L1 - L10 Flashcards
Pharmacokinetic Terms
- loading dose, steady state, half-life
Loading Dose
- given to help patient reach therapeutic level quickly and safely
Steady State
- drug given = same amount being excreted in one dosing cycle giving constant drug serum level
HalfLife
- time taken for half of drug to be excreted
Pharmacodynamics
- Potency
- ED50
Potency
- amount of drug required to produce 50% of the max response it is capable of producing
ED50
- conc. of drug that induces specific clinical effect in 50% of subjects
BP Control by Body
- Blood pressure increases causing inc. firing of Baroreceptors in Carotid Arteries & Aorta
- received by sensory neurons in medulla which dec. Symp output & inc. Parasymp output
- lower Symp. output = less NA release & less vasoconstriction
- this decreases peripheral resistance & BP.
- inc. symp output = more ACh release & less Electrical Impulses, slowing HR and BP
RAAS system
- angiotensin II effects
- Ang II increases sympathetic activity, increasing BP
- acts on adrenal gland to release aldosterone
- aldosterone drives Na+ reabsorption & water retention - it promotes release of ADH from pituitary
- increases sodium & chloride reabsorption
Electron Transition
- rotational
- vibrational
- electronic
electrons only go from non-bonding orbitals to anti-bonding
Electronic transition > vibrational > rotational
Rotation - wide low peak
vibrational - mid peak
electronic - high narrow peak
Hypertensive Stages
- pre, 1st, 2nd, acute
120-139 / 80-89 : pre hypertensive
140-159 / 90-99 : stage 1 hypertension
- advise to avoid risk factors and review in 1yr
160 - 179 / 100-109 : stage 2 hypertension
- treat immediately with statins, hypertensives etc
> 180/110 : acute hypertension needs hospitalisation
BP Calculation
- Secondary HTN Causes
MAP = CO x TPR (total peripheral resistance)
- renal disease
- cushings syndrome
- crohns syndrome
- coarctation (aorta narrowing)
Renovascular Hypertension
- Athero
- Fibromuscular dysplasia
Atherosclerosis 75 - 90%
- atherosclerotic plaque build up in arteries
Fibromuscular Dysplasia 10 - 25%
- overgrowth of kidney artery cells causing blockage
HTN & CVD Risk Factors
HTN
- ethnicity , smoking , hypercholesterinaemia (high LDL) , obesity , stress , physical inactivity
CVD
- atherosclerosis , Heart Failure , arrythmias , angina - MI
Consequences of HTN
- Heart
- Kidney
- Nervous System
Heart - inc. workload in LV from higher afterload
Kidney - can cause sclerosis (scarring)
Nervous System - can cause stroke
Chronotropy & Inotropy
chrono - measure of heart rate
ino - measure of force of contraction
Hypertension Mechanisms
- SA Node parasympathetic Control
SA node has muscarinic and B1 receptors:
- BP increases, increasing parasymp output
- more ACh at SA muscarinic receptors which lowers HR
HR decreases on para output , less NA released:
- causes vasodilation of arteries
- lower contraction at myocardial cells
Sympathetic Output on Myocytes
- Noradrenaline Effects
- increased permeability for Na+ & Ca2+ on nodal cell plasma membranes
- action potential to be reached quicker as Na+ flows INTO cell to depolarise it
- causes stronger contraction of heart as Ca2+ enters via Na+/Ca2+ symport from inc. sodium
Parasympathetic Effect on Heart
- ACh effects
- lowers permeability of Na+ and Ca2+ in nodal cell membranes
- increases permeability of K+
- this causes higher ion efflux , extending action potential upstroke and lowering HR
Enzymes as Drug Target
- Enzyme Use
- enzymes accelerate reactions by lowering energy required for reaction
induced fit:
- active site is close to correct shape for substrate binding
- substrate binding alters enzyme structure which strains the bonds
Pi & Sigma Bonds
Pi Bonds
- target for catalysation because susceptible
- 1 bond in a double bond is pi
- weaker bond so this is why it is targeted
Sigma Bond
- strong bonds
- bond present as single bond and one in double
Acid/Base Catalysis
- non-ionised & ionised
- non-ionised bases act as a basic catalyst, accepting protons
- ionised bases act as acidic catalyst, donating protons to other molecules
- ionised acid accepts protons
- non-ionised acid donates protons
Types of Enzyme Inhibitors
Competitive
- shaped like substrate and binds to active site.
- compensated by higher substrate concentration
- methotrexate is reversible comp. inhibitor
Non-Competitive
- binds to allosteric site to change conformation of active site
Uncompetitive
- inhibitor only binds to enzyme/substrate complex
Hypertension Monitoring & Targets
< 140/90 - monitor every 1-5 years
- this is target BP for those with hypertension
> 140/90 - treat if they are high risk (existing CVD, diabetes, obese) or if QRISK over 20%
- if they have complicated hypertension (high risk) then BP target should be <130/80 mmHg
HTN Management
- ACE-I (1st line)
- Enalapril 1st line in HF
- Ramipril 1st line in MI then HF
ramapril , lisinopril
- blocks ACE enzyme in lung to block conversion of Ang1 to Ang2 , reducing vasoconstriction
S/E
- dizziness, take at night if occurs
- cough (ACE breaks down bradykinin which builds up to cause cough) change med if bad
HTN Treatments
- CCB’s
Blocks L-type Ca2+ calcium channels in vessels to reduce contraction and in heart to reduce contraction.
Verapamil + Diltiazem
- rate limiting CCB affects heart. rhythm control for arrhythmias
Amlodipine
- non-rate limiting affecting vessels. used in HTN
S/E - ankle swelling , hot flushes , rash
Diuretics
- Thiazides
- Loop Diuretics
Thiazides
- affects chlorine & sodium reabsorption which reduces water reabsorption to decrease resistance & blood volume
- used in HTN
Loop Diuretic
- NOT USED FOR HYPERTENSION
- used in Heart Failure to clear oedema
Alpha Blockers
- blocks effect of sympathomimetic catecholamines
Noradrenaline & Adrenaline - stops vasoconstriction by reducing these, and encourages vasodilation
- A1 increases constriction in smooth muscle
HTN Treatment
- AB/CD therapy
<55 & Caucasian - ACE-I first line
- then give CCB or Diuretic if not properly controlled
> 55 or ethnic - CCB
- then give ACE-I or ARB if worsens
Beta Blocker
- 1st line angina
- not for HTN
- secondary prevention after MI
- blocks binding of Noradrenaline at beta receptors
- reduces vasoconstriction and lowers heart rate.
Co-Morbidities
- affects cardiac output so not used for HTN
- DO NOT give with rate limiting CCB or diuretic
Aspirin
- secondary CVD prevention
secondary - 75mg daily
Antiplatelet Action
- Aspirin is an NSAID, blocking COX-1
- COX-1 produces Thromboxane A2 which is a platelet recruiter and activator
- blocking COX-1
HTN Types
- whitecoat
- Malignant
Whitecoat
- unusually high because of stress in medical setting
- give ABPM reader over 24hrs. limit is 135/85
Malignant
- HTN even when on all drugs (ACE-I, CCB, Thiazide)
- rama 2.5mg OD, amlo 5mg OD, bendro 2.5mg OD
- doesnt have to be max dose of meds, just on 3
Statins
- primary and secondary prevention
primary
- 10yr CVD risk >20%
- no cholesterol target , used to reduce atherosclerosis
Secondary :
- simvastatin 40mg regardless of BP
- Atorvastatin given if QRISK higher than 10%
HTN Exacerbating Drugs
NSAIDS - Only used short term
- excreted in kidneys instead of sodium.
Oestrogen - Oral contraceptives only given along with blood tests every 6 months because lead to water retention
Sympathomimetics
- can cause vasoconstriction so need monitoring
Effervescent Tablets & Antacids
- are high in sodium so NOT given to high-risk patients
ACE Binding Sites
- S1
- S2’
- S1’
- Zn2+
- S1 Terminal - binds with aromatic groups
- S2’ Terminal - can bind aliphatic & carboxylate group
- S1’ Terminal - can bind to aromatic/aliphatic groups
- Zn2+ Terminal - ion that can bind negatively charged groups
Enalaprilat Binding
- key features
Enalaprit has poor physiochemical properties:
- LogP -0.5 so too hydrophilic to pass through cell membrane
- good bioavailability though once in blood
- S1 - binds to aromatic ring
- S2’ - binds to aliphatic group and adjoined carboxylate
- S1’ - binds to methyl group (aliphatic)
- Zn2+ - group will bind to electron rich carboxyl group
Captopril Drug History
- used less because of rash & loss of taste
Atheroma
- form in high pressure environments like arteries
- accumulation of intracellular & extracellular lipid in the intima of large and medium arteries
- NOT found in veins because venous circulation back to heart is low pressure
Atherosclerosis (asymptomatic)
- arterial wall thickening from atheroma build-up over decades
main sites: aorta, coronary artery and leg arteries
Monck Berg Atherosclerosis:
- affects small-medium arteries.
- calcium deposits in the middle layer, calcifying arteries independent from atherosclerosis
Atheroma Features
- fatty streak
- fibrous plaque
- complicated plaque
Fatty Streak
- elevated zone on arterial wall from lipid accumulation. LDL’s become oxidised by free radicals and are then recognised by scavenger monocytes/macrophages and deposited in the arterial wall
Fibrous Plaque
- lipid accumulates & become foam cells. macrophages from foam cells attract SMC from tunica media, forming a cover over the lesion.
Complicated Plaque
- ulcers on fibrous cap rupture to expose plaque contents and leading to thrombosis
Atheroma Prevention
- lifestyle
- secondary
Lifestyle :
- no smoking, diet (low fat), reduce alcohol, regular exercise
Secondary :
- antiplatelet (aspirin)
- statins (atorva 20mg OD)
