 Cancer / Anit-Metabolites/ METHOTREXATE….

 Cancerous cells have faster rate of metab than normal cells so take up METHOTREXATE more
rapidly
 ADMIN- admin for 5 days & repeat in abt 4 wks
 TREATS-
 Choriocarcinoma- involves placenta/ testicle
 Acute Leukemia
 OVERDOSE-
 admin folic? acid- referred to as Leukovorin Rescue-
 provides bone marrow w/ activated folic acid wch allows bld cell reproduction to occur
 ADVERSE EFFECTS- NVD/ bone marrow depression/ GI ulceration/
 Bone marrow depression bad bc possible development of Aplastic Anemia
 PURINE ANTAGONISTS-
 (Several subs are needed for DNA synthesis- including a cpl of purine bases- Adenine & Guanine)
 MERCAPTOPURINE- is purine antagonist
 Has chemical structure similar to Adenine
 So competes w/ Adenine in formation of the nucleotide, Adenilic Acid
 When Mercaptopurine is used, an abnormal nucleotide is forms wch prevents successful
replication of DNA= normal cellular production does NOT occur
 ORALLY- to TREAT acute and chronic Leukemia
 SIDE EFFECTS- nausea/ vomiting/ bone marrow depression/ liver toxicity CLADRIBINE
 CLADRIBINE (Leustatin)- is newer purine antagonist
 TREATS- Harricell Leukemia
 MAJOR TOXICITY- bone marrow depression
 PYRIMIDINE ANTAGONISTS-
 3 Pyrimidine bases needed for synthesis of DNA & RNA- Thiamine/ Uracil/ Cytosine
 Prevent normal synthesis and replication of DNA
 FLUOROURACIL- is Pyrimidine antagonist
 Competes w/ Uracil
 TREATS- solid tumors
 ORAL or IV
 ADVERSE EFFECTS- nausea/ vomiting/GI ulceration/ bone marrow depression/ hair loss
 CYTARABINE- is Pyrimidine antagonist
 Competes w/ Cytosine
 Admin IV to TREAT certain Leukemia’s
 Miscellaneous Anti-Neoplastic drugs
 Usually used in combo w/ other Anti-Neoplastics
 Plant extracts-
 Periwinkle plant- contains alkaloids that inhibit tumor growth
 2 most important alkaloids- VINCRISTINE & VINBLASTINE-
 They bind to microtubules and produce metaphase arrest
 Vincristine- nuero-toxicity / Vinblastine- Leucopenia (low wbc)
 ADVERSE EFFECTS-
 Both cause severe pain if drug leaks out of bld vessels into tissues
 Vinblastine can cause fatal reaction if admin intrathecally (around spine)
  ETOPOSIDE- derivative from May Apple plant
 Inhibits an enzyme needed for function of DNA
 ADVERSE EFFECTS- Alopecia (hair loss)/ Leucopenia/ nausea/ vomiting
 HACLATAXOL (Taxol)
 Originally from bark of Ewe Tree
 Binds to microtubules to arrest Mitosis
 Hormones- Hormone Antagonists-
 (certain tumors are hormone dependent, usually involving reproductive organs- ex.
Prostate, breast, uterus- tumor won’t grow if the hormone not present)
 Last resort- surgical removal of ovaries (for breast cancer) or removal of testes (for
prostatic cancer) eliminate production of the sex hormone = ↓ growth of the cancer-
 Current TREATMENT- Hormone Antagonists- bind to hormone receptors and block
action of sex hormones to inhibit tumor growth
 TAMOXIFEN- blocks estrogen receptors to prevent action of estrogen in stim growth of
(hormone dependent) tumor
 Used after surgery to prevent growth of any remaining cancerous cells
 SIDE EFFECTS- similar to post-menopausal syndrome
 Nausea/ hot flashes/ rash/ vaginal bleeding
 LEUPROLIDE- is analog of gonadotropin releasing hormone (GNRH from hypothalamus)
 Normal GNRH stimulates secretion of FSH and LH from anterior pituitary wch stim
sex hormone production
 Leuprolide inhibits release of FSH and LH so blocks sex hormone production
 TREATS- prostate cancer/ other conditions where inhibiting hormone production is
needed
 SIDE EFFECTS- headache/ hot flash/ impotence in men
 Antibiotics (used to treat cancer)-
 DACTINOMYCIN / BLEOMYCIN / some others-
 Interfere w/ synthesis of DNA = inhibit cell reproduction
 Drugs in this group are too toxic to treat bacterial infections
 TOXICITY- most common is bone marrow suppression
 Radioactive compounds (isotopes)-
 Emit radiation damaging to cell nuclei
 Have limited use
 Most Anti-Neoplastic drugs have FDA prego category of D or X
 Cause harmful fetal effects
 Not to use during prego if possible to avoid (unless benefit outweighs possible risk to fetus)

Medicinenet.com/ diseases and conditions index/ highlight C for cancer

Several topics available

 PARASYMPATHETICS DIVISION continued

 AUTONOMIC NS
  Only selective nerves are stimulated
 Stim can be confined to a particular system
 Ex.- contraction of bladder during urination
 Peripheral autonomic nerves-
 DEF*- branches of cranial & spinal nerves that travel out to cardiac or smooth muscle of
internal organs
 Made up of neurons traveling together to same destination
 (in peripheral NS -GANGLIA- collection of synapses)
 PRE-GANGLIONIC NERVE- neurons that emerge from spinal cord
 POST-GANGLIONIC NERVE- neurons that travel from ganglia out to internal organ
 GANGLIA- collection of synapses of pre- & post- ganglionics
 Main difference b/t symp and parasymp nerves- the neurotransmitter released by the post-
ganglionic
 BOTH release ACH from ganglia but-
 In symp- NE is released from post-ganglionic fiber
 Act on ADRENERGIC RECEPTORS (which respond to the NE)
 In parasymp- ACH is released from post-ganglionic fiber
 Act on CHOLINERGIC RECEPTORS (which respond to the ACH)
 The receptors are at cardiac/ smooth muscle membrane sites
 The neurotransmitter that is released from post-ganglionics- stim the internal organs & produces
changes that are characteristic of that branch of the autonomic NS (para or symp)

Effects of PARASYMP stim are produced by release of ACH / ACH binds to cholinergic receptors

Effects of SYMP stim are produced by release of NE from adrenergic nerve endings or EPI from
adrenal medulla

 Drugs effecting symp NS

 Symp NS regulates activity of internal organs and glands during physical exertion or other
stressful situation
 During this time peripheral symp nerves (adrenergic nerves) release NE
 The NE binds to adrenergic receptors to produce Fight or Flight response
 Also adrenal medulla releases EPI
 The EPI binds to adrenergic receptors as well
 EPINEPHRINE
 Released by adrenal medulla- ↑ release during stress
 Called ADRENALINE
 EPI and NE are chemically similar called CATECHOLAMINES
 TO PRODUCE SYMP RESPONSE-
 NE is formed in adrenergic nerve ending
 Then stored in granules in nerve ending
 When stim the NE is released
 NE travels over to membrane of involuntary muscle and attaches to adrenergic receptors (on
the membrane) to produce symp response
 Most of the NE is taken back up afterwards and is then either
 Reused
  Destroyed by the enzyme MAO (MonoAmine Oxidase)
 EPI and NE
 are both adrenergic transmitters that stim many organs to ↑ symp activity
 but can produce different effects
 EPI- causes relaxation in some organs
 Ex.- respiratory passages are relaxed (bronchodilation) by EPI
 Goes along w/ FoF- more oxygen to lungs
 Two main types of adrenergic receptors for NE and EPI- depending on type of effect
 ALPHA α and BETA β
 Some organs may have more than 1 type of receptor but usually only 1 dominates and
determines overall response of the organ
 ALPHA ADRENERGIC RECEPTORS (α-receptors)
 Found on smooth muscle membranes
 If stim by NE or EPI-
 Produce contraction
 Can get vasoconstriction of most bld vessels

ALPHA stimulation causes smooth muscle contraction

β-2 receptor stimulation causes smooth muscle relaxation (at certain sites)

 BETA ADRENERGIC RECEPTORS (β-receptors)

 Found on cardiac and some smooth muscle membranes
 β-1 receptors-
 in the heart
 stimulated by NE or EPI- causes↑ HR / ↑ Force of Contraction
 β-2 receptors-
 Stimulated by EPI- causes-
 Vasodilation in skeletal muscle bld vessels and coronary arteries
 Bronchodilation
 NE does NOT stim β-2 receptors
 Two main drugs that affect SYMP NS are Sympathomimetics and Sympatholytics
 SYMPATHOMIMETICS-
 Prod effects similar to stimulation of the symp NS (mimic’s symp NS)
 ↑ bp / ↑ HR/ bronchodilation
 Useful to TREAT patient in shock/ cardiac arrest/ respiratory difficulty
 ALPHA ADRENERGIC DRUGS- drugs that produce contraction of smooth muscle by stim α-
receptors (includes EPI and NE)
 BETA ADRENERGIC DRUGS- drugs that stim the heart thru β-1 and relax smooth muscle
thru β-2 (includes EPI)

Epinephrine is one of the few substances that stim both Αlpha and Beta

 SELECTIVE BETA-2 ADRENERGIC DRUGS- A few β adrenergic drugs that selectively stim
β-2 receptors
 Used primarily as bronchodilators (action on lungs)
 SYMPATHOLYTICS (adrenergic blocking drugs)-
 Blocks or inhibits symp activity so-
 ↓ bp / ↓ HR
 TREATS-
 Beneficial for patient w/ hypertension or angina/ certain types of arrhythmia
 ALPHA ADRENERGIC BLOCKERS- Drugs that block α effects of NE or EPI
 NON-SELECTIVE BETA ADRENERGIC BLOCKERS- drugs that block EPI effects from β-
1 and β-2 receptors
 SELECTIVE β-1 ADRENERGIC BLOCKERS- only block β-1 effects (level of heart)
 Both α and β blockers ↓ symp activity (esp. in CV cardiovascular system)
 The blocking drug competes w/ EPI or NE for receptors
 When blocked- prevents EPI or NE from producing their effects
 Another method to inhibit symp system- ↓ formation and release of NE
 ADRENERGIC NEURONAL BLOCKERS- Drugs that act at the neuronal ending to ↓
formation and release of NE
 ALPHA ADRENERGIC DRUGS-
 Prototype is NE
 Have chem structure and effects very similar to NE
 Most important chem effect- contracts smooth muscle
 Vasoconstriction of most bld vessels
 Contraction of sphincters in GIT and UT (urinary tract)- inhibits movement along these
pathways
 Midriasis (dilation of pupils)
 ADMIN- IV infusion
 TREATS-
 Hypotension- After surgery may have ↓ bp so give α drugs to ↑ bp and help maintain
circulation
 Decongestion effect- vasoconstriction of nasal passageways- inc. in OTC cold and allergy
meds
 A few used in ophthalmology- to dilate pupil (midriasis) and as ocular decongestant (to get
red out)
 α drugs that cross bld-brain barrier
 Ex. Amphetamines
 Produce central effect to suppress appetite
 Major ADVERSE EFFECTS-
 Due to excessive vasoconstriction
 Hypertension/ hypertensive crisis/ heart palpitations/
 May lead on to cerebral hemorrhage/ cardiac arrhythmias
 Must use extreme caution- when dealing w/ hypertensive or cardiac patient
 Paranteral admin- need to take bp frequently
 SIDE EFFECTS of decongestant use-
 Irritation of sinus and eyes- due to excessive dryness bc vasoconstriction causes ↓ in bld
flow
 IV needle needs to be checked frequently to make sure drug isn’t infiltrating the skin-
  If infiltration of α drugs occur- leads to intense vasoconstriction in bld vessel of skin
causing skin cells to die or gangrene
 BETA ADRENERGIC DRUGS-
 Have selective action to combine w/ β-receptors
 Most β drugs produce very few α effects- EXCEPT EPI
 Most important ACTION of β drugs-
 Stim heart- β-1
 Bronchodilation- β-2
 The most potent β drug that produce both these effects is ISOPROTERENOL-
 the dual action (heart and broncho) is main reason it can’t be used for asthma bc may
over-stim heart as well – so use Selective β-2 drugs
 β-2 also stim smooth muscle of uterus- relaxes uterus= inhibits contractions
 clinical indications for EPINEPHRINE-
 drug of choice for immediate treatment of acute allergic reactions
 ex- anaphylactoid shock (can be caused by insect stings, certain drugs, other allergens in
sensitive indiv’s-
 causes difficult breathing/ ↓ bp/ other shock sx
 admin EPI by subcutaneous injection- stim α and β receptors
 ALPHA EFFECTS of EPI-
 certain surgical procedures
 alpha effect ↓ bld flow=↓ bleeding
 in combo w/ certain local anesthetics to get vasoconstriction
 Prolongs action of local anesthetic by ↓ bld flow=anesthetic remains in bld near
injection longer
 BETA EFFECTS of EPI-
 . β-1 stim good for patients in cardiac arrest
 . β-2 stim (bronchodilation) good for asthma
 EPINEPHRINE & ISOPROTERENOL as bronchodilators
 Beta Drugs
 May produce CNS effects
 Ex- restlessness/ tremors/ anxiety
 Main ADVERSE effects of OLDER β drugs ( EPI & Isoproterenol)
 Overstimulation of heart- causing palpitations or other arrhythmias
 If patient has existing heart disease- BE CAREFUL
 BETA-2 EFFECTS-
 . β-2 dilate (vasodilation) bld vessels in skeletal muscle-
 Can ↓ bp but usually not cause hypotension
 Selective β-2 drugs- if give dosage too high can stim β-1 receptors also
 So may get overstim of heart from β-1 effect
 When using β-2 drugs to arrest pre-term labor-
 Can cause variety of CV effects and complications-
 Must monitor fetal HR/ maternal HR and bp

10/07
 DOPAMINE
 Functions as neurotransmitter in brain
 Formed as a precursor in the synthesis of NE in peripheral autonomic
 When prepared as drug (ex. INTROPIN)
 IV
 Produces several cardiovascular effects useful to treat circulatory shock
 LOW DOSE- stimulates dopaminergic receptors in renal and mesentery bld vessels and ↑ renal
bld flow
 MODERATE DOSE- stimulates β1 receptors that act on heart for ↑ contractility with ↑ CO as
result
 ↑ CO and ↑ renal bld flow are important in treating shock bc in shock the bp ↓ and cardiac
functions ↓
 HIGH DOSE- stimulates α-receptors and get vasoconstriction
 Admin by CONTINUOUS IV INFUSION
 Effects disappear right after stopping infusion
 ADVERSE EFFECTS from OVERDOSE
 Excessive stim of heart
 ↑ bp (associated w/ Alpha effects
 DOBUTIAMINE
 Similar to Dopamine but gives greater β1 effects (More ↑ myocardial contractivity)
 MAIN TREATMENT- acute heart failure using IV INFUSION
 α-BLOCKERS (Alpha adrenergic blocking drugs)
 compete w/ NE for binding to α-receptors
 prevents NE from producing symp response so ↓ normal symp activity
 MAJOR ALPHA ORGANS- bld vessels
 The effect of α-blockade =
 Vasodilation
 ↓ bp
 TREATS –
 Hypertension
 Some peripheral vascular conditions
 Ex. Poor bld flow to an extremity or skin (improves bld flow)
 Used to diagnose PHEOCHROMOCYTOMA
 Involves tumor of Adrenal Medulla
 Bc of tumor- get production of excessive secretion of catecholamines and severe
hypertension
 If used, the α-blocker causes dramatic ↓ in bp
 BENIGN PROSTATIC HYPERPLASIA (enlarged prostate)
 Enlarged prostate interferes w/ urine flow thru urethra
 α-blockers relax smooth muscle along urinary tract to improve flow
 Whenever 1 div is blocked, the other div appears to ↑
 ex. if use α-blockers, symp is blocked, so side effects are similar to ↑ of parasymp activity
 so after α-blockade you can expect-
 miosis (pupil constriction)
 nasal congestion
  ↑ GI activity
 α-blockers interfere w/ normal CV reflexes
 some patients experience ORTHOSTATIC HYPOTENSION (↓ bp when standing up, some
patients faint)
 β-BLOCKERS (beta adrenergic blockers)
 β-blockers bind to β receptors and antagonize β effects of EPI and NE
 If indiv has hypertension, angina, or arrhythmias-
 May have ↑ symp activity so may have excessive EPI and NE released
 So give β-blocker to prevent EPI and NE from producing symp effects
 Heart is one of the most important β organs-
 Is β 1
 ↓ decreases activity of heart- ↓HR/ ↓ force of contraction/ ↓ of impulse conduction thru cardiac
conduction system
 No known use for β 2-blockers
 Divided into NON-SELECTIVE(blocks β 1 and β 2) & SELECTIVE(block β 1 only)
 SELECTIVE β-BLOCKERS
 THERAPUTIC DOSE- blocks only β 1
 HIGHER DOSE- starts blocking β 2 also
 Main DIFFERENCES b/t β-blockers-
 Duration of Action (DoA)
 Extent of drug metabolism
 Β-blockers also effect carbohydrate and lipid metabolism
 Interference to carbohydrate metabolism is insignificant unless indiv has diabetes bc may have
hypoglycemia (low bld sugar)
 May ↑ serum lipid levels, esp. triglyceride levels
 NANDOLOL and ATENOLOL (β-blockers)
 Are lipid INsoluble (and water soluble)
 So don’t pass into brain
 Excrete un-metabolized in urine
 ESMOLOL
 Is short acting β-blocker
 IV
 Quick onset to ↓ ventricular HR in cases of SUPRAVENTRICULAR TACHYCARDIA (which
can cause congestive failure)
 PROPRANOLOL
 1st β-blocker used clinically
 Is non-selective
 ↓ HR / ↓ Force of Contraction of heart/ ↓ conduction velocity
 Usually this causes ↓ bp which ↓ work required by heart and ↓ oxygen consumption required
 Beneficial for various cardiovascular conditions
 Esp. if has hyperactivity of symp NS
 ORAL or IV
 ORALLY-
 Picked up by portal system and carried to liver
 Undergoes 1st –pass metabolism so ↓ amount of drug that gets into systemic circulation
  Propranolol is most lipid soluble of β-blockers
 So passes readily into brain to exert effects of-
 Sedation
 Depression
 ↓ in symp activity- important in helping to ↓bp
 TREATS-
 Angina / hypertension/ arrhythmias
 Glaucoma- ↓ inter-ocular pressure
 Migraines- ↓ frequency of attacks
 β-blockers admin after myocardial infarction (MI) chronically to ↓ incidence of additional
MI’s and sudden cardiac death
 Propranolol continued…
 Side effects
 NVD
 Serious effects when heart function is seriously reduced bc can lead to
 Bradycardia (Slow heart)
 Congestive heart failure or cardiac arrest
 Shouldn’t be used in patients w/ asthma or other respiratory conditions
 bc is NON selective B blocker so can cause bronchoconstriction
 Can cause respiratory emergency
 β blockers that gain access to brain like propranolol can cause
 Drowsiness / mental depression
 Drug interactions of β-blockers (that lead to problems)
 Therapy of β- blockers w/ other drugs that ↓CV function
 drugs that ↓CV function like Cardiac Glycosides (digitalis group)
 Anti-arrhythmic drugs
 Ca blockers
 These drug interactions will Lower ↓ HR and CO (cardiac output) excessively
 Which can lead to hypotension (low pressure) or (drug induced) congestive failure
 ADROGENIC NEURONAL BLOCKERS (ANB)
 Main activity (occurs at end of adrenergic nerve) is formation of NE
 NE is synthesis from AA (amino acids)-Tyrosine or Phenylalanine
 Can interfere w/ formation and storage of NE
 Monoamine Oxidase (MAO) converts down NE
 Alpha-Methyldopa (a-m)
 Interferes w/ NE, greatly reduces amount of NE formed
 Less NE formed = Less NE released = ↓ sympathetic activity
 Can convert methyldopa into alpha-methyl NE as a false transmitter
 The alpha-methyl NE is stored just like regular NE
 The false transmitter is neurotransmitter-like substance that reduces neuronal activity
 Main use of METHYLDOPA is to treat hypertension (high bp)
 Most important Site of Action (SoA) is the vasomotor center of medulla in brain-
 To reduce sympathetic output-
  Have formation of Alpha-Methyldopa NE (false transmitter) at medulla and leads to ↓
sympathetic output to vascular smooth muscle = vasodilation
 Ex. You have vasodilation so bp drops
 ADVERSE EFFECTS
 During initial treatment w/ methyldopa may get-
 Drowsiness and sedation but disappear w/ continued therapy
 NVD / nasal congestion / bradycardia (slow heart)
 Some adv reactions can cause-
 Liver dysfunction / drug fever / hemolytic anemia / a lupis like syndrome- (eruptions of
skin and symptoms like arthritis)
 RESERPINE
 Found from plant in India
 Site of Action- in adrenergic nerve ending
 Prevents storage of NE in storage granules
 So ↑ brkdwn of NE under Monoamine Oxidase
 Bottom line- ↓ NE levels in nerve ending (is being depleted )= ↓ symp activity
 TREATS-
 Hypertension-
 ↓ symp activity/ ↓ symp output
 As result - vasodilation and ↓ bp
 would be used w/a diuretic (when treating hypertension)
 Produces CNS sedation and tranquilization
 Psychoses-
 Prior to modernization of anti- psychotic drugs
 Still used today for pat who haven't responded to other psychotics
 SIDE EFFECTS
 Related to decreased sympathetic act
 Similar to parasympathetic stimulation
 Includes- salivation / diarrhea/ nasal congestion/ bradycardia/ excessive hypotension
 Possible CNS effects-
 Excessive sedation
 Psychiatric disturbances ( inc. confusion & hallucinations)
 Can cause mental depression which can lead to suicide attempts
 At high doses can cause sx of Parkinson’s (tremors/ muscular rigidity)
 GUANETHIDINE
 Is POTENT ANB
 Can act in 2 ways
 Can prevent release of NE from nerve ending & deplete storage granules of NE- both lead
to significant ↓ of symp activity
 TREAT- severe hypotension
 ORALLY
 Has long half-life
 So long that effects can continue for up to 10 days after stopping treatment
  ADVERSE EFFECTS
 Are caused by decreased sympathetic activity
 ↑diarrhea/ nasal congestion/ bradycardia/ lead to orthostatic hypotension (faint when stand
up)/ impotency in males
 GUANADREL
 Similar to Guanethidine
 TREATS- hypertension
 ADVANTAGE- lower incidence of adverse effects than Guanethidine
 PSNS (PARASYMPATHETIC NERVOUS SYSTEM)
 (sympathetic produce fight or flight) but Parasympathetic regulates activity during rest
 Ex.- Digestion/ elimination of waste
 Parasymp stimulation
 ↑ speed up act if GIT/ genital urinary systems
 ↓ in CV activity
 Parasymp neurotransmitter is acetylcholine (ACH)
 CHOLINERGIC NERVES = Nerves that release acetylcholine
 CHOLINERGIC RECEPTORS = Receptors that respond to cholinergic stimulation
 CHOLINERGIC DRUGS = Drugs that bind to cholinergic receptors and produce effects similar
to acetylcholine
 CHOLINERGIC BLOCKING DRUGS = Drugs that bind to cholinergic receptors but DON’T
produce effect-
 Prevent acetylcholine from acting on cholinergic receptors
 At cholinergic nerve ending-
 Acetylcholine is produced and stored in granules
 When cholinergic nerve is stimulated-
 Acetylcholine is released and travels to membrane of smooth or cardiac muscle and
attaches to cholinergic receptors
 After attaches- triggers changes that result in parasymp stimulation and effects

 MUSCARINE
 Extract from a mushroom
 Produces effects similar to ACH but only at MUSCARINIC RECEPTOR SITES- (post-
ganglionic parasymp receptor sites)
 MUSCARINIC DRUGS or cholinergic drugs- act at muscarinic receptor sites and act like ACH
and Muscarine
 ANTI-MUSCARINIC or anti-cholinergic drugs- drugs that BLOCK ACH at muscarinic receptor
sites

 NICOTINIC-NEURAL RECEPTORS (n-n receptors)

  ARE- Cholinergic receptors at ganglionic sites
 (BOTH symp and parasymp ganglionic sites)
 Acetylcholine is the neurotransmitter at parasymp and symp ganglia
 Nicotinic comes from NICOTINE (an alkaloid derived from nicotine plant
 LOW DOSES - stim autonomic ganglia
 HIGH DOSES- BLOCK the autonomic ganglia
 GANGLIONIC STIMULANTS = Drugs that act like ACH or low dose of nicotine
 GANGLIONIC BLOCKERS = Drugs that BLOCK ACH or act like high dose nicotine
 NICOTINIC-MUSCLE RECEPTORS (Nm)
 Cholinergic receptors at the neuro-muscular junction (NMJ) (at the level of skeletal muscle)
 Nicotine stim (acts like ACH) at the NMJ w/ skeletal muscle
 Drug that BLOCK effects of ACH at neuromuscular junction (NMJ) = NEUROMUSCULAR
BLOCKERS or SKELETAL MUSCLE RELAXANTS
 Cholinergic drugs mimic actions of ACH at the muscarinic receptors =
PARASYMPATHOMIMETICS (-mimicking the action of ACH at the muscarinic receptors)
 CHOLINERGIC DRUG GROUPS- DIRECT and INDIRECT ACTING
 Cholinergic drugs used-
 To constrict pupil (Miosis) for exam
 Treat Glaucoma (used topically)
 Glaucoma causes ↑ pressure that can destroy retina so treated w/ eye drops of cholinergic
drugs
 Miosis promotes better drainage of eye to help lower the pressure
 DIRECT ACTING cholinergic drugs-
 Bind to muscarinic receptors and produce effect similar to ACH
 ACH isn’t useful as drug bc has extremely short DoA but DERIVATIVES useful
 Ex. PETHANECHOL
 Produce effects like ACH but are more slowly in-activated by the enzyme (acetyl
cholinesterase) = longer DoA
 Stimulate parasymp system similar to ACH
 EFFECTS
 ↑ GI secretions/ motility
 ↑ in genital urinary activity
 Bronchoconstriction
 Miosis (pupil constriction)
 Vasodilation (↓ bp)
 ↓HR
 A few ALKALOIDS have parasympathomimetics effects too
 ex. MUSCARINE AND PILOCARPINE
 Muscarine not used as drug but comes up in cases of accidental poisoning
 Pilocarpine is a drug that acts like ACH-
 Used in eye drops to treat Glaucoma (to get constricted pupils)
 Bc of short DoA of the derivatives- DIRECT acting cholinergic drugs are rarely used systemically
 PETHANECHOL is exception-
 Can be given orally to stimulate urinary tract and intestinal tract
 Used bc certain drugs tend to shut things down in certain conditions (esp. elderly) and can
cause urinary retention/ intestinal stasis
 Can admin Pethanechol sev times a day to stimulate urination & defecation
 Main ADVERSE EFFECTS-
 Over stimulation of bladder/ intestine so end up w/ diarrhea and urinary frequency
 INDIRECT ACTING cholinergic drugs called- ANTI-CHOLINESTERASES-
 Inhibit the enzyme acetyl cholinesterase=so inhibits brkdwn of ACH=↑ ACH
 ACH will accumulate at all cholinergic receptor sites (nicotinic & muscarinic)
 ACH effects are prolonged bc more receptors stimulated
 All anti-cholinesterases produce effects like ACH-
 parasymp stimulation for PARASYMPATHOMIMETICS effects
 ADVERSE EFFECTS
 Caused by excessive stim of parasymp NS
 Sx like- NVD/ blurred vision/ excessive sweating/ muscular tremors/ bronchoconstriction/
bradycardia/ hypotension
 TOXIC OVERDOSE- muscular paralysis/ respiratory depression (can cause death)
 To TREAT ADVERSE EFFECTS-
 Use anti-cholinergic drug (ex. ATROPINE)-
 It competes w/ ACH for m. receptors to reverse effects of the excessive cholinergic stim
 (dentist gives ATROPINE to cut back on salivation)
 ATROPINE used in drug overdose when treating MYASTHENIA
 CHOLINERGIC CRISIS-
 describes excessive drug overdose when treating Myasthenia
 high concentration of ACH gives excessive stim of cholinergic receptors but can get
blockade of nicotinic receptors (which may lead to respiratory paralysis of skeletal
muscle)
 The blockade of nicotinic receptors may lead to respiratory paralysis of skeletal muscle
 Would need to stop the anti-cholinesterase drugs until ACH levels ↓ to normal
 ATROPINE- wld be used to treat the effects of excessive muscarinic stim
 Divided into couple sub-groups- reversible inhibitors / irreversible inhibitors
 REVERSIBLE INHIBITORS of Anti-cholinesterases
 Used in diagnosis and treatment of MYASTHENIA GRAVIS
 A disease that affects skeletal muscle
 Characteristically has insufficiency of ACH activity
 Used to reverse effects of drugs that block cholinergic and nicotinic receptors
 EDROPHONIUM- 30mins
 drug that has shortest DoA in group- only 30mins
 given IV to diagnose MYASTHENIA
 NEOSTIGMINE- 3 hrs
 PYRIDOSTIGMINE- 4 ½ hrs
 AMBENONIUM- 6 hrs
 Prev drugs-
 used ORALLY to treat Myasthenia
 used IV to reverse effects excessive cholinergic blockade
  are all QUARTERNARY AMINES (-charged particles)
 Bc charged- they don’t cross bld-brain barrier so Only function out at peripheral
receptor sites
 On other hand- PHYSOSTIGMINE
 Is NOT charged so can get into brain
 TREATS-
 EYE DROPS- Glaucoma
 PARENTERALLY- to reverse effects of excessive anti-cholinergic blockade in CNS
 IRREVERSIBLE INHIBITORS of Anti-cholinesterases
 Are derivatives of organophosphate compounds
 Used in insecticides & pesticides/ Used as chemical warfare agents
 Has extremely long DoA- bc forms irreversible bonds w/ the enzyme
 ECHOTHIOPHATE (Phospholine)
 TREATS-
 Used in very small doses in eye drops for Glaucoma
 Large dose- produces severe toxicity- (CHOLINERGIC CRISIS)- which can quickly
produce respiratory paralysis and death
 ex.- Farmers who spray field w/ insecticides using irreversible inhibitor derivatives may suffer
from CHOLINERGIC CRISIS unless protection used when spraying
 Use ATROPINE and PRALIDOXIME (Protopam) to treat the Cholinergic Crisis
 PRALIDOXIME (or Protopam)
 Can reactivate the enzyme acetyl-cholinesterase, ? after it has been inhibited by ?
 But treatment must be soon- most effective immediately after exposure
 Also is antidote for organic phosphate warfare chemicals
 Indirect Acting (Anti-Cholinesterase) are more widely used that DIRECT acting cholinergic drugs
 Were used to TREAT-
 Myasthenia/ urinary retention/ intestinal paralysis
 Now used to TREAT-
 Alzheimer’s
 Glaucoma- used topically in eye drops to lower inter-ocular pressure
 Constricted pupil = better drainage = ↓ pressure
 In TREATING MYASTENIA GRAVIS-
 Is auto-immune disease- body produces antibody that act against n-m receptors so indiv
suffers loss of muscle tone and strength
 Can use PYRIDOSTIGOMINE-
 Is longer acting anti-cholinesterase drug
 Is reversible anti-cholinesterase
 ORAL
 Leads to ↑ ACH levels = ↑ patient strength (muscle tone)
 In treating urinary retention or Paralytic Ileus (intestines shutdown)
 Use NEOSTIGMINE-
 Stim bladder contraction/
 In treating Alzheimer’s
 Alzheimer’s
  Had ↓ in ACH levels in brain
 Leads to deterioration of mental function
 Use TACRINE (Cognex) / DONEPEZIL (Aricept)
 They ↑ ACH levels in brain
 Produce best results in early stages of disease
 LECITHIN
 Used w/ anti-cholinerase drug
 Antidote to skeletal muscle blockers
 In high dosage of blockers can cause respiratory paralysis
 Use NEOSTIGMINE
 ↑ ACH levels = antagonize skeletal muscle blockers
 Antidote to anti-cholinergic drug poisoning (like ATROPINE and SCOPOLAMINE)
 Block cholinergic (muscarinic) receptors = effects similar to ↓ symp activity which causes-
 Tachycardia (fast heart)/
 central effects in brain- seizures / coma
 PHYSOSTIGMINE
 Crosses bld barrier
 ↑ ACH levels that compete w/ anti-cholinergic drugs for receptors
 ANTI-CHOLINERGIC DRUGS (called PARASYMPATHELITIC DRUGS)
 DEF* Cholinergic blocking drugs that bind to cholinergic receptors
 Act by competitive antagonism of ACH
 ATROPINE / SCOPOLAMINE
 Are of oldest anti-cholinergic drugs
 Newer synthetic drugs made now
 USE (TREATS)-
 ↓ activity of vagus nerve (vagus nerve is parasymp, acts as heart brake, so heart speeds up)
 So used clinically to ↑ HR when HR is to slow
 May be given pre-op to dry up some respiratory secretions
 Treat asthma- bc causes bronchodilation
 Dentists use bc ↓ salivary secretions
 ↓ GI secretions
 Once used to ↓ gastric secretions in peptic ?

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 Anti-cholinergic drugs of the genital urinary system

 TREATS- urinary incontinence (overactive bladder)
 Urinary anti-cholinergic drugs promote urinary retention
 CONTRAINDICATED- in case of hypertrophy of prostate (enlarged prostate)
 Would ↑difficulty in urination

 Anti-cholinergics that get into brain

 Usually cause depressant effect-
  Drowsiness/ sedation
 SCOPOLAMINE-
 Found in some OTC sleep aids
 Higher dose of ATROPINE or SCOPOLAMINE
 Can produce excitation/ delirium/ hallucinations
 May produce CNS depression leading to respiratory arrest and death
 TREAT- Parkinson’s
 Motion sickness- SCOPOLAMINE
 Ocular effects- midriasis (dilated pupil) / loss of accommodation of eye
 Used for eye exams
 Can ↑ ocular pressure so don’t give to indiv w/ Glaucoma bc dilation of pupil interferes w/
drainage of inter-ocular fluid
 ADVERSE EFFECTS
 Urinary retention / constipation/ flushing (reddening of skin)/ dry skin/ fever/ tachycardia/
CNS symptoms (stim or depression)
 TOXIC EFFECTS-
 Hyperpyrexia and CNS depression can be severe and lead to depression of vital centers of
brain
 If not treated can lead to respiratory paralysis and death
 These BELLADONA ALKALOIDS are found in many common plant subs.
 Some non-edible plant berries
 Some cases children eat them and are poisoned
 Wld develop fever/ tachycardia/ dry mouth/ dry & red skin/ pupil dilation
 Needs emergency treatment
 Could lead to respiratory paralysis & death w/in few hours
 TREAT-
 Induce vomiting/ pump stomach (gastric lavage)/ admin activated charcoal & saline
cathartics
 Admin PHYSTOSTIGMINE- by IV to antagonize actions of anti-cholinergic drugs –
 PHYSTOSTIGMINE is particularly useful for CNS sx like delirium/ coma
 Drugs that effect Autonomic Ganglia
 ACH is neurotransmitter for both symp & parasymp but before ACH found- it was known that
nicotine stim the ganglia (so called nicotinic neural receptors- nn receptors)
 Nicotine stim the ganglia (at nicotinic neural receptors)
 GANGLIONIC STIMULANTS- Drugs that stim nicotinic neural receptors
 No clinical condition that would need ganglionic stim so not of interest but smoking
cigarettes causes ganglionic stim-
 Effects both symp and parasymp- symp stim dominates in CV (cardiovascular)/
parasymp stim dominates in GI tract/ also stim CNS (wch gives the pleasurable effect)
 So- ↑ HR/↑ bp/ ↑ GI activity
 NICORETTE GUM / NICODERM (trans-dermal patches)
 Nicotine and tobacco smoke- harmful to fetus
 Smoking and nicotine substitute use- avoid during prego
 n-n receptors-
 GANGLIONIC BLOCKERS-drugs that block effects of ACH at the nn receptors
 Disadvantage- Have no selectivity so many side effects so new selective drugs are now
used
 ↓ CV activity/ ↓ GI activity/ ↓ activity of genital urinary systems
 Can cause bradycardia/ hypotension/ ↓ intestinal secretions & motility/ ↓ urination/
impotence in males
 TRIMETHAPHAN-
 Is cortinary ammonium ions- these ions are permanently charged and poorly
absorbed from GI tract- so given IM/ IV
 MECAMYLAMINE-
 Is NOT charged so is almost completely absorbed by GI tract- so given ORALLY
 Main use- TREAT severe hypertension when other drugs not effective
 ACTION- blocks ganglia- blocks symp causing vasodilation
 Is potent anti-hypertensive but produces many ADVERSE EFFECTS-
 Caused by excessive blockade of autonomic ganglia so combo of anti-cholinergic
and anti-adrenergic effects (bc effects both symp & para)
 So gets ↓ GI activity/ dry mouth/ constipation/ visual disturbances/ ↓ CV activity
(inc. ↓ CO/ hypotension-low bp)/ ↓ genital urinary function (causing urinary
retention & impotency)
 Contraindicated in indiv w/ Glaucoma- (bc dilation of pupil can lead to ↑ in ocular
pressure)
 Used in combo w/ other anti-hypertensives- so can reduce dose of Mecamylamine
 Drug interactions of ganglionic blockers-
 w/ Adrenergic drugs- Antagonism of anti-adrenergic effect of ganglionic blocker
(esp. on CV system)-
 Causing CV stim
 w/ Adrenergic Blocking drugs- may give additive anti-adrenergic effects-
 Causing hypotension/ CV collapse
 w/ Cholinergic Drugs- antagonism of anti-cholinergic effects of ganglionic blockers
(esp. at GI & Urinary tracts)-
 causing ↑ GI activity/ ↑ urinary activity
 w/ Anti-Cholinergic Drugs- may get additive anti-cholinergic effects
 w/ Vasodilator Drugs- may get additive vasodilation
 causing hypotension/ CV collapse possible
 HYPERTENSION
 Condition when bp in arterial system is normally high
 One of leading causes of cerebral strokes/ heart attacks/ kidney disease
 Estimated- 10% of US population has it
 Sx usually appear years later, after disease caused perm organ damage already
 Estimated- only half are aware they have it
 Most cases- abt 90%- cause is unkown
 If cause unknown- ESSENTIAL HYPERTENSION
 If cause IS known- SECONDARY HYPERTENSION
 Bp is known by 2 factors- bp=CO*PR
 CO (cardiac output= HR * stroke volume)
  Stroke volume is amt of bld pumped from left ventricle
 SV may be70ml pumped out w/ each beat and HR may be 70 beats/min
 So--- CO=70*70=4900mlmin (abt 5litersmin)
 And PR (peripheral resistance)-
 Referring to degree of constriction of arterioles
 Main factor ↑ PR is vasoconstriction
 Vasoconstriction (↑ PR) and ↑ bp can be done by symp stim
 Can be by NE or EPI or ANGIOTENSIN2 (is a vasoconstrictor)
 Drugs that give vasodilation wld ↓ PR
 ↑ in Stroke Volume (SV), HR, or PR wld ↑ bp ~bp=HR*SV*PR
 Symp stim can ↑ all of them
 ↑ in symp activity goes along w/ hypertension
 FACTORS that may affect bp (not believed to be cause but if control these factors it may ↓ bp-
 Sodium restriction
 Weight loss
 Stop smoking
 Exercise
 Relaxation techniques
 Kidney involvement- usually a ↓ in renal bld flow
 ↓ in renal bld flow ↑ bp bc-
 RENIN released into bld wch stim formation of ANGIOTENSIN
 ANGIO 1 converted to ANGIO 2-
 ANGIO-2 is a potent vasoconstrictor so ↑ PR wch should ↑ bp
 ANGIOTENSIN acts on adrenal cortex to release aldosterone
 Aldosterone = ↑ reasorp of Na & and indirectly reasorp of H20
 Renal Angiotensin Aldosterone RAA system-
 Regulates (maintains) bld volume and bp
 Disturbance in RAA system may contribute to cases of hypertension
 ACE INHIBITORS- Angiotensin-Converting Enzyme Inhibitors
 Inhibit formation of ANGIO= ↓ actions of RAA sys (wch will ↑ bld volume & bp)
 Now have newer drugs that ↓ bp by blocking Angiotensin receptors (instead of inhibit ANGIO
formation)
 ANTI-HYPERTENSION THERAPY
 Vasodilators
 Ca antagonists (Ca blockers)
 ACE inhibitors
 Used in combo in advanced hypertension
 Known for many yrs that salt restriction ↓ bp
 Used before discovery of drugs to treat hypertension
 Diuretics
 ↓ level of salt in body to ↓ bp
 THIAZIDE and Thiazide like diuretic drugs-
 Are preferred diuretics for treating hypertension
  ↓ bp bc- diuresis ↓ bld volume and have direct action on arterial walls/ can ↓ sodium
in ? (wch ↓ ability of vasoconstrictors like EPI & NE to ↓ bp?)
 Gets vasodilation- ?
 Used alone to treat mild hypertension / Combo therapy for moderate to severe cases
 Once a day dosing for effective treatment
 CHLOROTHIAZIDE (is thiazide) / CHORTHALIDONE (is thiazide-like)
 FUROSEMIDE (Lasix)
 Is organic ? diuretic
 Used in patients w/ reduced renal function so need more potent diuretic effect
 Potassium sparing diuretics-
 Used when K ?
 ADVERSE EFFECTS of diuretics
 Caused by excessive loss of H20, Na & K ions
 Leads to dehydration/ muscle weakness/ fatigue
 May interfere w/ renal excretion of uric acid- uric acid levels ↑ = sx of gout
 May interfere w/ insulin- bld glucose ↑ (hyperglycemia)- bad for diabetic
 Sympathetic blockers
 Block hyperactivity of symp NS (↓ symp activity to ↓ bp by acting on CNS)
 ↓ symp output from medulla caused vasodilation
 CLONIDINE-
 Has central action that inhibits CV center in medulla
 ADVERSE EFFECTS- dry mouth/ constipation/ drowsy
 Don’t stop abruptly bc may cause hypertensive crisis in patient
 Reduce it over 2 wk pd
 GUANETHIDINE-
 Interferes w/ release of NE from the nerve ending
 METHYLDOPA-
 Central action that inhibits CV center in medulla