PHARMACY Lecture Notes - Lecture 1: Inotrope, Acidosis, Hyperlipidemia
1
Drug
MOA
Effects
Pharmacodynamics/
Pharmacokinetics
Clinical Application
Toxicity/Toxicity Management
DIURETICS (lowers BP by depleting the body of Na+, and reducing Blood volume)
• After 6-8 weeks, CO returns toward normal while peripheral resistance declines
• Effective in lowering BP by 10-15 mmHg
• Severe cases of HPN, used in combination with sympathoplegic and vasodilator drugs to control the tendency toward Na retention First choice and cost effective
Thiazides
HYDROCHOLOROTHIAZIDE
Inhibit Na/Cl transporter in DCT
Normal CO, but Peripheral
resistance decreases
Use in patients with mild to moderate
hypertension with normal renal and
cardiac function
• Hypokalemic Metabolic
Alkalosis
• Hyperuricemia
• Impaired CHO tolerance
• Hyperlipidemia
• Hyponatremia
• Hypercalcemia
• Allergic reaction (sulfonamide
hypersensitivity) Photosensitivity
• Haemolytic anemia
• Thrombocytopenia
Loop Diuretics
FUROSEMIDE
- MOST POTENT
DIURETICS
AVAILABLE
Inhibits NK2Cl Transporter in the thick
ascending loop inhibiting Na Cl
reabsorption
-reduces blood volume without
decreasing peripheral vascular
resistance.
-loop diuretics increases urinary
water, Na+, K+, Calcium and
Magnesium excretion
• Commonly used in patients with fluid
overload
• Used in severe hypertension
• Multiple drugs with Na-retaining
propertiens are used
• Cardiac failure /cirrhosis
• Hypokalemic metabolic alkalosis
• Ototoxicity
• Hyperuricemia
• Hypomagnesemia
• Skin rash, eosinophilia, interstitial
nephritis
• Hypersensitivity
Potassium sparing
Diuretics
Inhibit Na reabsorption (K+ & H+
Excretion in distal and Collecting
tubules)
- Limited natriuretic activity.
• Useful both to avoid excessive potassium
depletion and to enhance natriuretic
effects of other diuretics
• Hyperkalemia
• Hyperkalemia
• Hyperchloremic Metabolic Acidosis
DRUGS ALTERING SYMPATHETIC FUNCTION
- Moderate to severe hypertension: most effective drug includes an agent that inhibits function of the sympathetic nervous system
- Common adverse effects: sedation, mental depression, disturbances of sleep including nightmares. Lowering blood pressure by altering sympa function can have compensatory mechanism which is retention of sodium by the kidney and
expansion of blood volume
Are most efficient when taken concomitantly with a diuretic
CENTRALLY ACTING SYMPATHOPLEGIC DRUGS
(Lowers BP by reducing PERIPHERAL TOTAL VASCULAR RESISTANCE, (-) cardiac function, (-) increasing venous pooling in capacitance vessels)
- Reduces sympathetic outflow from vasomotor center in the brainstem but allowing these centers to retain sensitivity with the baroreceptor activity
Drug
MOA
Effects
Pharmacodynamics/Pharma
cokinetics
Clinical Uses
Toxicity/Toxicity Management
2
METHYLDOPA
Alpha-adrenoreceptor
agonist
REVIEW!
Alpha2 receptors->
decreases release of NTA
DRUG INTERACTIONS
1.) LEVODOPA
2.) LITHIUM
3.) NSAIDs, TRICYCLICS,
- Analog of L-Dopa and is converted
to alpha-methyldopamine and
alpha-methylnorepinephrine
- Antihypertensive action due to
stimulation of central alpha
adrenoreceptors by
alphamethylnorepinephrine or
alpha methyldopamine
- Lowers bp by reducing
peripheral vascular resistance
with a variable reduction in
heart rate and cardiac output
- Cardiovascular reflexes
remain intact
- Decreases renal vascular
resistance
- Maximal
antihypertensive effect: 4-6
hours
- effects: persist
up to 24 hours
- highly
dependent on accumulation
and storage of metabolite
alpha methylnorepinephrine
in the vesicles of nerve
endings, its action diminish
after the parent drug has
disappeared from the
circulation
- half-life: 3-7
hours
- Bioavailability:
25%
INDICATIONS:
-drug of choice for HYPERTENSION during
pregnancy
- Patients with renal insufficiency
CONTRAINDICATIONS:
1.) LIVER DISEASE
2.) DIALYSIS PATIENTS
3.) BLOOD DYSCRIASIS
4.) OLDER ADULTS
MOST COMMON ADVERSE EFFECT:
Sedation at the onset of treatment Other
adverse effects:
• REBOUND HYPERTENSION:
sudden cessation due to
increased outflow-> increased
intensity
• GI Symptoms: nausea,
vomiting, diarrhea
Long-term therapy: patients may complain
persistent
• mental lassitude and impaired
mental concentration.
• Nightmares, mental depression,
vertigo & extrapyramidal signs may
exist.
SYMPATOMIMETICS
Increased BP
• Lactation for both man and woman
probably mediated by inhibition of
dopaminergic mechanism
• Developing a positive COOMBS
TEST:
makes cross-matching blood for
transfusion difficult and rarely
associated with haemolytic anemia,
hepatitis and drug fever
CLONIDINE (CATAPRES)
• Derivative of
2imidazoline
• EMERGENCY DRUG in
HTN CRISIS. As
needed medication
(impeding stroke,
chest pain) we need
to lower it gradually
• Bind more tightly to α2 receptors
than α1
• Decreased sympathetic effects
and increases parasympathetic
tone-> low blood pressure and
bradycardia
• Binds to a non-adrenoreceptor site
(IMIDAZOLINE RECEPTOR)->
Mediate antihypertensive effects
-decreased NTA release->
decreased
catecholamines>decreased
sympa effects
- lowers BP by
decreasing heart rate and relaxation
of capacitance vessels and
decreased in PVR - reduction in
arterial BP-> decreased renal
vascular resistance and
maintenance of renal blood flow
- More effective in
decreasing heart rate and cardiac
output than methyldopa
Guanabenz, Gunfacine are alpha
adrenoreceptor agonist
- Lipid soluble
- Rapidly enters the
brain from the
circulation
- Short half life
- Oral clonidine must be
given 2x a day
INDICATIONS:
• HPN
• Nicotine/opiate withdrawal
• Vascular headaches
• Glaucoma
• Ulcerative colitis
• Tourette’s syndrome
• Severe pain in CA patients
-rarely causes postural hypotension -
severe hypotension can complicate
overdose.
Abrupt withdrawal can cause
lifethreatening hypertensive crisis:
REBOUND HPN.
(nervousness, tachycardia, headache and
sweating)
- Withdrawal should be done gradually
with other antihypertensive agents
substituted
- Treatment:
Administration of alpha and beta
adrenoreceptor blocking agents TOXIC
EFFECTS:
• Dry mouth
• Sedation
CONTRAINDICATIONS:
• Px who are at risk for developing
mental depression
• Concomitant treatment with
tricyclic antidepressants
3
GANGLION-BLOCKING AGENTS
-Competitively block nicotinic cholinoreceptors on post ganglionic neurons in both sympa and para ganglia
- drugs directly block the nicotinic ACH channel Adverse effects:
- Sympathoplegia (orthostatic HPN and sexual dysfunction) and parasympathoplegia (urinary retention, constipation, glaucoma, blurring vision, dry mouth)
ADRENORECEPTOR ANTAGONIST
- beta blockers
- Alpha-1 blockers
BETA-ADRENORECEPTOR BLOCKERS
- Either selective for the Beta-1 or Non-selective
- Higher doses will block beta-2 receptors
- Decrease CO, PVR depending on cardioselectivity and partial agonist activity
PROPANOLOL (non
selective beta antagonist
BETA1=BETA 2)
- First to shown
effective in
hypertension and
ischemic heart
disease
- Prevents reflex
tachycardia results
from treatment with
vasodilators
-Decreases BP primarily as a result of
decreased CO
- inhibits stimulation of renin
production by catecholamines mediated
by beta 1 receptors
- May also act on peripheral
presynaptic Beta adrenoreceptors to
reduce sympathetic vasoconstrictor
nerve activity
-
- reduces BP without prominent
postural hypotension.
- Propanolol can be
administered twice
daily
- Eliminated via hepatic
metabolism and have
short half life
- Most beta antagonist
have half-life=3-10
hours except esmolol
(10-15 minutes) o
Use in arrhythmias
during surgery
- Hypertension and ischemic heart disease
- Principal toxicities: blockade of
cardiac, vascular or bronchial Beta
receptors
- Bradycardia
- Asthma
- Peripheral vascular insufficiency
- Diabetes
- Does not cause orthostatic
hypotension
Beta 1 Selective
METOPROLOL
ATENOLOL
- Most widely used B
blockers
-less likely to cause bronchospasm
- safer in patients with
asthma/COPD, diabetes and
peripheral vascular disease
METOPROLOL: highly
metabolized by CYP2D6
with high first pass
elimination.
ATENOLOL: not extensively
metabolized and is excreted
primarily in the urine
Half-life=6 hours
Plus Alpha Blocking
properties
LABETALOL
CARVEDILOL
- Both beta blocking and vasodilating
effects
Labetalol: 3:1 ratio of Beta:alpha
antagonism
Useful in treating hypertension of
pheochomocytoma and
hypertensive emergencies
Carvedilol: non selective Beta
adrenoreceptor blocker
- Orally given
- Administered to
racemic mixture
Document Summary
Diuretics (lowers bp by depleting the body of na+, and reducing blood volume) After 6-8 weeks, co returns toward normal while peripheral resistance declines. Severe cases of hpn, used in combination with sympathoplegic and vasodilator drugs to control the tendency toward na retention (cid:0) first choice and cost effective. Inhibits nk2cl transporter in the thick ascending loop inhibiting na cl reabsorption. Reduces blood volume without decreasing peripheral vascular resistance. Loop diuretics increases urinary water, na+, k+, calcium and. Drugs altering sympathetic function (cid:0) use in patients with mild to moderate. Hypokalemic metabolic hypertension with normal renal and cardiac function. Useful both to avoid excessive potassium depletion and to enhance natriuretic effects of other diuretics. Moderate to severe hypertension: most effective drug includes an agent that inhibits function of the sympathetic nervous system. Common adverse effects: sedation, mental depression, disturbances of sleep including nightmares.
