DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM

Parts of the Nervous system

1. Central nervous system
- brain, spinal cordc
2. Peripheral nervous sytem
- neurons outside the brain and spinal cord

a. Somatic
- voluntary
- innervates skeletal muscles

b. Autonomic
- involuntary
- innervates organs
i. Sympathetic
ii. Parasympathetic

Pathway: brain stem/ spinal cord→ preganglionic neuron (NT)→ post-ganglionic neuron (NT)→ target organ

Autonomic Nervous System

Sympathetic/ Adrenergic
‘Fight or flight’ system
- dominant during stressful
situations
Ganglion Acetylcholine- nicotinic
receptor
Target organ Norepinephrine- adrenergic
receptor (α,β)
adrenal medulla:
epinephrine/ adrenaline-
adrenergic receptor
Parasympathetic/
Cholinergic
‘Rest and digest’ system
- dominant during tranquil
conditions
Acetylcholine- nicotinic
receptor
Ach- muscarinic receptor

Pupils Pupil dilates (mydriasis) Pupil constricts (miosis)

Lacrimal glands tearing
Salivary glands Thick, viscid secretions Copious, watery saliva
Trachea and Bronchioles bronchodilates- β2 Bronchoconstricts,
(Lungs) inc. secretions
Heart Inc. HR/ tachycardia Dec. HR/ bradycardia
(chronotropic) Dec. contractility
Inc. contractility (inotropic)- β1
Blood vessels Skeletal muscle- vasodilates
Skin, mucus membrane, GIT-
vasoconstricts→
inc. resistance→HTN-α1
GIT Dec. motility→ constipation Inc. motility→ diarrhea
Bladder Bladder relaxes, Sphincter Bladder contracts, sphincter
closes→ urinary retention- α1 opens→ urination
Male genitalia Ejaculation Erection
Uterus Relaxation- β2 Contraction→ labor
Synthesis and Release of Acetylcholine
1. synthesis of acetylcholine
- transport of choline inhibited by hemicholinium
2. uptake into storage vesicles
- protected from degradation
3. release of neurotransmitter
- botulinum toxin- blocks release
- spider venom- promotes release
4. binding to receptor
5. degradation by acetylcholinesterase
Ach→ acetate + choline
6. recycling of choline
Cholinergic agonists
acetylcholine→ muscarinic receptors
1. direct- acting - bind, activate receptor
2. indirect-acting
- inh. acetylcholinesterase→ inc. Ach
Ach→ Acetate + choline
DIRECT-ACTING CHOLINERGIC AGONISTS
A. Choline esters
- Ach hydrolyzed by Achase
- Bethanechol, Carbachol are resistant to Achase;
carbamic acid esters
- β-methyl group in methacholine, bethanechol
reduces nicotinic activity
1. Acetylcholine
- prototype
- no clinical use because of widespread effects
and rapidly hydrolyzed by Achase
- S/E: DUMBELS
2. Bethanechol (Urecholine)
- inc. intestinal motility after surgery (bowel)
- urinary retention (bladder)
- “BBB”
-S/E: DUMBELS
3. Carbachol
- glaucoma
4. Methacholine
- diagnosis of asthma
B. Alkaloids
- pilocarpine, arecoline- tertiary amines; well absorbed
- muscarine- quaternary amine; less absorbed
1. Pilocarpine
- alkaloid from Pilocarpus sp.
- glaucoma- miosis, drains aqueous humor→
dec. ocular pressure
S/E: enter CNS- hallucinations, seizures;
DUMBELS
2. Arecoline
- from betel nut (Areca catechu)
3. Muscarine
- from mushroom Amanita muscaria
INDIRECT-ACTING CHOLINERGIC AGONISTS /
CHOLINESTERASE INHIBITORS
1. organic derivatives of phosphoric acid
(organophosphates)
2. carbamic acid esters of alcohols bearing quaternary or
tertiary ammonium groups (carbamate insecticides,
neostigmine, physostigmine, pyridostigmine)
3. simple alcohols bearing a quaternary ammonium group
(edrophonium)
A. Organophosphates
- irreversibly inhibit Achase due to covalent
binding
- lipid soluble, well absorbed, good CNS
penetration except for echothiophate (quaternary
amine)
a. isofluorophate, echothiophate- glaucoma
b. malathion, parathion- pesticides; converted to the active
malaoxon, paraoxon
c. tabun, sarin, soman- chemical warfare/ ‘nerve gas’
- S/E: DUMBELS
- Antidote:
1. pralidoxime- reactivates Achase by
removing OP; should be given before
Achase loses one of its alkyl groups
(aging)
2. atropine- anticholinergic/ muscarinic
blocker
B. Carbamates
- physostigmine, insecticides- tertiary amine; more
lipid soluble; well absorbed
- neostigmine- quaternary amine; poorly absorbed
1. Physostigmine
- aka eserine
- alkaloid from Calabar bean/ordeal bean
Physostigma venenosum
- intestinal and bowel atony, glaucoma
- antidote for anticholinergic poisoning- atropine,
phenothiazine, tricyclic antidepressant
2. Neostigmine (Prostigmin)
– treatment of myasthenia gravis (autoimmune-
destroys nicotinic receptors→ weakness,
ptosis)
– antidote for tubocurarine poisoning-
neuromuscular/nicotinic blocker
4. Pyridostigmine (Mestinon)
- tx of myasthenia gravis
5. Carbamate insecticides
- carbaryl, methylcarbamate (Baygon)
C. Quaternary amine e. Pirenzepine
- peptic ulcer
1. Edrophonium (Tensilon)
- diagnosis of MG (Tensilon test- f. Benztropine (Cogentin), Trihexyphenidyl (Artane),
inc. strength, dec. ptosis) Biperiden (Akineton)
*Spider venom - Parkinson’s disease
- promotes release of acetylcholine Other drugs that block muscarinic receptors:
1. antihistamines
CHOLINERGIC ANTAGONISTS/ BLOCKERS 2. antipychotics
3. tricyclic antidepressants
1. Muscarinic blockers S/E: constipation, urinary retention etc…
- atropine, scopolamine- esters of tropic acid and organic 2. Neuromuscular blockers/ Skeletal Muscle Relaxants
base tropine or scopine. - block nicotinic receptors in muscles→ paralysis
- scopine have an oxygen bridge between carbon 6 and 7 - resembles acetylcholine:
- homatropine is a semisynthetic compound produced by succinylcholine- 2 Ach
combining tropine with mandelic acid pancuronium- 2 Ach fragments
- 2 quaternary nitrogens- prevents entry to the
a. Atropine CNS
- aka hyoscyamine a. Nondepolarizing
- prototype - tubocurarine from Curare (Strychnos sp.) used
- alkaloid from deadly nightshade (Atropa as arrow poison in South America
belladonna) and jimsonweed (Datura stramonium) - pancuronium, atracurium, vecuronium
Belladonna/pretty lady- dilated pupils - facilitates intubation for mechanical ventilation,
muscle relaxant during surgery
effects: reverse of DUMBLS: - S/E: brochoconstriction, hypotension due to
Constipation histamine release; respiratory paralysis
Urinary retention - Antidote: neostigmine
Mydriasis, paralysis of accommodation b. Depolarizing
(cycloplegia)→blurring of vision - succinylcholine
Bronchodilation, tachycardia - depolarizes (transient fasciculations)→
Dry mouth, dec. sweating repolarizes (flaccid paralysis)
hallucinations - facilitates intubation for mechanical ventilation,
Mnemonics: muscle relaxant during surgery
hallucinations- ‘mad as a hatter’ - S/E: bronchoconstriction (due to histamine
blurring of vision- ‘blind as a bat’, glaucoma release), hypotension, respiratory depression,
dry mouth- ‘dry as a bone’ arrhythmia, malignant hyperthermia (fever, muscle
tachycardia, cutaneous vasodilation/ flushing- ‘red rigidity)
as a beet’
dec. sweating- ‘hot as hare’ Antidote: dantrolene-
Block Ca release→ dec. Muscle contraction
Uses: 3. Ganglionic blockers
1. Ophthalmoscopic examination- mydriasis a. Hexamethonium, mecamylamine, trimethaphan
(contraindicated for patients with glaucoma) - block ganglia without prior stimulation
2. Organophosphate poisoning - hypertension- rarely used due to lack of
3. Bradycardia selectivity
b. Nicotine
S/E: constipation, urinary retention etc… - initially stimulate then block ganglia
- tobacco, cigarettes (Nicotiana tabacum)
b. Scopolamine (Buscopan, Transderm-Scop) dependence
- aka hyoscine - patch, gum (Nicorette), nasal spray- smoking
- alkaloid from henbane (Hyoscyamus niger) cessation, prevents nicotine withdrawal
- prevent motion sickness- transdermal patch c. Lobeline
-S/E: constipation, urinary retention… - from Indian tobacco (Lobelia inflata)
c. Homatropine (Isopto Homatropine), Cyclopentolate
(Cyclogyl), Tropicamide (Mydriacyl)
- ophthalmoscopic examination
d. Ipratropium (Atrovent)
- quaternary amine- more peripheral effect (lungs),
less CNS effects
- asthma
 β2
Parasympathetic Ganglion blocked - bronchodilation
dominant - uterine relaxation
Heart- bradycardia Tachycardia - glucagon release→ glycogenolysis→ inc. glucose levels
Eye- miosis Mydriasis
GIT- inc. motility Dec. motility Adrenergic Agonists/ Sympathomimetics
Bladder- urination Retention Phenylethylamine
- parent compound
- benzene + ethylamine
Sympathetic Ganglion blocked Cathecholamines
dominant - contain OH at 3, 4 (catechol ring)
Arterioles- Vasodilation - epinephrine, norepinephrine, isoproterenol,
vasoconstriction dobutamine, dopamine
Sweat glands- inc. Dec. sweating - maximal a, B activity
sweating - rapid inactivation by COMT in the intestines-
cannot be given orally
- polar- poor CNS penetration
Botulinum toxin (BOTOX)
- from Clostridium botulinum Non-cathecholamines
- blocks release of acetylcholine - absence of one or both OH in 3,4
- wrinkle treatment, blepharospasm, - phenylephrine, ephedrine, amphetamine
- ‘floppy baby’ syndrome- honey-fed infant - longer duration of action since it is not activated by
COMT
Adrenergic Agonists and Antagonists - can be given orally
- good CNS penetration
Synthesis and Release of Norepinephrine C. Substitution on the alpha carbon
- methylation blocks oxidation by MAO
1. Synthesis - ephedrine, amphetamine
- tyrosine (tyrosine hydroxylase)→ - may promote NE release- indirect-acting activity
dihydroxyphenylalanine/DOPA (decarboxylase)→
dopamine D. Substitutions on the beta carbon
- rate-limiting step is hydroxylation of tyrosine - OH- direct-acting activity
2. Uptake into vesicles
- dopamine enters vesicle (B-hydroxylase)→ Direct acting
norepinephrine - directly bind to the receptor
- norepinephrine is protected from degradation in 1. α, β agonists
vesicle a. epinephrine/ adrenaline
- reserpine inhibits transport into vesicle - anaphylaxis (bronchodilator)
3. Release - cardiac arrest
- Ca causes release of NE - local anesthetics
- guanethidine blocks NE release eg. lidocaine (1:100,000)- prolongs effect
4. Binding to receptor S/E: HTN, arrhythmia, MI,
5. Removal pulmonary edema/hemorrhage
- methylated by catechol O-methytransferase b. Norepinephrine (Levophed)
(COMT) - shock/ hypotension-
- oxidized by monoamine oxidase (MAO) inc. HR, contractility; vasoconstriction →
- recaptured/reuptake by neuron- inh. by cocaine inc. BP
- urine metabolites: vanillylmandelic acid (VMA), c. Dopamine (Docard)
metanephrine, normetanephrine - shock/ hypotension
- congestive heart failure
Receptors: - renal failure to increase blood flow-
α1 dopamine receptors- dilation of renal vessels
- vasoconstriction→ inc. resistance→
inc. BP Low dose : dopamine receptors
- closure of bladder sphincter Moderate dose : β-receptors
- mydriasis High dose : α-receptors
α2
- inh. of NE release 2. Alpha agonists
- inh. insulin release α1- agonists
1. Phenylephrine (Neo-Synephrine, Dimetapp)
β1 - nasal decongestant, shock, mydriatic
- inc. heart rate, contractility S/E: HTN
- lipolysis
2. Phenylpropanolamine - benign prostatic hyperplasia-prevents urinary
(Neozep, Decolgen, Tuseran, Disudrin, Sinutab), retention
Pseudoephedrine (Sudafed) S/E: orthostatic hypotension especially after the
- nasal decongestant first dose
3. Methoxamine 2. α2 blocker
- hypotension - yohimbine
α2- agonists - impotence- penile injection
- clonidine (Catapres) 3. α1, α2 blockers
methyldopa (Aldomet) a. phenoxybenzamine
- tx of HTN- dec. NE release - irreversible, long-acting
- HTN due to pheochromocytoma
3. Beta agonists (adrenal medulla tumor→ epinephrine release)
a. β1 agonists S/E: postural hypotension
-dobutamine (Dobutrex) b. phentolamine
-congestive heart failure - reversible, short-acting
S/E: tachycardia, arrhythmia - pheochromocytoma induced HTN
b.β2 agonists S/E: postural hypotension
- albuterol/ salbutamol (Ventolin)
Terbutaline (Bricanyl), metaproterenol Beta blockers
- asthma 1. Nonselective blockers
- terbutaline- premature labor/ tocolytic – dec. - propranolol, timolol, nadolol
uterine contraction - used for HTN, post-MI, angina pectoris, SVT,
S/E: stimulates B1 at high doses: palpitations, heart failure
tremors - propranolol- migraine, stage fright,
c. β1 and β2 agonists hyperthyroidism
- isoproterenol - timolol- glaucoma
- cardiac arrest, asthma (rare) - S/E: bradycardia, heart block,
S/E: HTN, palpitations, arrhythmia bronchospasm in patients with COPD/asthma
Brochoconstriction- contraindicated for asthmatics
Indirect-acting 2. Selective blockers
- promotes NE release - metoprolol, atenolol, esmolol, acebutolol
1. Tyramine - also blocks B2 receptors at high doses
- red wine, beer, cheese, chocolates 4. Combined alpha and beta blockers
- can cause HTN in patients taking MAO inhibitors - Labetalol, carvedilol
(depression) 5. With partial agonist activity/
intrinsic symphatomimetic activity
2. Amphetamines - Pindolol, acebutolol
- attention deficit hypereactivity disorder (ADHD), - Cause some bronchodilation
appetite suppression - For treating patients with asthma
S/E: HTN, tachycardia, dependence, insomnia,
seizures psychosis

Mixed = Direct and Indirect Agonists

1. Ephedrine
- alkaloid from ma huang (Ephedra sinica)
- urinary incontinence, bronchospasm,
hypotension, nasal congestion, narcolepsy
S/E: HTN, tachycardia, arrhythmia, insomnia
3. Metaraminol
- hypotension

Adrenergic antagonist/ blockers

Direct acting
- directly blocks receptors
Alpha-blockers
1. α1 blockers
- prazosin, doxasozin, terazosin
- HTN- dec. vasoconstriction-
dec. resistance→ dec. BP
DRUGS FOR PSYCHIATRIC & NEUROLOGIC .
DISORDERS S/E:
• drowsiness, dependence
Excitatory neurotransmitters • respiratory depression (+ ethanol, other CNS
- opens Na or Ca channels/ influx→ depolarization depressants)
(more positive)→ nerve impulse
- e.g. Norepinephrine, Dopamine, Acetylcholine, Antidote: Flumazenil (Anexate)- GABA receptor antagonist
Glutamate, Aspartate
B. Barbiturates
Inhibitory neurotransmitters MOA: Barbiturates increase the duration of GABA-
- opens Cl channels→ hyperpolarization (more mediated chloride ion channel opening
negative) → no nerve impulse 1. Ultra-short (20 min): Thiopental (Pentothal)
- e.g. glycine, gamma-aminobutyric acid (GABA) 2. Short-acting (3-8 h):
Pentobarbital (Nembutal)
Sedative-Hypnotics (Minor Tranquilizers) Amobarbital (Amytal)
3. Long-acting (1-2 d): phenobarbital (Luminal)
Anxiety
Types: Uses:
1. Panic disorder- recurrent unexpected panic attacks 1. induction of anesthesia- Thiopental
that can occur with agoraphobia in which patients fear 2. seizures in children- Phenobarbital
places in which escape might be difficult. 3. anxiety- Pentobarbital, Amobarbital
2. Specific phobia- intense fear of particular objects or
situations (e.g. snakes, heights); most common psychiatric S/E:
disorder Drowsiness, dependence, respiratory depression,
3. Social phobia-intense fear of being scrutinized in social paradoxical excitation
or public situations (e.g., giving a speech, speaking in Cytochrome P450 induction→
class). inc. metabolism→ dec. drug levels
4. Generalized anxiety disorder- intense pervasive worry (warfarin, theophylline, phenytoin,
over virtually every aspect of life valproate,carbamazepines, oral contraceptives)
5. Post-traumatic stress disorder- persistent 3. Buspirone (Buspar)
reexperience of a trauma, efforts to avoid recollecting the - serotonin agonist
trauma, and hyperarousal - non-sedating, no dependence
6. Obsessive-compulsive disorder- recurrent
obsessions and compulsions that cause significant Others sedative-hypnotics:
distress and occupy a significant portion of one’s life 1. Zolpidem (Ambien, Stilnox)
- not a Bz but acts on Bz receptor
TREATMENT: 2. Chloral hydrate
A. Benzodiazepines - ‘knockout drops’
- Increase the frequency of GABA-mediated chloride ion - converted to trichloroethanol (active)
- for preoperative sedation
channel opening
3. Antihistamines
1. Short-acting (2-8 hrs) - diphenhydramine (Benadryl), doxylamine
- Oxazepam (Serax) - (Unisom), hydroxyzine (Atarax, Iterax)
- Triazolam (Halcion)
- Clonazepam (Klonopin, Rivotril) Antipsychotics
- Midazolam (Versed, Dormicum) - aka neuroleptics, major tranquilizers
2. Intermediate-acting (10-20 hrs) - “Neuroleptics” because of their tendency to
- Lorazepam (Ativan) cause movement disorders
- Alprazolam (Xanax, Xanor)
- “Major tranquilizers” vs minor tranquilizers (eg.
- Temazepam (Restoril)
3. Long-acting (1-3 days) benzodiazepines)
- due to active metabolites Psychosis
- Diazepam (Valium, Anxionil) - symptoms of delusions, hallucinations, and
- Flurazepam (Dalmane) disorders of thought
- Chlordiazepoxide (Librium) - due to inc. dopamine levels (as in amphetamines)
Uses:
1. Anxiety- alprazolam, diazepam Schizophrenia
2. Seizures- diazepam, clonazepam, lorazepam - characterized by positive and negative symptoms,
3. Insomnia- flurazepam, midazolam a pattern of social and occupational deterioration,
4. Pre-operative sedation- midazolam and persistence of the illness for at least 6 months
 - - 1% of population, inheritable Chemical Classification
Positive symptoms: - Phenothiazines
1. Hallucinations- auditory, visual, tactile, and/or o Aliphatic- chlorpromazine
olfactory hallucinations; voices that are o Piperazine- fluphenazine, perphenazine
commenting o Piperidine- thioridazine
2. Delusions- persecutory, grandiose, paranoid, - Butyrophenones- haloperidol
religious; thought broadcasting, thought insertion - Thioxanthenes- thiothixene
3. Bizarre behavior- aggressive/agitated, odd - Dihydroindolines- molindone
- Diphenylbutylpiperidines- pimozide
clothing or appearance, odd social behavior,
- Dibenzoxapine- clozapine, quetiapine
repetitive-stereotyped behavior - Benzisoxazole- Risperidone
Negative symptoms- affective flattening, alogia, asociality
Positive symptoms respond more consistently with
medications. Negative symptoms are less responsive. Movement Disorders:
1. Extrapyramidal symptoms (EPS)
- aka neuroleptic-induced parkinsonism
- most common (15%)
- coarse tremors, rigidity, bradykinesia
- Risk: high potency
- Tx: lower dose, anticholinergics
2. Acute Dystonia
- Muscular spasm, involuntary movement
- Spasmodic torticollis, trismus, tongue protrusion,
opisthotonos, upward mov’t of eyes (oculogyric crisis)
- Risk: high-potency antipsychotics
- Onset: early in tx (days)
- Tx: IM/IV anticholinergics (benztropine,
diphenhydramine, biperiden)
3. Akathisia
- Subjective feeling of muscular discomfort
- Agitated, pace relentlessly, alternately sit and stand
- Risk: recent increase/onset of meds
- Onset: 1st month of therapy
- Tx: beta-blockers (propranolol), BZDs (lorazepam),
clonidine
Typical Atypical 4.Neuroleptic malignant syndrome (NMS)
Thioridazine (Mellaril, Melleril) Clozapine (Clozaril, - idiosyncratic, life-threatening
Chlorpromazine (Thorazine, Leponex)
- Motor: Muscular rigidity, dystonia, agitation
Laractyl, Psynor) Quetiapine (Seroquel)
Perphenazine (Trilafon) Ziprasidone (Geodon, - Autonomic: hyperpyrexia, hypertension
Thiothixene (Navane) Zeldox) - Tx: discontinue meds, supportive, dantrolene,
Fluphenazine (Prolixin, Modezine, Aripiprazole (Abilify) bromocriptine
Phlufdek, Sydepres) Olanzapine (Zyprexa)
Haloperidol (Haldol, Serenace) Quetiapine (Seroquel)
Risperidone (Risperdal) 5. Tardive dyskinesia
- choreoathethoid movements
- Tongue protrusion/twisting,lip puckering
- Risk: elderly, long-term tx, female,
- Onset: years after tx
- Tx: lower dose, change meds

OTHER ADVERSE EFFECTS:

- Agranulocytosis- clozapine, chlorpromazine
- Pigmentary retinopathy- thioridazine
- ECG changes- prolonged QT interval- ziprasidone

Other uses of antipsychotics:

1. Antiemetic (blocks dopamine receptors)-
prochlorperazine
 2. Intractable hiccups- chlorpromazine S/E: priapism (prolonged, painful erection)
3. Pruritus (antihistamine)- promethazine (Zinmet, 4. Tianeptine (Stablon)
Thaprozine - selective serotonin reuptake enhancer (SSRE)

Antidepressants Antimanic Agents/Mood Stabilizers

Depression Bipolar disorder

- lack of NE, serotonin, dopamine - depression with manic episodes

1. Tricyclics Antidepressants (TCAs)

- three-ring nucleus
- prototypes: amitriptyline, imipramine (Tofranil)
Others:
Clomipramine (Anafranil) Desipramine (Norpramin),
trimipramine (Surmontil)Maprotiline, nortriptyline
(Pamelor), protriptylineDoxepine, amoxapine,
Dosulepine/Dothiepin (Prothiaden

MOA: inhibits neuronal reuptake of NE, serotonin,

dopamine

S/E:
orthostatic hypotension (alpha blocker)
Dry mouth, constipation, blurred vision, urinary
retention- (anticholinergic ) Lithium carbonate (Eskalith, Quilonium)
Cardiac toxicity - DOC
Sexual dysfunction - unknown mechanism
2. Serotonin-specific reuptake inhibitors (SSRIs) - Narrow therapeutic index
MOA: inhibits serotonin reuptake - Therapeutic range: 0.6-1.2 mEq/L
- fluoxetine (Prozac)- prototype Adverse Effects
sertraline (Zoloft), paroxetine (Paxil, Seroxat),
fluvoxamine (Luvox, Faverin), Minor: tremor, polyuria, gastrointestinal
Citalopram (Celexa, Lupram), Escitalopram distress, memory problems, acne exacerbation, weight
(Lexapro) gain
S/E: impotence/dec. libido, Long term: hypothyroidism
+ MAO inhibitor→serotonin syndrome- Toxicity: ataxia, coarse tremor, confusion, coma, sinus
hyperthermia, muscle rigidity, myoclonus arrest, and death
Interactions:
3. Monoamine oxidase inhibitors (MAOIs) diuretics- dec. Na→ inc. Li;
MAO A- serotonin, norepinephrine excessive Na intake→ dec.Li
MAO B- dopamine
Anticonvulsants
- phenelzine (Nardil), isocarboxacid, Seizures
tranylcypromine (Parnate)- inhibits both MAO A - Excessive abnormal electrical discharge from
cortical neurons
and MAO B
- moclobemide (Aurorix)- inhibits MAO A only; - Causes: idiopathic, CNS infection, fever, metabolic
disturbance , cerebral trauma
for depression
- selegeline- inhibits MAO B only; for Parkinsonism Epilepsy
- recurrent unprovoked seizures
S/E: hypertension (+ tyramine-rich foods- cheese,
Types
chicken liver, beer, red wine)
1. Partial Seizure
- Focal area in the brain is involved
Other antidepressants:
- Types:
1. Venlafaxine (Effexor) a. Simple partial
- Serotonin and NE reuptake inhibitor (SNRI) o No impairment of consciousness
2. Mirtazapine (Remeron) o motor or sensory symptoms
- noradrenergic and specific serotonergic
antidepressant (NaSSA) b. complex
3. Trazodone (Desyrel), Nefazodone (Serzone) - with impairment of consciousness
- with automatisms
- Inhibits reuptake of serotonin, antagonist at 5-
2. Generalized
HT2 - Entire brain is involved
 a. Tonic-clonic/ Grand mal GI disturbance, rare pancreatitis and hepatotoxicity,
- Tonic phase- loss of consciousness, rigidity sedation and ataxia at high doses,
- Clonic phase- jerking movements of entire body fetal malformation (spina bifida)
b. Absence/ Petit mal CyP450 inhibitor (phenytoin, carbamazepine,
- In children Phenobarbital)
- brief loss of consciousness (10s) blank stare, 4. Phenobarbital / Phenobarbitone (Luminal)
blinking, facial twitching - MOA: GABA-mediated
c. Myoclonic - for seizures in children
- brief jerks S/E: sedation, paradoxic hyperactivity in children and
elderly, CyP450 inducer (warfarin, phenytoin, valproate,
MOAs: OCPs)
1. Sodium channel blockers 5. Primidone (Mysoline)
- Phenytoin, carbamazepine, valproic acid - related to Phenobarbital, acts on GABA receptor
2. Calcium channel blockers S/E: CNS depression
- Ethosuximide 6. Ethosuximide (Zarontin)
3. GABA-mediated - for absence seizures
- closes Ca channels
- Benzodiazepines, phenobarbital, gabapentin,
S/E: GI disturbance, headache, dizziness, rare: blood
tiagabine dyscrasia, SJS, SLE
7. Benzodiazepines
Indications - diazepam, lorazepam for status epilepticus, frank
1. GTC and partial seizures seizures
- valproic acid, carbamazepine, phenytoin - clonazepam for myoclonic seizures
2. Absence S/E: CNS depression
- ethosuximide, valproic acid 8. Gabapentin (Neurontin)
3. Myoclonic - GABA analog/ for partial seizures
S/E: CNS depression: drowsiness, dizziness, ataxia
- clonazepam, valproic acid
9. Lamotrigine (Lamictal)
4. Status epilepticus - for partial seizures/ blocks Na channels
- diazepam, lorazepam, phenytoin S/E: headache, dizziness, ataxia, rashes, SJS
Febrile seizures- phenobarbital 10. Topiramate (Topamax)
- derivative of fructose
1. Phenytoin (Dilantin, Epilantin) - Na-channel blocker, potentiates GABA
- MOA: closes Na channels S/E: drowsiness, ataxia, headache
CNS: ataxia, nystagmus, diplopia
Connective: hirsutism, gingival hyperplasia 11. Tiagabine (Gabitril)
“Fetal hydantoin syndrome”- cleft palate, congenital heart - prevents uptake of GABA
disease, microcephaly, growth and mental retardation S/E: confusion, dizziness
CyP450 inducer (carbamazepine, valproate, warfarin, 12. Magnesium Sulfate
OCPs) - for eclampsia (HTN + proteinuria + seizures)
Displaced from protein binding by aspirin, sulfonamides S/E: CNS, cardiovascular and respiratory depression
Antidote: Calcium chloride/gluconate
Fosphenytoin- aqueous (phenytoin: ethylene glycol), given
IM/IV ANTI-PARKINSON DRUGS
2. Carbamazepine (Tegretol) Parkinson’s disease
- also used for trigeminal neuralgia - cardinal signs: tremors (resting), rigidity, akinesia,
MOA: closes Na channels postural difficulties
S/E: - pill-rolling tremor, mask-like facies, bent posture,
CNS effects: dizziness, ataxia, diplopia shuffling gait, depression, dementia
GI: nausea, vomiting - due to loss of dopamine-producing neurons in the
Metabolic: hyponatremia substantia nigra
Hematopoietic: leukopenia - imbalance between acetylcholine and dopamine
Derma: rashes, SJS
CyP450 inducer (warfarin, phenytoin, valproate, OCPs), Drugs for Parkinson’s Disease
autoinducer (induces its own metabolism) - Dopamine precursor- levodopa/carbidopa
- Dopamine agonist- bromocriptine, pergolide
3. Valproic Acid + Na valproate (Depakene)
Divalproex Na (Depakote) - MAO inhibitors- selegeline
- closes Na channels - COMT inhibitors- entacapone
- 90% protein bound- displaced by phenytoin and - Amantadine
aspirin - Muscarinic antagonists- benztropine, trihexyphenidyl
S/E:
Levodopa-Carbidopa (Sinemet)
- most effective drug, however prolonged use decreases 2. Ropinirole (Requip)
its efficacy S/E: syncope, hypotensions, hallucinations, drowsiness
- dopamine does not cross the blood-brain barrier
- levodopa can penetrate the brain and decarboxylated to C. MAO (Monoamine oxidase) Inhibitor
dopamine 1. Selegiline / Deprenyl (Eldepryl)
- levodopa is decarboxylated in the GIT- nausea, vomiting, - selective MAOB inhibitor
arrhythmia, hypotension S/E: HTN (high doses also inhibits MAOA)
- carbidopa- inh. peripheral decarboxylase
D. COMT (Catechol O-methyl transferase) Inhibitors
Interactions: 1. Tolcapone (Comtan, Tasmar)
+ MAOIs →HTN S/E: hepatotoxicity
+ pyridoxine→ inc. decarboxylase activity
+antipsychotics→ block dopamine receptors E. Dopamine releaser
1. Amantadine (Symmetrel)
A. Ergot-derived Dopamine Agonists: - also used as antiviral for influenza
1. Bromocriptine (Parlodel, Provasyn) S/E: livedo reticularis (skin discoloration), seizures in
o ergotamine derivative (from ergot Claviceps overdose
purpurea)
o also used in treatment of hyperprolactinemia- F. Anticholinergics/ Antimuscarinics
benztropine (Cogentin), biperiden (Akineton),
galactorrhea, amenorrhea, impotence
trihexyphenidyl (Artane)
S/E: same as levodopa, arrythmia - For mild symptoms especially tremors
S/E: dry mouth, constipation, urinary retention, blurring
2.Pergolide (Permax) of vision
o Ergosine derivative
o S/E: same as levodopa, arrythmia

B. Non-ergot dopamine agonists

1. Pramipexole (Sifrol)
S/E: hypotension, drowsiness, hallucinations,
constipation
 Cardiovascular System

I. HYPERTENSION Sympathetic blockade → orthostatic

 most common cardiovascular disorder hypotension, sexual dysfunction
 sustained BP ≥ 130/80 (systolic/ diastolic) 5. Postganglionic Adrenergic Neuron Blockers
 Reserpine, Guanethidine
⎯ deplete catecholamine stores in the brain
Anti-HPN Drugs & in the peripheral adrenergic system
A. Sympatholytics ⎯ rarely used due to low efficacy & side
1. Centrally-Acting / α Agonist effects
2
 Methyldopa, Clonidine, Guanabenz,
Guanfacine
B. DIURETICS
⎯ presynaptic α agonist → ↓ NE release  ↓ Na, H 0 retention → ↓ BV→ ↓ CO
2
2
by(-) feedback
C. VASODILATORS
⎯ activity of methyldopa: due to stimulation 1. Hydralazine
of central alpha adrenoceptors by  directly relaxes arterioles → ↓ PR
methyldopamine & methylNE  hypertensive crisis (IV or IM) → HPN crisis:
⎯ S/E: BP 210/150 or above
 sedation, dry mouth, depression  S/E: reflex tachycardia, systemic lupus
 methyldopa: false (+) Coomb’s test erythematosus
for hemolytic anemia 2. Minoxidil
 clonidine: rebound hypertension on  directly relaxes arteriolar smooth muscle → ↓
withdrawal PR
2. α Blockers  decreases renal vascular resistance
1
 Prazosin, Terazosin, Doxazosin  S/E: hypertrichosis
⎯ block α → ↓ vasoconstriction → ↓ PR 3. Sodium Nitroprusside
1  has potent effects on both the arterial &
⎯ S/E: orthostatic hypotension especially venous systems
st
 acute hypertensive crisis (IV)
after the 1 dose  S/E: hypotension, cyanide toxicity
3. β Blockers 4. Diazoxide
 ↓ HR, contractility → ↓ CO  exerts a direct action on the arterioles
 block stimulation of renin secretion  acute hypertensive crisis (IV)
 selectivity:  hypoglycemia due to hyperinsulinism
(prevents insulin release)
 S/E: hypotension, hyperglycemia
Selective Non-Selective D. Calcium Channel Blockers
Betaxolol Propranolol  have natriuretic effect. No need for diuretic
Bisoprolol Penbutolol  for patients with HPN + Angina/diabetes
Esmolol Carteolol 1. Dihydropyridines:
Atenolol CarvedILOL (α & β)  1st gen: Nifedipine
Acebutolol LabetALOL (α & β)  2nd gen: Amlodipine, Felodipine, Isradipine,
Nicardipine, Nisoldipine, Nimodipine
Metoprolol Timolol
(selective in cerebral vasculature) vascular
Celiprolol Nadolol smooth muscles
a. vasodilation - ↓ PR
 intrinsic sympathomimetic activity: 2. Non-dihydropyridines:
⎯ Pindolol, Penbutolol, Acebutolol, Carteolol  Verapamil & Diltiazem
 release catecholamines ⎯ vascular smooth muscles & cardiac
 maintain satisfactory HR muscles
 may also prevent bronchoconstriction ⎯ vasodilation - ↓ PR
 S/E: hypotension, bradycardia, CHF, ⎯ (-) inotropic / chronotropic effect - ↓ CO
bronchospasm (asthma, COPD patients) E. ACE Inhibitors
4. Ganglionic Blockers  ↓ angiotensin II → ↓ vasoconstriction → ↓ PR
 Trimethaphan, Hexamethonium  ↓ angiotensin II → ↓ aldosterone → ↓ Na, H 0
⎯ rarely used due to side effects: 2
 Parasympathetic blockade → urinary retention → ↓ blood volume → ↓ CO
retention, blurring of vision  ⬆ bradykinin level →vasodilation
  Pathway: Angiotensinogen → Angiotensin I →
Angiotensin II
 USES:
 Alone: HPN/ CHF/ MI
 (+) diuretic: HPN in black and white
 ACEI and/or ARBS: slow progression of
diabetic nephropathy.
 DI: (+) thiazides → enhance hypotensive action,
plus reducing thiazide induced hypokalemia; (+)
Potassium supplements → hyperkalemia‼
 S/E:
 First-dose hypotension
 Dry cough (most frequent symptom)
 Functional renal failure
 Hyperkalaemia
 Fetal injury
 Urticaria and angio-oedema
 Sulfhydryl group-related effects
⎯ heavy proteinuria
⎯ Neutropenia
⎯ rash
⎯ taste disturbance
F. ANGIOTENSIN II RECEPTOR BLOCKERS (ARB)
 Candesartan cilexetil, Eprosartan, Irbesartan,
Losartan, Olmesartan, Telmisartan, Valsartan
 block the binding of angiotensin II to the
angiotensin II receptors → ⬇ TPR (afterload) and
venous tone (preload)
 S/E: no dry cough, hypotension, hyperkalemia,
teratogenic
G. Renin Inhibitor
 Aliskiren
 Direct renin inhibitor
 S/E: diarrhea, hyperkalemia
II. ISCHEMIC HEART DISEASE
 form of heart disease with primary manifestations
that result from myocardial ischemia due to
atherosclerotic CAD
 Coronary Artery Disease (CAD): refers to a
number of diseases other than atherosclerosis
causing a narrowing of the major epicardial
coronary artery; may present as acute MI,
unstable angina, chronic stable angina or variant
angina
 Angina Pectoris: most common form of IHD;
applied to varying forms of transient chest
discomfort that are attributable to insufficient
myocardial oxygen
 Types of Angina
A. Stable or Classic or Typical or Exertional
(Angina of Effort) or Atherosclerotic
Angina
 most common form
 exertion, emotional stress, or a heavy
meal usually precipitates chest discomfort
 coronary artery obstruction due to
atherosclerotic plaque
 usually relieved by rest, nitroglycerin, or
both
B. Prinzmetal’s or Vasospastic or Variant
Angina or Atypical or Rest angina
 usually occurs at rest rather than with
exertion or emotional stress
 due to coronary artery spasm
 spasm occur at any time, even at night
C. Unstable or Crescendo or Rest Angina or
Preinfarction
 the patient experiences:
⎯ rest angina
⎯ severe new-onset angina
⎯ increasing angina
⎯ decreased response to rest or
nitroglycerin
 due to advanced coronary atherosclerosis
D. Angina Decubitus
 norturnal angina
Strategies
 ↑ O delivery (supply)
2
 ↓ O requirement (demand)
2
 ↑efficiency of oxygen utilization
Anti-anginal Drugs
A. Nitroglycerin (SL, spray, transdermal patch, oral, IV
infusion) Isosorbide dinitrate; mononitrate (SL, oral)
Pentaerythritol tetranitrate (SL); Erythritol
tetranitrate (SL, oral)
 converted to nitric oxide (NO) → inc. cGMP →
smooth muscle relaxation → vasodilation
 venodilation & arterial dilation → ↓ O demand
2
and overall reduction in myocardial fiber
tension
 S/E: throbbing headache; Flushing; postural
hypotension; reflex tachycardia → due to
increased heart rate and contractility); tolerance
“Monday Disease” → industrial disease caused by
chronic exposure to organic nitrates; headache,
dizziness and tachycardia after 2 days absent.
 For nitrites (not nitrates) → methemoglobinemia
⎯ Cyanide toxicity: CN-cytochrome oxidase
complex → oxidative metabolism and cell
death. Methemoglobin, however, has higher
affinity to cyanide than in cytochrome oxidase.
 C/I: sildenafil (PDE5 inhibitor): synergism →
dangerous hypotension
B. CALCIUM CHANNEL BLOCKERS
 Nifedipine, Amlodipine, Felodipine, Isradipine,
Nicardipine, Nisoldipine, Nitrendipine, Bepridil,
Diltiazem, Verapamil
 DOC for Prinzmetal’s angina
 Verapamil and Diltiazem (used also in
supraventricular tachycardia, pulmonary
hypertension and Raynaud’s phenomenon)
 MOA: blockade of L-type voltage dependent
calcium channels → ⬇ contractility; ⬇ heart rate;
vasodilation
 S/E: Constipation (verapamil); Nausea; Flushing;
Dizziness; heart failure; AV blockade; sinus node
depression
C. β BLOCKERS +

 Propranolol; Metoprolol; Atenolol; Nadolol;  no H , no Na reabsorption → diuresis

Timolol; Acebutolol; Betaxolol; Bisoprolol Esmolol;  Indication:
Pindolol ⎯ glaucoma (↓aqueous humor → ↓ intraocular P)
 ↓ HR, contraction→ ↓ O demand → ⎯ acute mountain sickness
2  S/E: metabolic acidosis (loss of bicarbonate),
vasoconstriction (opposing to calcium channel hypokalemia, drowsiness, paresthesias, allergy
blockers) B. LOOP (HIGH-CEILING) DIURETICS
 ⬆ diastolic filling time → ⬆ oxygen supply  Furosemide, Torsemide, Bumetanide, Ethacrynic
 prophylaxis only, not for acute attack Acid
 beneficial if combined with nitrates because the  decrease Na reabsorption by inhibiting the
latter causes reflex tachycardia which is + + -
counteracted by the former Na /K /2Cl transporter in the loop of Henle
 S/E: Bradycardia; arteriovenous nodal block;  Uses: CHF, acute pulmonary edema, acute
decompensated congestive heart failure hypercalcemia
III. DIURETIC AGENTS  S/E: ototoxicity, hypovolemia, hypomagnesemia,
 ↑ urine flow hypokalemia, hyperuricemia, allergy
 inhibit Na reabsorption, water follows C. THIAZIDE DIURETICS
Nephron Parts  Hydroflumethiazide; Methyclothiazide;
 Nephron: main functional unit of the kidney Metolazone; Polythiazide; Quinethazone;
Part Reabsorption of Diuretic Trichlormethiazide
Action  increase urinary excretion of Na & H O by
2
Proximal Na+, K+, Ca2+, carbonic + -
Convoluted Mg2+, glucose, anhydrase inhibiting Na -Cl symporter in the DCT
Tubule amino acids, inhibitors  Uses: HTN, renal calcium stone formation
(PCT) NaHCO3  S/E: hypokalemia, hyponatremia,
Loop of active reabsorption loop diuretics hypomagnesemia, hypercalcemia,
Henle of Na+, K+ & Cl- hyperuricemia, hyperglycemia, hyperlipidemia,
secondary allergy
reabsorption of D. POTASSIUM-SPARING DIURETICS
Ca2+ & Mg2+  Spironolactone; Amiloride; Triamterene;
Eplerenone
Distal active reabsorption thiazide  inhibit Na reabsorption, K secretion at the
Convoluted of Na+ & Cl- diuretics collecting tubule
Tubule Ca2+ reabsorption  combined with loop, thiazide diuretics to prevent K
under parathyroid loss
hormone control  hyperaldosteronism (Conn’s syndrome), CHF
 Spironolactone (aldosterone antagonist)
Collecting Na+ reabsorption potassium-  S/E: hyperkalemia, gynecomastia, impotence
Duct coupled to K+& H+ sparing (due to structural similarity with progesterone)
secretion diuretics E. OSMOTIC DIURETICS
 Mannitol, Urea
 osmotic effect in PCT & thin descending limb of
A. CARBONIC ANHYDRASE INHIBITORS loop of Henle
 Acetazolamide, Dorzolamide, Brinzolamide  lowering of intracranial pressure, removal of toxins
+ -  S/E: hypovolemia, pulmonary edema;
 CO2 + H2O → H2CO3→ H + HCO3 Contraindication: CHF
+ +
 H exchanged for Na in the PCT

Diuretic Mechanism Uses Side effects

Carbonic anhydrase Inhibits carbonic anhydrase in the Glaucoma Metabolic acidosis
inhibitors proximal convoluted tubule, eyes, Acute mountain (high- Hypokalemia
Acetazolamide CNS→ altitude) sickness Drowsiness,
Dorzolamide sodium and bicarbonate excretion paresthesia
Brinzolamide Allergy
(sulfonamides)
Loop diuretics Inhibits Na/K/2Cl transporter in the Acute pulmonary edema, Hypokalemia
Furosemide (sulfonamide) loop of Henle ascites Hypovolemia
Ethacrynic acid hypercalcemia Ototoxicity
(phenoxyacetic acid) Sulfonamide allergy
Bumetanide
Thiazide diuretics Inhibits Na-Cl symporter in the distal hypertension Hyponatremia,
Hydrochlorothiazide convoluted tubule hypokalemia
(sulfonamide) Hyperglycemia
Hyperuricemia,
hyperlipidemia
Sulfonamide allergy
Potassium sparing
diuretics
Spironolactone and Spironolactone- aldosterone Potassium wasting with Hyperkalemia
eplerenone (steroids) antagonist in the collecting tubule diuretics (with K supplements
Amiloride and triamterene Amiloride- blocks sodium channels Aldosteronism (Conn’s and ACEIs)
syndrome) Spironolactone-
gynecomastia
Osmotic diuretics
Mannitol Osmotic effect in the proximal Reduce intracranial Hyponatremia,
Glycerin, isosorbide, urea convoluted tubule pressure in neurologic pulmonary edema
(rarely used) conditions

IV. CONGESTIVE HEART FAILURE  inhibits phosphodiesterase → ↑ cAMP → ↑

 complex clinical syndrome that can result from Ca
any cardiac disorder that impairs the ability of  inodilators
the ventricle to deliver adequate quantities of  S/E: hypotension, arrhythmia,
blood to the metabolizing tissues during thrombocytopenia
normal activity or at rest  Note: These agents should not be used in
 Causes: chronic failure because they have been
⎯ impaired contraction - MI, arrhythmia shown to increase morbidity and mortality
⎯ increased work load – HTN 3. Dopamine
 Strategy:  2-5 mcg/kg/min: renal D receptor
1
⎯ ↑ contractility – inotropics  5-10 mcg/kg/min: β receptor
⎯ ↓ resistance – vasodilators 1
⎯ ↓ fluid retention - diuretics  >10 mcg/kg/min: α receptor
1
4. Dobutamine
A. INOTROPICS - ↑ force of contraction  β & β agonist with some α agonist effect
1. Digoxin 1 2 1
 ⬆ contraction; ⬇ heart rate  produces less tachycardia
 no longer considered first-line drugs in the  Not for chronic failure (also dopamine), due to
treatment of heart failure (Katzung, 9th ed) tolerance, lack of oral efficiacy and
 MOA: inhibits Na-K ATPase pump arrythmogenic effects)
 low therapeutic index B. Vasodilators
 DI: (+) verapamil, quinidine, amiodarone →  ↓ PR
displacement of digoxin from tissue-protein  Clinical Studies:
binding sites and competing with digoxin for ⎯ Nitrates + Hydralazine → ⬇ mortality rates
renal excretion. among African americans
 S/E: Digitalis toxicity (especially if ⎯ Prazosin did not benefit patients.
hypokalemic); anorexia; fatigue, headache & ⎯ CCBs have no value in heart failure.
malaise; mental confusion & disorientation;  Nitroprusside; Hydralazine; Prazosin; Nitrates;
alterations in visual perception (green-yellow Nesiritide - Atrial peptide vasodilator, diuretic for
halo on bright objects); arrhythmia →atrial Acute severe decompensated failure
tachycardia with A-V block (most classic)  S/E renal damage, hypotension
 Digoxin Toxicity Management: C. DIURETICS
 Lidocaine or Phenytoin  ↓ Na, H O retention
 Cholestyramine 2
 Digoxin-specific Fab fragment antibodies  Thiazide
Digoxin Digitoxin ⎯ mild CHF
Lipid medium high ⎯ edema management
solubility ⎯ S/E: hypokalemia, hyperglycemia,
Half-life short long hyperuricemia, hyperlipidemia
excretion renal hepatic ⎯ Note: Thiazide + digoxin: increase digoxin
toxicity (due to hypokalemia)
2. Inamrinone, Milrinone  Loop Diuretics
⎯ Furosemide, Torsemide, Ethacrynic acid,
Bumetanide
 ⎯ acute and chronic heart failure, especially
acute pulmonary edema
 Aldosterone Antagonists
⎯ Spironolactone, Eplerenone
D. β BLOCKERS
 For many years the prevailing view was that -
blockers are contraindicated in CHF
 Rationale of Use:
⎯ ⬆ circulating plasma norepinephrine levels
correlate, ⬇ survival in CHF
⎯ It appears that norepinephrine levels are more
than just markers of disease severity:
norepinephrine is actually directly toxic to
cardiac myocytes, at least in culture.
⎯ The addition of either an α- or β-blocker
confers partial protection from norepinephrine
damage. Combined α- or β-blockade (e.g
carvedilol) confers additive protection
 Bisoprolol, Metoprolol, CarvedILOL
E. Angiotensin-converting enzyme inhibitors
 this are now the first line agent for CHF
 D/I: Potassium sparing diuretics + ACEI →
hyperkalemia
V. Arrhythmia
 deviations from the normal heartbeat pattern
 they include: abnormalities of impulse
formation & conduction disturbances
Myocardial Action Potential
 Verapamil, Diltiazem
Others:
 Adenosine
 Atropine
 Digoxin
 Magnesium sulfate
A. Sodium Channel Blockers
 all group 1 drugs reduce both phase 0 (rate of
rise/upstroke) and phase 4 sodium currents
(wavy lines) in susceptible cells.
 Group 1A
⎯ ⬇ upstroke
⎯ ⬇ phase 3 potassium current (I )
K
⎯ ⬆ action potential (AP) duration
⎯ ⬆ effective refractory period (ERP)
⎯ ⬇ conduction velocity
1. Procainamide
 Atrial and ventricular arrhythmias,
especially after myocardial infarction
 Procainamide is a particularly useful
antiarrhythmic drug, effective in the
treatment of supraventricular, ventricular,
and digitalis-induced arrhythmias.
 Increased arrhythmias, drug fever,
agranulocytosis, SLE-like syndrome
(fatigue, arthralgia, myalgia & low-grade
fever)
2. Disopyramide
 Similar to procainamide but longer
duration of action
 toxicity includes antimuscarinic effects
and heart failure
3. Quinidine
 Similar to procainamide but toxicity
includes cinchonism (tinnitus, headache,
gastrointestinal disturbance) and
thrombocytopenia.
4. Moricizine
 life-threatening arrhythmias
 Not classified as IA or IB, but shows
effect as them

 Group 1B
⎯ ⬇ action potential duration
+
⎯ ⬆ outward K current
⎯ Minimal ⬇ in upstroke
Vaughan Williams’ Classification of Antiarrhythmic 1. Lidocaine
Drugs  DOC for digitalis-induced arrhythmia
 Class I (Na Channel Blockers)  DOC for sustained ventricular arrhythmia
 IA: Quinidine, Procainamide, Disopyramide after acute MI
 IB: Phenytoin, Lidocaine, Mexiletine, Tocainide  S/E: CNS reactions (most pronounced);
 IC: Flecainide, Propafenone, Moricizine sedation or excitation
 Class II (β Blockers) 2. Mexiletine
 Propranolol, Esmolol, Acebutolol  Similar to lidocaine but oral activity and
 Class III (K Channel Blockers) longer duration of action
 Bretylium, Amiodarone, Sotalol, Ibutilide, Dofetilide  For acute or chronic ventricular
 Class IV (Ca Channel Blockers) arrhythmias
 While it is not at present an indication for
use, there is interest in using mexiletine to
treat the congenital long QT syndrome
when an abnormality in the SCN5A gene
(LQTS 3) has been found.
⎯ S/E: Bronchospasm; cardiac depression,
atrioventricular (AV) block, hypotension
2. Esmolol
⎯ Selective B -receptor blockade
1

3. Phenytoin ⎯ Given via IV only, 10-min duration.

 an anticonvulsant and not a true local ⎯ Used in perioperative and thyrotoxicosis
anesthetic arrhythmias
 sometimes classified with the group 1B
antiarrhythmic agents because it can be C. Potassium Channel Blocker
used to reverse digitalis-induced  ⬆ AP duration
arrhythmias  ⬆ ERP
 Also in ventricular arrhythmias in  delaying repolarization without altering phase 0
children  Class III drugs have a significant risk of
4. Tocainide proarrhythmia because of the prolongation of
 structural similarity to Lidocaine action potential and the induction of torsades de
 For symptomatic ventricular arrhythmias pointes
refractory to more conventional therapy 1. Amiodarone
⎯ Refractory arrhythmias; used off-label in
 Group IC many arrhythmias (broad spectrum of
⎯ No effect on action potential therapeutic action)
⎯ Marked ⬇ in upstroke ⎯ 1st choice antiarrhythmic for shock-
⎯ ⬇ conduction velocity refractory ventricular
1. Flecainide fibrillation/ventricular tachycardia
 Refractory arrhythmias ⎯ S/E: Thyroid abnormalities, deposits in
 intractable supraventricular arrhythmias skin and cornea, pulmonary fibrosis,
 most types of atrial arrhythmias optic neuritis; Torsades de pointes;
 Now restricted to use in persistent Photosensitivity
arrhythmias that fail to respond to ⎯ Peripheral neuritis
other drugs 2. Sotalol
 Increased arrhythmias; CNS excitation ⎯ Ventricular arrhythmias and atrial
2. Propafenone fibrillation
 supraventricular arrhythmias and life- ⎯ Dose-related torsade de pointes; cardiac
threatening depression
 ventricular arrhythmias in the absence of 3. Ibutilide
structural heart disease ⎯ Treatment of acute atrial fibrillation
3. Moricizine ⎯ Ibutilide is IV only
⎯ Torsade de pointes
Drug Uses Side effects 4. Dofetilide
Class IA ⎯ Treatment and prophylaxis of atrial
Procainamide All types; AF, Hypotension, lupus fibrillation
VT
Quinidine Cinchonism (HA, vertigo,
⎯ Torsades de pointes
tinnitus) Drug Uses Side effects
GI upset, inc. digoxin levels, Bretylium Refractory Arrhythmia, hypotension
torsades de pointes post-MI VF
Disopyramide Antimuscarinic Sotalol oral Torsades, bradycardia,
Class IB asthma
Lidocaine VT/VF; IV Convulsions, allergy Ibutilide and AF torsades
Mexiletine Oral Dofetilide
Tocainide Oral Agranulocytosis D. Calcium Channel Blocker
Class IC  reduce inward calcium current during the AP and
Flecainide Refractory VT proarrythmic during phase 4 (wavy lines)
Propafenone  Major effect: ⬇ conduction velocity is slowed in the
Moricizine AV node
 refractoriness is prolonged
B. Beta-Blockers  Verapamil & Diltiazem
 Cardiac membrane stabilization ⎯ AV nodal arrhythmias, especially in
 Prolong ERP prophylaxis
1. Propranolol ⎯ 1st line agents for the suppression of
⎯ Postmyocardial infarction as paroxysmal supraventricular tachycardia
prophylaxis against sudden death stemming from AV nodal reentry
ventricular fibrillation & thyrotoxicosis
 ⎯ S/E: Cardiac depression; constipation,
hypotension A. Anticoagulants
⎯ Nifedipine and the other dihydropyridines - prevents clot formation
are not useful as antiarrhythmics

Drug Uses Side effects

Verapamil AF (1st line); Hypotension Heparin Warfarin
IV, oral Chemistry Sulfated Coumarin
Diltiazem Oral glycosaminoglycan

E. Miscellaneous Anti-Arrhythmics a. unfractionated

1. Adenosine b. low-MW
⎯ AV node that causes marked Mechanism Activates Inhibits vitamin K
hyperpolarization and conduction block antithrombin synthesis
⎯ endogenous product of the metabolism of Uses Post-MI, Prevention of
adenosine triphosphate prevention of DVT DVT and PE,
⎯ Acute nodal tachycardias and PE Atrial fibirillation
⎯ DOC for paroxysmal supraventricular Artificial heart
tachycardia valves
⎯ If asthmatic: verapamil Route IV or SC (not IM→ Oral, IV
⎯ S/E: Flushing, bronchospasm, chest pain, hematoma)
headache Monitoring Activated partial Prothrombin time
2. Potassium ion thromboplastin (expressed as
time INR)
⎯ Digitalis toxicity and other arrhythmias if
serum K is low Target 1.5-2.5x control INR 2-3
⎯ Both hypokalemia and hyperkalemia are Side-effects Bleeding, allergy, Bleeding,
associated with arrhythmogenesis. thrombocytopenia teratogenic
⎯ Severe hyperkalemia causes cardiac Antidote Protamine sulfate Vitamin K
arrest (1mg/100 units)
3. Magnesium sulfate
Heparin and related agents
⎯ Poorly understood, possible increase in
+ + 1. Unfractionated heparin
Na /K ATPase activity - MW= 5,000-30,000 daltons
⎯ Indications: Digitalis arrhythmias and other 2. Low molecular weight heparins (LMWH)
arrhythmias if serum Mg is low; Torsades - Enoxaparin, dalteparin, tinzaparin
de Pointes - Longer half-life
⎯ S/E: Muscle weakness, severe - Less bleeding, routine aPTT unnecessary
hypermagnesemia can cause respiratory 3. Danaparoid Na
paralysis, - Mixture of 3 sulfated glycosaminoglycans: heparin,
Drug Uses Side effects dermatan and chondroitin
Adenosine PSVT (1st line); Flushing, 4. Fondaparinux Na
short duration (15 hypotension
s)
Magnesium Torsade de point Direct thrombin inhibitors
sulfate - derived from hirudin obtained from the saliva of
the medicinal leech Hirudo medicinalis
- Lepirudin, Bivalirudin, Desirudin
- anticoagulant for patients with heparin-induced
thrombocytopenia (HIT)

B. Thrombolytics
-dissolves clot
DRUGS AFFECTING BLOOD - converts plasminogen→ plasmin (fibrinolytic)
1. Streptokinase
Review Coagulation Pathway - protein from streptococci
- MI, DLVT, PE
Virchow’s triad of thrombus formation: - S/E: hemorrhage, allergy
1. venous stasis- illness, surgery, paralysis, obesity 2. Tissue plasminogen activators
2. vascular injury- surgery, trauma, atherosclerosis - Alteplase, Reteplase, Streptokinase
3. hypercoagulable states- malignancy, antiphospholipid - MI, DLVT, PE
antibodies, estrogens - only binds to plasminogen bound to fibrin
 - S/E: hemorrhage - Uses: prevention of MI, stroke
a. Clopidogrel
-S/E: nausea, vomiting, diarrhea, hemorrahe
b. Ticlopidine
- S/E: neutropenia
3. Dipyridamole
- prevention of stroke and MI; nuclear cardiac
C. Antiplatelets stress testing
-inh. platelet aggregation - inhibits adenosine reuptake→dec. platelet
-prolongs bleeding time aggregation
- Uses: prevention of MI, stroke - inhibits phosphodiesterase→ inc. cGMP→
1. Aspirin vasodilation
- prevents thromboxane synthesis by inhibiting 4. Glycoprotein IIb/IIIa inhibitors
cyclooxygenase - Abciximab, Eptifibatide, Tirofiban
- Uses: prevention of MI, stroke - for patients undergoing percutaneous coronary
- S/E: GI ulcer, bleeding intervention (angioplasty)
2. Thienopyridines -S/E: bleeding
- blocks ADP receptor in the platelet cell
membrane
ANEMIA 1. Bile acid-binding resins
- characterized by a decrease in hemoglobin or - cholestyramine, colestipol, colesevelam
RBCs - positively-charged ammonium polymers
1. Iron deficiency anemia - bind to negatively-charged bile acids and
- characterized by hypochromic microcytic anemia excreted in feces, interrupts enterohepatic
- caused by inadequate dietary intake, inadequate circulation→
GI absorption, increased demand inc. synthesis of bile acids from cholesterol
(eg. pregnancy), blood loss and chronic diseases - effects: ↓LDL ↑VLDL
- Dx: serum ferritin- earliest and most sensitive -S/E: GI discomfort (constipation, bloating,
test; CBC, peripheral blood smear flatulence)
dec. absorption of fat soluble vitamins
Oral iron products: 200 mg elemental iron in 2-3 divided reduced bioavailability of acidic drugs (warfarin,
doses nicotinic acid, paracetamol etc.)
Salt % elemental iron
Fe sulfate 20 2. Niacin/ Nicotinic Acid
60-65 mg/325 mg tablet - aka Vitamin B3
Fe glucontae 12 - blocks lipolysis in adipose tissue which reduces
Fe fumarate 33 circulating free fatty acids
Polysaccharide iron complex 100 - effects: ↓LDL ↓VLDL ↑HDL
Carbonyl iron 100 - S/E: flushing, itching, hepatitis, hyperglycemia,
hyperuricemia
Parenteral iron preparations: - take aspirin after and avoid alcohol and hot
• Sodium ferric gluconate-IV drinks to prevent flushing and pruritus
• Iron dextran- IM, IV
3. HMG-CoA reductase inhibitors
• Iron sucrose- IV
- lovastatin, simvastatin, atorvastatin, pravastatin,
fluvastatin, rosuvastatin
2. Vitamin B12-deficiency anemia
- structural analogs of HMG-CoA intermediate
- macrocytic cells
- inhibits 3-hydroxy-3-methylglutaryl coenzyme A
- caused by inadequate dietary intake, decreased
(HMG CoA) reductase interrupting the conversion
absorption (eg. pernicious anemia- lack of intrinsic
of HMG-CoA to mevalonate, the rate-limiting step
factor)
in cholesterol synthesis
- distinguished from folate deficiency by neurologic
- most potent total and LDL lowering agents
abnormalities (numbness and paresthesias)
- effects: ↓LDL
- Tx: oral, parenteral or intranasal gel
- S/E: constipation, elevated liver enzymes,
cyanocobalamin
myopathy, rhabdomyolysis
3. Folate-deficiency anemia
4. Fibrates
- megaloblastic anemia
- clofibrate, gemfibrozil, fenofibrate
- no neurologic abnormalities
- increases activity of lipoprotein lipase
- Tx: oral folate 1 mg daily
- effects: ↓LDL ↓VLDL ↑HDL
4. Anemia in chronic kidney disease
- S/E: GI disturbance, gallstones, myositis
- due to deficiency of erthropoeitin
- Tx: epoetin alfa, darbepoetin alfa SC, IV;
5.Ezetimibe
iron supplementation
- interferes with absorption of cholesterol in the
intestines
Hyperlipidemia
- effects: ↓LDL
- elevation of one or more of the following:
- adjunct with statins
cholesterol, phospholipids, or triglycerides
- S/E: GI upset
- elevated LDL and reduced HDL are associated
with coronary heart disease
 ENDOCRINE SYSTEM

Pituitary Gland Hypothalamus Peripheral Peripheral Hormone Effects

Gland

A. Anterior Pituitary
1. adrenocorticotropic corticotrophin Adrenal cortex Glucocorticoids Gluconeogenesis
(ACTH)/coticotropin releasing (CRH) (cortisol), during stress
Mineralocorticoids Sodium and water
(aldosterone) retention→ inc. blood
volume
2. growth hormone Growth hormone Bones,
(GH) releasing (GHRH) muscles- growth
3. thyroid stimulating Thyrotrophin Thyroid Triiodothyronine (T3) Increase metabolic rate
(TSH)/thyrotropin releasing (TRH) Thyroxine (T4)
4. follicle stimulating Gonadotrophin Ovary Estrogen Growth of endometrium
(FSH)/gonadotropin releasing (GnRH) Secondary sex
characteristics- breast,
hips
5. luteinizing Gonadotrophin Ovary Progesterone Growth of endometrium
(LH)/gonadotropin releasing (GnRH) Testis Testosterone Secondary sex
characteristics in males
6. Prolactin Prolactin Milk production
Releasing (PRH)

B. Posterior Pituitary
1. Vasopressin/ Water reabsorption in
antidiuretic hormone kidney tubules
(ADH)

2. Oxytocin Milk ejection, uterine

contraction
Characteristics Of Acromegaly:
Growth Hormone macrognathia
DEFICIENCY protrusion of the chin
macroglossia
Treatment widening of space between the teeth
GH replacement frontal bossing/embossed eyebrows
Side Effect: Creutzfeldt-Jakob disease thickened skin
Prions
administering of human growth hormone derived from Treatment:
cadaver pituitary glands. 1. Surgical removal of tumor causing pressure in GH
release
Preparations 2. Somatostatin/Octreotide
Somatrem
therapeutically equivalent drug SOMATOMEDINS
Sermorelin INSULIN LIKE GROWTH FACTORS
infusion of GHRH Polypeptide growth factor
used to assess status of GH deficiency secreted by liver and tissues
Effects
Growth Hormone Stimulate incorporation of SO4 into cartilage
EXCESS Stimulate collagen formation
A) Prepubertal Increase cell division in the body
Effect:
B) Post-pubertal (adult)
Effect: Growth Hormone Inhibiting Hormone
SOMATOSTATIN
originally isolated from the hypothalamus, also found in the
neurons throughout the body
Analogue: OCTREOTIDE Endogenous:
USE: ❑ Cortisol (Hydrocortisone)
acromegaly caused by hormone-secreting tumors ❑ Cortisone
❑ Corticosterone
Adrenocorticotropic Hormone
Glucocorticoids
CORTICOTROPHIN
Sources of ACTH preparations:
THERAPEUTIC USES
a) anterior pituitaries of domestic animals (antibodies can
• Allergy
form)
b) synthetic human ACTH preparations= COSYNTROPIN • Hematologic disorders
preferred in the diagnosis of adrenal insufficiency • Collagen vascular disease
• Inflammation of bones and joints
MINERALOCORTICOID • Skin disease
Aldosterone Mineralocorticoids
Physiologic effects = Pharmacologic effects
Glucocorticoid • Reabsorption:
 gluconeogenesis Na, HCO3, Water
 protein catabolism • Secretion:
 lipolysis K, Cl, H
Anti-inflammatory effect • Endogenous:
Inhibits phospholipase A
Aldosterone, Desoxycorticosterone
 prostaglandin synthesis
 leukotriene synthesis MINERALOCORTICOID
 capillary permeability Adrenocortical Antagonists
 mast cells (Inhibitors of adrenocorticoid synthesis)
 phagocytosis 1. Metyrapone
 IL-2 and T cells • MOA:
Stabilize lysosomal membrane • Use: test for adrenocortical function
 histamine and serotonin release 2. Aminogletethimide
• MOA: Use: eliminate estrogen and
Addison’s Disease
androgen production; Breast CA
Primary adrenocortical insufficiency
Autoimmune destruction of adrenal cortex 3. Ketoconazole
• MOA:
 ACTH
 GLUCOCORTICOID • Use: Cushing Syndrome
 ANDROGENS 4. Mitotane
 MINERALOCORTICOID • MOA: Use: most commonly used in
Mental lethargy conjunction with pituitary irradiation
Weight loss
Hypoglycemia Thyroid hormones and drugs
Hyperkalemia Overview
Hypotension Thyroid gland
Dehydration facilitates in the normal growth and maturation by
 ACTH maintaining the level of metabolism in the tissues that is
Secondary Adrenocortical Insufficiency optimal for their function
Thyroid hormones are important for:
Adrenocortical Excess Growth and development
CUSHING’S SYNDROME Body temperature
Pharmacologic doses of glucocorticoids Energy levels
Bilateral hyperplasia of adrenal glands
Cushing’s disease if due to  ACTH Thyroid Hormones: deficiency
Myxedema coma
Pheochromocytoma
Tumor of chromaffin cells of adrenal medulla SYNTHETIC LEVOTHYROXINE (T4)
Excess catecholamines Preparation of choice for replacement and suppression
Rapid heart rate High BP therapy
High blood glucose elevated BMR Stable
Flushing of face nervousness Uniform content
Sweating  GIT motility Low cost
Long half-life
Glucocorticoids Conversion to both T4 and T3
 Not used alone
DESSICATED THYROID May exacerbate thyrotoxicosis
Though inexpensive, not recommended Contraindications:
Antigenicity Chronic use in pregnancy
instability Cross placenta
Variable hormone content Cause fetal goiter
Lugol’s solution
LIOTHYRONINE (T3) MOA:
3-4x more active than levothyroxine, but not recommended S/E:
Higher cost hypersensitivity reaction, Iodism
Short half-life (24 hours) Sialodenitis, conjunctivitis, rhinitis
Greater potential for carditoxicity Antithyroid drugs
Advantages:
LIOTRIX Simplicity
A 4:1 combination of synthetic T4 and T3 Inexpensive
Expensive Relatively nontoxic
Same disadvantage as levothyronine Absence of glandular dysfunction
Disadvantages:
Grave’s Disease “Escape” from iodide block
Thyroid Hormones Aggravation of thyrotoxicosis
HYPERSECRETION Allergic reactions
Thyrotoxic Crisis or thyroid storm Delay onset of thioamide therapy
Rare, Life-threatening Prevent RAI therapy for several weeks
Fever, delirium, seizures, coma, vomiting, diarrhea,
jaundice 4. RADIOCONTRAST DYES
Cardiac failure, arrhythmia, hyperthermia Ipodate
Treatment: PTU then iodide Iopanoic Acid
MOA:
Precipitating factors:
Acute illness 5. PROPRANOLOL
Surgery -Beta-blocker
Radioiodine therapy MOA:
Hyperthyroid
6. DEXAMETHASONE
TREATMENT MOA:
1. THIOAMIDES
Propylthiouracil (PTU) 7. RAI (I131)
Methimazole MOA
Carbimazole Indications:
MOA: only isotope used for the treatment of thyrotoxicosis.
* PTU-also inhibits peripheral conversion Pharmacokinetics:
S/E: given as oral solution, I is rapidly absorbed, concentrated
pruritic maculopapular rash (most common) in the thyroid, and incorporated into storage follicles
Rash, urticaria, fever, arthralgia (1-5%)
Hepatitis, SLE-like syndrome, agranulocytosis (<1%) Contraindication:
hepatitis (PTU) pregnancy, crosses the placenta
obstructive jaundice(methimazole) excreted in breastmilk

2. ANIONIC INHIBITORS
(Inorganic anions)
K perchlorate Pancreas
Thiocyanate Overview
MOA: The pancreas is both an ENDOCRINE and EXOCRINE
S/E: organ
Aplastic anemia (KClO4) ENDOCRINE: Insulin, glucagon, somatostatin
Nephrotic syndrome EXOCRINE: digestive enzymes

3. IODIDES INSULIN
KISS 4 Main Sites of Action:
Lugol’s solution 1. Glucose transporters to facilitate glucose
Indications: movement across cell membranes.
Thyrotoxic symptoms improve within 2-7 days.
 2. Liver to increase storage of glycogen and
decrease post-absorptive catabolism.
3. Muscle to promote protein and glycogen
synthesis.
4. Adipose tissue to reduce free fatty acids and
promote triglyceride storage.
BIGUANIDES
Euglycemic or antihyperglycemic
Reduce fasting and postprandial glucose
MOA:
Liver: Decrease the amount of glucose made by the liver
Muscles and Fat Tissue: Increase insulin sensitivity of
muscles and adipose tissue

ORAL ANTIDIABETIC DRUGS Metformin

SULFONYLUREAS USE:
Most effective for individuals with recent DM onset (<5 for obese patients
years). Type 2 DM who do not respond to SU alone
Reduce both fasting and post-prandial glucose Side effects:
Should be taken shortly before meals. GI: anorexia, nausea, vomiting, abdominal discomfort,
C/I: hepatic and renal failure diarrhea
MOA: Lactic acidosis
➢ Stimulate pancreatic release of insulin Megaloblastic Anemia
➢ Inhibit pancreatic release of glucagons C/I:
➢ Increase insulin binding capacity Renal failure, Radiographic contrast studies, Seriously ill,
➢ Decrease hepatic extraction of insulin acidosis
Cannot readily control the symptoms of DM because of its
MOA
1st Generation Sulfonylureas
Patients fail to respond initially when blood glucose level is
Chlorpropamide
high
Longest half-life (60-90 hours)
Better to add a secretagogue
Has most side effects
Metformin + SU
Avoided in initial treatment
α-GLUCOSIDASE INHIBITORS
Tolbutamide
Hypoglycemic
Fastest onset of action (30 mins)
Prior to ingestion of meal
Most cardiotoxic
MOA:
Inhibit alpha-glucosidase
Acetohexamide
Unique, reduce postprandial hyperglycemia by delaying
Converted to an active metabolite (hydrohexamide)
glucose absorption
Tolazamide
Side Effects:
Flatulence, Diarrhea, Abdominal pain
2nd Generation Sulfonylureas
Acarbose: maybe hepatotoxic
Glyburide/
C/I:
Glybenclamide
Chronic or intestinal bowel disease
Glipizide
Gliclazide
THIAZOLIDINEDIONE (TZDs)
Glimepiride
Euglycemic
Side effects:
MOA:
Hypoglycemia
Insulin sensitizers by stimulating PPARy receptors—
Blood dyscrasias
increase skeletal muscle sensitivity
Disulfiram-like reactions (with 1st generation agents and
Decrease hepatic gluconeogenesis
Glipizide)
Major site of action: adipose tissue
Weight gain
Side Effects:
Hepatic failure: Reason for Troglitazone withdrawal
MEGLITINIDES
Edema
Repaglinide, Nateglinide
Mild anemia
Used mainly for controlling post-prandial glucose levels.
Expanded plasma volume
Taken shortly before meals
Weight gain
Can be used for patients allergic to SU
Contraindications:
MOA:
Liver disease
➢ Increase pancreatic insulin
CHF
secretion Pregnancy*
➢ Short-duration of action: 1-3 hours
Side effects:
➢ Hypoglycemia SEX HORMONES
➢ Weight gain Menstrual Cycle
28 days + or - days
Varies from 28-40 days 2. Used in Hypogonadism
The time from ovulation to beginning of menses is
constant (14-15 days). ANALOGUES:
Leuprolide
Menstrual cycle Goserelin
Days 1-5: Menses—thick endometrial lining from the Nafarelin
uterus is sloughed off Histrelin
Days 6-14: Proliferative stage—stimulated by rising
estrogen levels produced by growing follicles of the These act as inhibitors of GnRH
ovaries, the endometrium is repaired, glands are formed in Effective in suppressing gonadal H
it and the endometrial supply is increased CLINICAL USE:
OVULATION occurs at the end of this stage in response to prostatic cancer
LH surge endometriosis
Days 15-28: Secretory stage precocious puberty
Corpus luteum produces progesterone
ESTROGEN
Progesterone Natural, steroidal
further increases the blood supply of the ovary ➢ Estradiol (E2)—major secretory estrogen
Causes the endometrial glands to increase in size and ➢ Estrone (E1), Estriol (E3)—formed from estradiol
begin secreting nutrients in the uterine cavity, which will
in the liver or from androstenedione and other
sustain the developing embryo
If fertilization occurs: embryo will produce a hormone androgens in peripheral tissues
similar to LH, which will cause the corpus luteum to Synthetic, steroidal
continue producing hormones. ➢ Ethynilestradiol, Mestranol, Quinestrol
If fertilization does not occur, the corpus luteum begins to Synthetic, Nonsteroidal
degenerate toward the end of this period when LH ➢ DES, Chlorotrianisene, Methallenestrel
declines.
ESTROGEN
Natural method of contraception EFFECTS:
Fertility awareness methods 1. Normal female maturation and development of
Periodic abstinence is also referred to: endometrium
a) Rhythm method 2. Metabolic effects
b) Natural family planning a. Dec bone resorption, Inc bone formation
c) Ovulation detection b. Inc HDL, Dec LDL
c. Inc biliary cholesterol secretion with dec bile acid
Temperature method secretion.
Within 24 hour preceding ovulation, there is a moderate d. Inc circulating levels of Factors II, VII, IX and X and Dec
drop in basal temperature followed by a noticeable rise in anti-thrombin III, Inc plasminogen levels
body temperature, usually 24 hours after ovulation
Estrogen: Therapeutic indications
Progesterone (thermogenic) Oral contraceptives (in combination with progestins)
Falling to rising temperature Treatment of menopausal symptoms
Abstinence 5 days after onset of menses until 3 days after Urogenital atrophy
transition of temperature Psychologic disorder
Acne
Calendar Method Osteoprosis
Based on 3 assumptions: Prostate CA
Ovulation occurs 14(+ 2) days before the onset of next
menses ESTROGEN
Sperm remain viable for 2-3 days Adverse Responses (dose-dependent):
Ovum survives for 24 hours a. Congenital reproductive tract abnormalities
Women tabulate menstrual period for at least 1 year b. Clear cell vaginal and cervical adenoCA in women
Subtract 18 from shortest cycle exposed to estrogens in – utero (esp DES)
Subtract 11 from longest cycle c. Endometrial CA
Cervical mucus method or Billing’s method d. Post-menopausal bleeding
Normal: thick, creamy white e. Nausea and Breast tenderness
Ovulation: clear and tenacious (like raw egg white) f. Hyperpigmentation
Abstinence 3-4 days after peak change g. Migraine headache
h. HTN
Gonadotropin Releasing Hormone
Function: TAMOXIFEN
1. controls release of FSH and LH
 ➢ Nonsteroidal, competitive partial agonist – inhibitor HORMONAL CONTRACEPTIVES
of estradiol at estrogen receptors. Combination Oral Contraceptives
➢ Antagonistic effects: blocks binding to receptors in (contain both Estrogen and Progestin)
▪ Provided as 21 or 28 day packs
estrogen receptor – containing neoplasia.
Estrogen component: Ethinyl estradiol, Mestranol
➢ Agonistic effects: metabolic effects on bone and
Progestin component: 19-Nor compounds
lipids
SIDE EFFECTS: Hot flushes, N&V Combination Oral Contraceptives
1. Monophasic
▪ Same amount of hormones in each pill
PROGESTINS
taken daily
Natural: Progesterone
Synthetic: 2. Biphasic
a. Progesterone derivatives: ▪ Provide 2-3 different pills with varying
❑ Hydroxyprogesterone caproate amounts of active
❑ Medroxyprogesterone acetate 3. Triphasic
❑ Megestrol acetate ▪ Ingredients are taken at a different times
b. Testosterone derivative: during the 21 day cycle.
❑ Dimethisterone
c. 19-Nortestosteone derivatives: PROGESTIN ONLY CONTRACEPTIVES
❑ Norethynodrel 1. Minipill
❑ Lynestrenol ▪ Low dose progestine (350 ug
❑ Norethindrone and its acetate Norethindrone or 75ug Norgestrel)
❑ Ethynodiol diacetate 2. Implant
❑ L-norgestrel ▪ Subdermal implant of 216mg of
d. 13-Ethyl 19-Nortestosterone derivatives—less Norgestrel(Norplant)
androgenic ▪ 5 yrs.
❑ Desogestrel 3. Intramuscular
❑ Norgestimate ▪ Given q3 months: 150mg
❑ Gestodone Medroxyprogesterone acetate
Effects (Depo-Provera)
↑ lipoprotein lipase activity 4. Intrauterine device
↑basal insulin and insulin response to glucose
▪ For yearly insertion: Progestasert
Hepatic glycogenesis and ketogenesis
Compete with aldosterone (but stimulate aldosterone
secretion) PROGESTIN ONLY CONTRACEPTIVES
Thermogenic effect (hypothalamus) POST COITAL Contraceptives
Depressant and Hypnotic effects on the brain ▪ Morning-after pills
Alveolobular development of secretory apparatus of the ▪ Ethinyl estradiol + Norgestrel, Ethinyl
breast Estradiol, Conjugated estrogen, Estrone,
Endometrial changes DES

Adverse Effects Chemical Contraceptive

HTN Gossypol
Reduction of plasma HDL levels in women (of the more From cottonseed
androgenic progestins) Destroys seminiferous tubule

ANTI-PROGESTINS Fertility Drugs

RU 486 (MIFEPROSTONE) 1. Clomiphene Citrate
MOA: ▪ MOA:
➢ Competitive antagonism of both Progesterone and
▪ May block negative feedback of
glucocorticoid to their receptors (in the presence of
endogenous estrogen with the end result
an agonist)
of inc amplitude of LH and FSH pulses
➢ Acts as a weak partial agonist when given alone
▪ S/E: multiple pregnancy
Administration during EARLY pregnancy result in abortion
2. HMG
S/E: Uterine bleeding and incomplete abortion
▪ Human Menopausal Gonadotropin
➢ + PGE1 intravaginally or Misoprostol PO =
▪ Urofollitropins
complete abortion
▪ Menotropins
▪ Contains FSH and LH
 ▪ Direct ovary stimulant preferred because free of pressor effects and longer-acting
3. HCG Administered intranasally
▪ Human Chorionic Gonadotropin major use of ADH and Desmopressin: Diabetes insipidus
▪ Acts like LH

Bone Homeostasis
ANDROGENS
Calcium Regulation
Testosterone
Function
Methyltestosterone
Regulation of neuromuscular irritability
Danazol
Normal muscle contraction
Nandrolone
Normal bone mineralization
Normal blood coagulation
Endogenous: Testosterone (dose: 8ug/day)—converted by
Regulates Ca, PO4 flux across cellular membrane in bone
5 a reductase to dihydrotestosterone
and kidney
Effects:
Increases serum Ca
Male differentiation
Decreases serum PO4
Pubertal changes
Increases osteoclast activity → bone resorption
Inc skeletal muscle
Stimulate kidney production of 1,25di(OH)vitD
Inc bone growth
Development of 2° sexual characteristics
Vitamin D
Produced in the skin from 7 dehydrocholesterol under
USE:
influence of UV light
Androgen replacement
Also found in food
Gynecologic disorders (endometrial bleeding)
PLANTS: Vitamin D2: ergocalciferol
Anabolism
ANIMALS: Vitamin D3:cholecalciferol
Refractory anemia
prohormone
Osteoporosis
Calcitriol: 1,25 (OH)2 vitamin D3
S/E:
Promotes intestinal absorption of calcium, PO4
Masculinizing
25 (OH) vitamin D:
Na and Water retention
Increase bone resorption
Cholestatic jaundice
Increase renal reabsorption of Ca, PO4
AROMATASE INHIBITORS
SECONDARY HORMONES
Anastrozole
Calcitonin
Letrozole
Secreted by parafollicular cells of thyroid
Use:
Regulation of calcium and bone metabolism
Treatment of advanced breast CA
Actions:
ANTIANDROGENS
Benign prostatic hyperplasia (BPH) Inhibits bone resorption → serum calcium
Common in men > 50 years old Increase renal excretion of filtered phosphate, calcium,
May be due to age-related increase in estradiol with sodium (dec. tubular reabsorption)
possible sensitization of the prostate to the growth-
promoting effects of DHT. Indication
Paget’s disease
Posterior Pituitary Hormones Postmenopausal osteoporosis
A. Oxytocin hypercalcemia
USE: Contraindication: hypersensitivity
1. Stimulate uterine contraction
2. Reinforce labor Glucocorticoid
3. Promote breastmilk ejection Antagonizes vitamin D-stimulated intestinal calcium
transport
ROUTE admnistered: Increase renal Ca excretion
IV: induce labor Blocking bone collagen synthesis
nasal spray: induce milk letdown Increasing PTH stimulated bone resorption
MOA: it contracts myoepithelial cells around the mammary
alveoli Estrogen
Reduces the bone resorption action of PTH
B. Antidiuretic Hormone Increases 1,25 (OH)2 vit D3 levels
Desmopressin Indication
Analog of vasopressin
NON-HORMONAL AGENTS Raloxifene
Indications Selective estrogen receptor modulator (SERM)
Hypercalcemia 2 to malignancy Reduces bone resorption and decreases bone turnover
Osteoporosis Estrogen agonist on bone
Syndrome of ectopic calcification Estrogen antagonist on breast and uterine tissue
Paget’s disease USE: prevention of osteoporosis