effects:  dysrhythmias, seizures, stroke, death.  In 2004, FDA banned  the sale of OTC products that contain ephedra.

 E.         Patient education concerning herbal medicines

 1.         Dose not standardized

 2.         Other ingredients (such as caffeine) may be present

                        3.         False conception that natural is safe

 Adrenaline

Alpha and Beta_1-2 agonist  Hypotensive states, adjunct for local

 anesthetics, asthma glaucoma

A.        Characteristics

                        1.         Prototype for nonspecific adrenergic agonists

                                    alpha-1 agonist:           decreases local blood flow

                                                                        increases blood pressure

                                    beta-1 agonist:            cardiac stimulation

                                    beta-2 agonist:            relaxes bronchioles

2.         Not effective orally

 3.         Short duration of action

 4.         Cardiovascular response

a.         Local injection mainly affects alpha-1 receptors à   vascoconstriction

 b.         Rapid iv injection of large doses à biphasic response

   1)         Initial alpha-1 vasoconstriction increases diastolic BP

2)         As [EPI] decreases, beta-2 vasodilation decreases diastolic

Pause for thought:  although topical administration of high [EPI]  is used to minimize hemorrhage via a vasoconstricting action, after the initial effects wear off, the opposite effect may occur.

c.         Slow iv infusion or sc injection à selective stimulation of beta  receptors (cardiac stimulation and vasodilation) increases systolic  and decreases diastolic BP.

  B.        Used as adjunct for local anesthesia (alpha-1)

                        1.         Concomitant administration (1:100,000 dilution common)

2.         Decreases local blood flow

  a.         Prevents systemic absorption of local anesthetic

     1)         Prolongs its local duration of action

   2% lidocaine alone à 44 to 100 min. duration

2% lidocaine + EPI (1:250,000) à 90 to 175 min. duration

2)         Minimizes systemic toxicity

b.         Checks local bleeding

   c.         Caution:  local ischemia

                        3.         Other vasoconstrictors:  levonordefrin (alpha-methyl-L-NE) 1:20,000

            C.        Control local bleeding (1:1000) and produce gingival retraction (use of  impregnated cords)

            D.        Treatment of shock (alpha and beta)

  1.         1:10,000 dilution (iv) or 1:1000 (sc)

                        2.         Drug of choice for acute allergic (anaphylaxis) or cardiac emergencies

 3.         Physiological histamine antagonist

            E.         Treatment of bronchial asthma (see VII below)

            F.         Side effects

                        1.         CNS:  restlessness, apprehension

                        2.         Peripheral adrenergic stimulation:

 a.         Tachycardia, dysrhythmias (beta-1)

 b.         Pallor, hypertension (alpha-1)

Use with caution in patients with cardiovascular disease after careful  analysis of risk/benefit.  Text Figure 6-5.

 G.        Drug interactions

 1.         Beta receptor antagonists

Combination with EPI capable of alarming increases in blood pressure

2.         General anesthetics

Dysrhythmias possible when EPI combined with halogenated hydrocarbon                                    anesthetics (halothane)

flumazenil

Romazicon

BZD antagonists

Other compounds which bind to the GABAA-chloride channel complex

1.    Has high affinity for CNS BZ receptors, but lacks efficacy (pure

competitive antagonist) 

2.    Used to reverse BZD anesthesia or treat overdose

a.    Ultra short half-life (0.7 to 1.3 hours)

b.    Repeated administration required 

3.    Does not affect CNS action of barbiturates, opiates or other CNS

depressants 

4.    Adverse effects  agitation, confusion, dizziness 

5.    May precipitate sudden withdrawal in BZD-dependent patients

fluoxetine

Prozac

SSRI's

A.   Many are in pairs: drug/active metabolite (Text Fig 12-8)

6.    Half-lives are typically longer than TCAs 

7.    SSRI's and suicidal behavior:  current controversy 

Black box warning about suicide thinking and behavior in 18-24 year old patients, especially during the first two months of treatment.

8.    Serotonin syndrome

a.   Hyperthermia, muscle rigidity, movement disorders, confusion,

coma ...

b.    Caution with MAOI, TCA, certain drugs for migraines

9.   Pregnancy warnings:  several have been associated with septal heart

defects

fluphenazine

Phenothiazines and related drugs (older, classic, typical, traditional):

D2 receptor antagonists (also Chlorpromazine (Thorazine): prototype)

B.   Fluphenazine (Prolixin)

1.    Most potent of the phenothiazine group                                2.    Advantages

a.    Low incidence of sedation and autonomic effects

b.    Long-acting form used im for non-compliant patients

3.    Disadvantages:  high incidence extrapyramidal

glycopyrrolate

Robinul

DRUGS AFFECTING CHOLINERGIC SYNAPSES:  Muscarinic (M) receptor antagonists:

6.         Synthetic quaternary ammonium compounds used in dentistry

a.         Example:  glycopyrrolate (Robinul)

 b.         Shorter duration than naturals, no CNS effects

   c.         Higher incidence of ganglionic blockade à hypotension

isoproterenol

Bbonchial and smooth muscle dilator; B2 effect.

cadiovascular effects:

increase HR because of reduced BP reflex response and direct increase.

most dilation (B stimulation.

drop diastolic pressure

levodopa

l-dopa, Sinemet, Sinemet CR

Replacement therapy for Parkinson's with a DA precursor 

Crosses blood-brain barrier (via active transport mechanism for amino acids) Converted to DA in brain by dopa decarboxylase (DDC): restores DA/ACh balance. Best of available agent

 B.   Peripheral DDC inhibitors1.    Carbidopa, given in combination with levodopa (Sinemet, Sinemet CR) 

combination

a.   Due to tolerance or disease progression?

b.    Use drug holidays (no longer recommended?) 

5.    On-off and wearing-off phenomenon

a.    Associated with high, changing, or low levodopa concentrations

b.   End of dose deterioration (early) to completely unpredictable (late)

c.    Due to lack of DA neurons for storage and metabolism?  DA

receptor sensitivity changes?

d.    Due to levodopa transport problem?

1)    Buildup of levodopa metabolites?

2)    Competition with dietary amino acids?

D.   Positive effects on movement tasks

1.    Improves movement velocity

2.    Reduces tremor and rigidity

Other vasoconstrictors:  levonordefrin (alpha-methyl-L-NE) 1:20,000

            Epinephrine

classification of anti depressants

 (ephedrine, amphetamine)

3.    SSRIs and most TCAs

D.  Indications:  atypical depressions, depressions unresponsive to other drugs

Lopressor, Toprol XL, Metozolv

Cardioselective (beta-1 blockers)

        1.         Prototype metoprolol (Lopressor, Toprol XL, Metozolv)

 2.         Cardioselective only at low doses

Versed

selected products Benzodiazepines

Preanesthetic medication and surgical adjunct

a.    IV agents used for induction (midazolam) 

b.    Cannot achieve level of surgical anesthesia alone

 a.   Improved absorption after im administration (compared to 

diazepam)

b.    Short acting (1.5 to 2.5 hours) 

c.    Effects enhanced by P450 inhibitors (erythromycin)

mimic the actions of ACh at the effector organ. Direct acting drugs.  Class = prototype

A.        Chemistry (Figure 9)

1.         Many are quaternary amines (+) structurally similar to ACh

a.         More resistant to AChE action

b.         More selective for muscarinic receptor

c.         Poor CNS penetration

 B. Organ effects with significant indications. Most of the direct effects are readily predicted from knowledge of the effects of parasympathetic nerve stimulation.

Eye, GI, GU

C.        Glaucoma

D.        Side effects due to M receptor stimulation (SLUD response):abdominal cramps, diarrhea, increased secretions (salivary, sweating, lachrymal,  nasopharyngeal), bronchoconstriction, decreased cardiac output and blood pressure

E.         Drug interactions:  cholinergic receptor agonists and antagonists

neostigmine

Prostigmin

Acetylcholinesterase (AChE) inhibitors

Prototypes pyridostigmine (Mestinon) and neostigmine (Prostigmin) (indirect cholinergic agonists)

1.         Indications rely on its ability to cause Ach accumulation at receptor sites

 a.         Muscarinic (M) stimulation:  GI/GU tracts, eye

  b.         Nicotinic (N_M) stimulation:  skeletal muscle

 2.         Structural similarity to ACh Many are quaternary amine compounds (+) with negligible distribution    into the CNS

nicotine products

(smoking cessation)

            A.        Mechanism:  activate nicotinic receptors in the brain

            B.        Products by prescription or OTC:  lozenges, nasal spray, gum, patches

            C.        Adverse effects:  nausea/vomiting, dizziness, weakness, irregular heartbeat, drug  interactions

norepinephrine

At post gang terminals of sympathetic system

Alpha and B1 stimulate

lowers pulse rate by reflex response. increases BP for constriction of BV than decrease HR.

alpha 1 increases heart rate

BV constict

nortriptyline

Aventyl

classic Tricyclic antidepressants (TCA) 

Prototypes:  amitriptyline (Elavil)/nortriptyline (Aventyl)

 a.    Administer amitriptyline (parent) à two active drugs circulate

 b.    Active metabolite (nortriptyline) also marketed separately

olanzapine/risperidone

Prototypes:  olanzapine (Zyprexa), risperidone (Risperdal)

"Atypical" (2nd generation) antipsychotics

As compared to older, phenothiazine-like drugs

1.    Different receptor blocking profile (less D2, more 5HT2)

 2.    Different side effect pattern

 a.    Lower incidence of extrapyramidal effects

 b.    Sedation/autonomic effects still present

 3.    May be better at reducing the "negative symptoms" of schizophrenia

 4.    New concerns with "atypicals" and hyperglycemia, weight gain and

 hypercholesterolemia 

a.    Average weight gain:  6.9 Kg in 6 months

 b.    Contributes to cardiovascular risk (especially elderly patients) 

c.    New Black Box warning

oxazepam

Serax

Benzodiazepines

not metabolized by P450 enzymes

a.    It has an intermediate half life (5-15 hours) and no active

metabolites

b.   Glucuronide conjugation less sensitive to liver function changes

with age or disease 

c.   Many prefer for elderly and patients with impaired hepatic function

phenobarbital

(Luminal) - long half-life (4-5 days) used as sedative and anti-epileptic

Dependence and Abuse potential -classified Schedule II (pentobarbital) to Schedule IV

Antiseizure Drugs (1912):  prototype barbiturate

Phenobarbital and benzodiazepines are effective for local anesthetic-induced seizures

C.   Major drawbacks 

1.   Sedation, dizziness, respiratory depression and reduced cognition 

2.   Drug interactions P450 related: the "king" of inducers

a.    Half lives shortened, bioavailability decreased

b.    P-gp transporters induced:  increased efflux from CNS and GI

c.    Both a and b may cause therapeutic failure

phentolamine

Alpha receptor antagonists:Nonselective (block alpha-1 and alpha-2 receptors):  

Phentolamine reverses EPI-induced blood pressure increases

phentolamine effects on local anesthesia would cause vasodilation (open up BV and wash away anesthestic)

1.         Alpha-1 blockade à decrease total peripheral resistance (TPR) and blood                                      pressure (BP)

2.         Alpha-2 blockade à increase NE release (via presynaptic receptors)

 a.         Significant reflex tachycardia

  b.         Attenuates hypotensive effect. 

3.         Rarely used for chronic indications

phenylephrine

Sympathomimetic drugs

Monoamine oxidase (MAO) inhibitors 

Alpha₁ agonist         Nasal congestion, hypotensive states

a.   Phenylephrine effects potentiated (normally metabolized by MAO)

b.   Indirect sympathomimetics (NE releasers) effects potentiated(ephedrine, amphetamine)

A.        Prototype alpha-1 agonist (little or no beta activity)

B.        Most indications rely on its ability to mimic NE at the vascular alpha-1 receptor 

1.         Increases blood pressure

  a.         Increases venous tone

b.         Increases TPR

  c.         Usually decreases cardiac output (CO)

 Little direct cardiac action, baroreceptor reflex response to BP change

 2.         Reduces local blood flow

a.         Used to achieve nasal and middle ear decongestion

 b.         Relieves itching and redness in hyperemic (blood-shot) eyes

c.         Shrinks hemorrhoids

 d.         Control bleeding (1:100 dilution)

  C.        Treatment of nasal congestion

1.         Mechanism - congestion

 a.         Nasal mucous membranes become edematous

 b.         Glandular secretions increased

2.         Mechanism - decongestion:  local vasoconstriction

 a.         Reduces edema and mucous production

 b.         Opens clogged nasal passages

 3.         Mechanism - rebound congestion (rhinitis medicamentosa)

a.         Ischemia of mucous membranes

 b.         Local irritative effects

4.         Other alpha agonists used topically

a.         Oxymetazoline (Afrin, Duration, etc.)

b.         Longer duration of action than phenylephrine

 5.         Nasal spray containing phenylephrine (Neo Synephrine)

6.         Oral administration often preferred

a.         Benefit: reduced rebound congestion

 b.         Drawback: increased systemic and CNS side effects

 1)         Caution:  patients with high blood pressure.  Serious  adverse effects possible.

 2)         Alternatives frequently have HBP on label:  do not contain decongestants

 c.         Ephedrine isomer:  pseudoephedrine (Sudaphed)

 1)         Very safe and effective

 2)         Drawback:  may be used to synthesize methamphetamine

 3)         Now "behind the counter"

  4)         Many former OTC products now contain phenylephrine   (PE)

 D.        Treatment of shock

Beneficial action:  improves circulation without cardiac stimulation.

pilocarpine

Salagen

Indicated for xerostomia:  restore protective effects of saliva

used for dry mouth secondary to radiation therapy

available as a gel, solution or sustained release insert for topical use

  1)         Pilocarpine(Salagen) used for dry mouth secondary to radiation therapy

  2)         Cevimeline  (Evomax)

 -           ACh analog that is selective for M1 and M3 receptors

  -           has a longer t ½ than pilocarpine with fewer cardiac  effects

   -           indicated for Sjogren’s syndrome

(Minipress)                                                                                           Alpha₁ antagonist                    

 Hypertension, benign prostate hyperplasia

Selective alpha-1 antagonists:  prazosin (Minipress) prototype

1.         Indicated for hypertension

a.         Decrease TPR, and venodilation

b.         Slight increase in heart rate (why?)

c.         Often used in combination

2.         Indicated for benign prostatic hyperplasia (BPH)

 a.         Alpha-1A receptor subtype predominates in the prostate

 b.         Alpha-1A receptor antagonists relax prostate smooth muscle and facilitate urine ouflow

c.         Selective alpha-1A antagonists available:  tamsulosin (Flomax)

prochlorperazine

Compazine

antipsychotics

Treatment of nausea and vomiting (phenothiazine class), especially

propranolol

(Inderal)                       Hypertension, cardiac dysrhythmias,

Beta receptor antagonists: Nonselective beta-1 and beta-2 blockers

2.         Beta-1 blockade:  therapeutic effects

3.         Beta-2 blockade:  adverse effects

  a.         May exacerbate asthma

  b.         May impair peripheral circulation, especially in extremities

  c.         May impair diabetics’ recovery from hypoglycemia

            B.        Cardioselective (beta-1 blockers)

1.         Prototype metoprolol (Lopressor, Toprol XL, Metozolv)

                        2.         Cardioselective only at low doses

            C.        Cardiovascular effects

1.         Heart

a.         Decrease heart rate and force of contraction

b.         Decrease cardiac output and thus blood pressure

2.         Vasculature

a.         Initial increase in TPR

b.         Eventual decrease in TPR

 D.        Indications

1.         Cardiovascular:  cardiac dysrhythmias, angina pectoris, hypertension,  prevention of myocardial infarction, congestive heart failure

2.         Misc:  chronic migraine, performance anxiety, glaucoma

Sudaphed

treatment of nasal congestion

Ephedrine isomer:  pseudoephedrine (Sudaphed)

1)         Very safe and effective

2)         Drawback:  may be used to synthesize methamphetamine

3)         Now "behind the counter"

4)         Many former OTC products now contain phenylephrine

pyridostigmine

Mestinon

Acetylcholinesterase (AChE) inhibitors

Prototypes pyridostigmine (Mestinon) and neostigmine (Prostigmin)

                        (indirect cholinergic agonists)

1.         Indications rely on its ability to cause Ach accumulation at receptor sites

 a.         Muscarinic (M) stimulation:  GI/GU tracts, eye

b.         Nicotinic (N_M) stimulation:  skeletal muscle

2.         Structural similarity to ACh Many are quaternary amine compounds (+) with negligible distribution into the CNS

Skeletal muscle indications

                                    Indicated for Myasthenia gravis

CNS indication (Alzheimer’s)

reserpine

Serpasil       action NE depletion                 indication: Hypertension

blocks vesicle uptake of NE into vesicles which would be excreted into synapse of adrgenergic synapse. depletes NE receptor agonists and antagonists

1.    Partially depletes CNS biogenic amines (norepinephrine, NE and 5-hydroxytryptamine, 5HT) and causes depression

2.   Therefore, depression may be due to a functional decrease in NE and 5HT

transmission, or its long-term consequences.

3.   Chronic decrease in NE and 5HT may result in receptor supersensitivity or

upregulation

selegiline

(Deprenyl, Eldepryl)

A.   Mechanism: inhibits MAOB and thus DA breakdown 

1.    Increases DA at synapse, restores DA/ACh balance

 2.    Neuroprotective

B.   Use 

1.    In early stages, may slow disease progression 

2. In later stages, administered with levodopa, may reduce on-off and wearing-off phenomena

C. Does not share all the adverse effects of the antidepressant MAO inhibitors

 1.They inhibit MAOA as well (enzyme for NE and 5HT):  leads to more drug

and food interactions 

2.    Caution:  at higher doses, selegiline loses specificity

D.   Is metabolized to amphetamine and methamphetamine

succinylcholine

Alectine

Neuro musclar Depolarizing blockers

 Drugs affecting NM nicotinic receptors

1.   Prototype and only drug available

2.   Resembles two ACh molecules joined together

contraction.

Slow metabolism and removal (compared to ACh)

1.    Extends depolarizion (Phase I block)

2.    Prevents any subsequent stimulation

3. Continuous infusion modifies receptor conformation (Phase II block or desensitization)

 temporary tremor and fasciculation followed by flaccid paralysis

Short duration of action (compared to other NMJ blockers)

1. Mainly metabolized by plasma cholinesterases (pseudo or butyryl

cholinesterases)

2. Prolonged apnea possible in patients genetically deficient in

cholinesterases or who receive AChE inhibitors

Other disadvantages

2. Excessive K+ release (due to muscle depolarization) may lead to

cardiac arrest and dysrhythmias

3.   Malignant hyperthermia, anaphylaxis and stimulation of ANS

ganglia may occur

thiopental

Pentothal

Barbiturates

b.    Pentobarbital (Nembutal) -intermediate half life (18-48 hours) -hypnotic (rarely used today)

c.    Phenobarbital (Luminal) - long half-life (4-5 days) used as sedative and anti-epileptic

2.    Metabolites are inactive

3.    Barbiturates cross the placental barrier

a.    Addicted mother, addicted baby

b.    Respiratory depression in newborn

tizanidine

Zanaflex

Muscle relaxant: Drugs used to treat spasticity

d-tubocurarine

NEUROMUSCULAR BLOCKING DRUGS 

Nondepolarizing blockers (Receptor antagonists)

N_M receptor antagonists:  block ACh action at the NMJ

Used during surgery to relax skeletal muscle

used to reverse the actions of non-deploraizing neuromuscular relaxants

tyramine

c.   Normally high first pass metabolism of tyramine by MAO so NE-releasing effects minimal

d.    Presence of MAO-A inhibitors à more tyramine bioavailable àmore NE released à hypertensive episode

Depakene, Depakote

antimanic drugs

mood stabilizers

venlafaxine

Effexor

Venlafaxine (Effexor)/desmethyl metabolite

2nd/3rd generation drugs antidepressants(also Bupropion (Wellbutrin))

Venlafaxine (Effexor)/desmethyl metabolite

1.    Inhibits NE and 5HT reuptake (SNRI)

2.   Has little anticholinergic action, sedation or orthostatic hypotension

3.    Effective for anxiety and depression

4.    Desmethylvenlafaxine (Pristiq) approved Feb 29, 2008 for

treatment of adult depression

block uptake of NE from adrengeric junction.

NE acculates in the synapse

Muscarinic (M) receptor antagonists

Motion sickness

 Scopolamine dosage form:  Transderm-Scop

1)         A patch applied to the skin (behind the ear) a few hours  before emesis is expected

2)         Slowly releases scopolamine from the reservoir